WO2019023555A1 - Polymer compositions - Google Patents

Abstract

Provided herein are methods and compositions related to polymer-coated bacteria.

Description

Polymer Compositions

RELATED APPLICATION

This application claims the benefit of priority to U. S. Provisional Patent Application serial number 62/538,467, filed July 28, 2017, which application is hereby incorporated by reference in its entirety.

SUMMARY

[0001] In certain aspects, provided herein are compositions comprising a bacterium and a polymer (e.g., in which the polymer coats the bacterium). In certain embodiments, the polymer can be a natural polymer or a synthetic polymer. In certain embodiments, the polymer coating protects the bacteria following administration to a human subject (e.g., from acid, bile, oxygen, enzymatic degradation, mechanical force, etc.). In some embodiments, the polymer enhances delivery of the bacteria to a therapeutic target in a subject, for example, by facilitating adherence and/or penetration to a mucus layer, such as the mucus layer in the stomach, small intestine or colon. In some embodiments the polymer layer improves therapeutic efficacy of the bacterium, such as by adding or enhancing immunological function.

[0002] In some embodiments, the polymer coating is functionalized with one or more functional residues. For example, the polymer can be functionalized with a therapeutic agent (e.g., an immune modulatory agent, a cytotoxic agent, a cell signaling agent, a

chemotherapeutic agent, an immunotherapeutic agent, an immunosuppressive agent, a radioactive agent, etc.). In some embodiments, the polymer is functionalized with an agent that enhances bacterial delivery and/or targeting. In some embodiments, the polymer is functionalized with an agent that enhances bacterial survival (e.g., nutrients or microbial signaling molecules).

[0003] In some embodiments, provided herein are methods of treating or preventing a disease or condition comprising administering to a subject (e.g., a human subject) a composition provided herein. In some embodiments, the disease or condition is a cancer. In some embodiments, the disease or condition is an inflammatory and/or autoimmune condition. In some embodiments, the disease or condition is an infectious disease (e.g., a bacterial infection, a viral infection, a parasitic infection). BRIEF DESCRIPTION OF THE FIGURES

[0004] Figure 1 shows two FACS histograms demonstrating the coating of

Bifidobacterium with PEI or chitosan polymers.

[0005] Figure 2 is a graph that shows that PEI-NAc polymer-coated Lactococcus lactis ssp. cremoris (Strain A) retains in vivo efficacy as compared to the powdered bacteria in a delayed-type hypersensitivity (DTH) model. The significance is p value of < 0.05 in a t- test. The number of dots at each dosage amount is equal to the number of mice surveyed in the experiment.

[0006] Figure 3 is a graph that shows that PEI-NAc polymer increases the retention of Lactococcus lactis ssp. cremoris (Strain A) at 24 h after administration. In the absence of a polymer coating, peak expulsion for Strain A occurs between 4-8 h. At 24 h after administration, uncoated Strain A (indicated in the graph as "powder") is completely excreted. The PEI-NAc polymer coating increases retention at 24 h.

DETAILED DESCRIPTION

Definitions

[0007] "Administration" broadly refers to a route of administration of a composition to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Administration by injection includes intravenous (IV), intramuscular (IM), intratumoral (IT) and subcutaneous (SC) administration. The pharmaceutical compositions described herein can be administered in any form by any effective route, including but not limited to intratumoral, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal {e.g., using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intra-arterial, and intrathecal, transmucosal {e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal {e.g., trans- and perivaginally), intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial. In preferred embodiments, the pharmaceutical compositions described herein are administered intratumorally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously.

[0008] As used herein, the term "antibody" may refer to both an intact antibody and an antigen binding fragment thereof. Intact antibodies are glycoproteins that include at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain includes a light chain variable region (abbreviated herein as VL) and a light chain constant region. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The term "antibody" includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies and antigen-binding antibody fragments.

[0009] The terms "antigen binding fragment" and "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to bind to an antigen. Examples of binding fragments encompassed within the term "antigen- binding fragment" of an antibody include Fab, Fab', F(ab')₂, Fv, scFv, disulfide linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES®, isolated CDRH3, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. These antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same manner as intact antibodies.

[0010] "Cancer" broadly refers to an uncontrolled, abnormal growth of a host's own cells leading to invasion of surrounding tissue and potentially tissue distal to the initial site of abnormal cell growth in the host. Major classes include carcinomas which are cancers of the epithelial tissue (e.g., skin, squamous cells); sarcomas which are cancers of the connective tissue (e.g., bone, cartilage, fat, muscle, blood vessels, etc.); leukemias which are cancers of blood forming tissue (e.g., bone marrow tissue); lymphomas and myelomas which are cancers of immune cells; and central nervous system cancers which include cancers from brain and spinal tissue. "Cancer(s)," "neoplasm(s)," and "tumor(s)" are used herein interchangeably. As used herein, "cancer" refers to all types of cancer or neoplasm or malignant tumors including leukemias, carcinomas and sarcomas, whether new or recurring. Specific examples of cancers are: carcinomas, sarcomas, myelomas, leukemias, lymphomas and mixed type tumors. Non-limiting examples of cancers are new or recurring cancers of the brain, melanoma, bladder, breast, cervix, colon, head and neck, kidney, lung, non-small cell lung, mesothelioma, ovary, prostate, sarcoma, stomach, uterus and medulloblastoma. [0011] A "combination" of two or more microbial strains includes the physical coexistence of the two strains, either in the same material or product or in physically connected products, as well as the temporal co-administration or co-localization of the two strains.

[0012] The term "decrease" or "deplete" means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000 or undetectable after treatment when compared to a pre-treatment state.

[0013] The term "epitope" means a protein determinant capable of specific binding to an antibody. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by a particular sequence of amino acids to which an antibody is capable of binding.

[0014] The term "gene" is used broadly to refer to any nucleic acid associated with a biological function. The term "gene" applies to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.

[0015] "Identity" as between nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the "FASTA" program, using for example, the default parameters as in Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al, Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., et al, J Molec Biol 215:403 (1990); Guide to Huge Computers, Mrtin J.

Bishop, ed., Academic Press, San Diego, 1994, and Carillo et al. (1988) SIAM J Applied Math 48: 1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include, DNAStar "MegAlign" program (Madison, Wis.) and the

University of Wisconsin Genetics Computer Group (UWG) "Gap" program (Madison Wis.)).

[0016] "Immunotherapy" is treatment that uses a subject's immune system to treat cancer or another dieseas or disorder and includes, for example, checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy.

[0017] The term "increase" means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10- fold, 100-fold, 10^Λ3 fold, 10^Λ4 fold, 10^Λ5 fold, 10^Λ6 fold, and/or 10^Λ7 fold greater after treatment when compared to a pre-treatment state. Properties that may be increased include immune cells, metabolites, and cytokines. [0018] "Innate immune agonists" or "immuno-adjuvants" are small molecules, proteins, or other agents that specifically target innate immune receptors including Toll-Like Receptors, NOD receptors, STING Pathway components. For example, LPS is a TLR-4 agonist that is bacterially derived or synthesized and aluminum can be used as an immune stimulating adjuvant, immuno-adjuvants are a specific class of broader adjuvant or adjuvant therapy.

[0019] The term "isolated" encompasses a microbe or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated microbes may be separated from at least about 10%, about 20%, about 30%>, about 40%, about 50%, about 60%), about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated microbes are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%o, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. The terms "purify," "purifying" and "purified" refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g. , whether in nature or in an experimental setting), or during any time after its initial production. A microbe or a microbial population may be considered purified if it is isolated at or after production, such as from a material or environment containing the microbe or microbial population, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%), about 80%), about 90%, or above about 90% and still be considered "isolated." In some embodiments, purified microbes or microbial population are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%o, about 98%, about 99%, or more than about 99% pure. In the instance of microbial compositions provided herein, the one or more microbial types present in the composition can be independently purified from one or more other microbes produced and/or present in the material or environment containing the microbial type. Microbial compositions and the microbial components thereof are generally purified from residual habitat products.

[0020] "Microbe" refers to any natural or engineered organism characterized as a bacterium, fungus, microscopic alga, protozoan, and the stages of development or life cycle stages (e.g., vegetative, spore (including sporulation, dormancy, and germination), latent, biofilm) associated with the organism. Examples of gut microbes include: Actinomyces graevenitzii, Actinomyces odontolyticus, Akkermansia muciniphila, Bacteroides caccae, Bacteroides fragilis, Bacteroides putredinis, Bacteroides thetaiotaomicron, Bacteroides vultagus, Bifidobacterium adolescentis, Bifidobacterium bifidum, Bilophila wadsworthia, Blautia, Butyrivibrio, Campylobacter gracilis, Clostridia cluster III, Clostridia cluster IV, Clostridia cluster IX (Acidaminococcaceae group), Clostridia cluster XI, Clostridia cluster XIII (Peptostreptococcus group), Clostridia cluster XIV, Clostridia cluster XV, Collinsella aerofaciens, Coprococcus, Coryne bacterium sunsvallense, Desulfomonas pigra, Dorea formicigenerans, Dorea longicatena, Escherichia coli, Eubacterium hadrum, Eubacterium rectale, Faecalibacteria prausnitzii, Gemella, Lactococcus, Lanchnospira, Mollicutes cluster XVI, Mollicutes cluster XVIII, Prevotella, Rothia mucilaginosa, Ruminococcus callidus, Ruminococcus gnavus, Ruminococcus torques, and Streptococcus.

[0021] "Microbiome" broadly refers to the microbes residing on or in body site of a subject or patient. Microbes in a microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microbes in a microbiome may be metabolically active, dormant, latent, or exist as spores, may exist planktonically or in biofilms, or may be present in the microbiome in sustainable or transient manner. The microbiome may be a commensal or healthy-state microbiome or a disease-state microbiome. The microbiome may be native to the subject or patient, or components of the microbiome may be modulated, introduced, or depleted due to changes in health state (e.g., precancerous or cancerous state) or treatment conditions (e.g., antibiotic treatment, exposure to different microbes). In some aspects, the microbiome occurs at a mucosal surface. In some aspects, the microbiome is a gut microbiome. In some aspects, the microbiome is a tumor microbiome.

[0022] The terms "polynucleotide", and "nucleic acid" are used interchangeably.

They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.

[0023] As used herein, "specific binding" refers to the ability of an antibody to bind to a predetermined antigen or the ability of a polypeptide to bind to its predetermined binding partner. Typically, an antibody or polypeptide specifically binds to its predetermined antigen or binding partner with an affinity corresponding to a KD of about 10^"7 M or less, and binds to the predetermined antigen/binding partner with an affinity (as expressed by KD) that is at least 10 fold less, at least 100 fold less or at least 1000 fold less than its affinity for binding to a non-specific and unrelated antigen/binding partner (e.g., BSA, casein).

[0024] The terms "subject" or "patient" refers to any animal. A subject or a patient described as "in need thereof refers to one in need of a treatment for a disease. Mammals (i.e., mammalian animals) include humans, laboratory animals (e.g. , primates, rats, mice), livestock (e.g. , cows, sheep, goats, pigs), and household pets (e.g. , dogs, cats, rodents). The subject or patient may be healthy, or may be suffering from a neoplasm at any developmental stage, wherein any of the stages are either caused by or opportunistically supported of a cancer associated or causative pathogen, or may be at risk of developing a neoplasm, or transmitting to others a cancer associated or cancer causative pathogen. In some

embodiments patients have lung cancer, bladder cancer, prostate cancer, ovarian cancer, and/or melanoma. The patients may have tumors that show enhanced macropinocytosis with the underlying genomics of this process including Ras activation. In other embodiments patients suffer from other cancers. In some embodiments, the subject has undergone a cancer therapy.

[0025] "Strain" refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species. The genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g. , a promoter, a terminator, a riboswitch, a ribosome binding site), the absence ("curing") of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non-native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Genetic signatures between different strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome. In the case in which one strain (compared with another of the same species) has gained or lost antibiotic resistance or gained or lost a biosynthetic capability (such as an auxotrophic strain), strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.

[0026] As used herein, the term "treating" a disease in a subject or "treating" a subject having or suspected of having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening. Thus, in one embodiment, "treating" refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.

Pharmaceutical Compositions

[0027] In certain embodiments, described herein are novel formulations of bacterial polymer compositions that exhibit therapeutic potential in the treatment of numerous diseases and disorders. In the formulations provided herein, a polymer coating on the microbe offers numerous advantages over existing microbial therapeutics. For example, the polymeric coatings protect the microbial compositions, by, for example, offering a barrier to

environment stressors (e.g., acid, bile, oxygen, enzymatic degradation, mechanical forces).

[0028] Additionally, the polymeric coatings in the compositions provided herein can aid in the delivery and targeting of a therapeutic agent. The compositions may adhere to or penetrate mucus layer, or alternatively may target a host cell surface (e.g., M cells, epithelial cells).

[0029] In further embodiments, the compositions provided herein may enhance or add immunological functionality. The polymer coating in the compositions described herein may be functionalized with proteins, drugs, and metabolites (e.g., antigens, immune stimulants) that enhance the therapeutic effect of the composition.

[0030] Further still, in some embodiments, the compositions enable maintenance or control of activity by, e.g., providing nutrients or signaling molecules to the bacteria. The compositions can be administered with prebiotics or host bidning factors.

[0031] In certain embodiments, provided herein is a compostion comprising a bacterium and a polymer.

[0032] In certain embodiments, the polymer partially coats the bacterium.

[0033] In alternative embodiments, the polymer fully coats the bacterium.

[0034] In certain embodiments, the composition comprises a plurality of bacteria. [0035] In certain such embodiments the polymer partially coats a plurality of bacteria.

Alternatively, the polymer may fully coat a plurality of bacteria.

[0036] In certain embodiments, the polymer is bound to a surface of the bacterium.

For example, the polymer may be bound to a surface of the bacterium through electrostatic interactions. Alternatively, it may be bound to a surface of the bacterium through one or more covalent bonds.

[0037] In certain embodiments, the polymer is positively charged. In certain such embodiments, the bacterium is negatively charged. Thus, electrostatic interactions may bind the polymer to the bacterium.

[0038] In certain embodiments, the polymer is selected from the group consisting of polycarbonates, polysaccharides, polyurethanes, polyamides, polyesters, polyethers, polyimides, polyimines, polyorganosiloxanes, polysulfides, polysulfones,

polytetrafluoroethylene, polysiloxanes, polyvinylarenes, polyacrylates, and oligosaccharides (e.g., cyclic oligosaccharides).

[0039] In certain embodiments, the polymer is selected from the group consisting of chitosan, alginate, polyethyleneimine, poly-y-glutamic acid, poly(beta-amino ester), polyglycolic acid, polylysine, cyclodextrin, collagen, polybrene, diethylaminoethyl-dextran, polyamidoamine, polyethylene glycol, propylene glycol, polystyrene, and polyvinylacetate.

[0040] For example, the polymer may be selected from the group consisting of chitosan, alginate, polyethyleneimine, poly-y-glutamic acid, poly(beta-amino ester), polyglycolic acid, polylysine, cyclodextrin, collagen, polybrene, diethylaminoethyl-dextran, and polyamidoamine; more preferably the polymer is selected from the group consisting of chitosan, alginate, polyethyleneimine, polyglycolic acid, and poly(beta-amino ester).

[0041] In certain embodiments, the polymer is selected from the group consisting of chitosan, alginate, and polyethyleneimine. For example, the polymer may be chitosan.

Alternatively, the polymer may be alginate. Alternatively still, the polymer may be polyethyleneimine.

[0042] In some embodiments, the polymer may comprise two or more crosslinked polymers.

[0043] In certain such embodiments, each crosslinked polymer is selected from the group consisting of polyurethanes, polyamides, polyesters, polyethers, polyorganosiloxanes, polysulfones, polytetrafluoroethylene, polysiloxanes, polyvinylarenes, and polyacrylates. For example, each crosslinked polymer may be selected from the group consisting of chitosan, alginate, polyethyleneimine, poly-y-glutamic acid, poly(beta-amino ester), polyglycolic acid, polylysine, cyclodextrin, collagen, polybrene, diethylaminoethyl-dextran, polyamidoamine, polyethylene glycol, propylene glycol, polystyrene, and polyvinylacetate.

[0044] In certain embodiments, the crosslinked polymers are polyethyleneimine and

N-acetyl cysteine. Such polymer is referred to herein as PEI-NAc.

[0045] In certain embodiments, polymer is covalently attached to a residue of a therapeutic agent.

[0046] Exemplary therapeutic agents are described below in the section entitled

"Therapeutic Agents."

[0047] In some embodiments, the polymer described herein is modified (either before, during or after administration to a subject) such that it is linked to a target-specific moiety. In some embodiments, the target-specific moiety is a cancer-specific moiety that has binding specificity for a cancer cell (e.g., has binding specificity for a cancer-specific antigen). In some embodiments, the target-specific moiety comprises an antibody or antigen binding fragment thereof. In some embodiments, the target-specific moiety comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the target-specific moiety comprises a ligand for a receptor expressed on the surface of a cell (e.g., a cancer cell) or a receptor-binding fragment thereof. In some embodiments, the target-specific moiety is a bipartite fusion protein that has two parts: a first part that binds to and/or is linked to the polymer and a second part that is capable of binding to a target cell, such as a cancer cell (e.g., by having binding specificity for a target-specific antigen, such as a cancer-specific antigen). In some embodiments, the first and/or second part comprises an antibody or antigen binding fragment thereof. In some embodiments, the first and/or second part comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the first and/or second part comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof. In certain embodiments, co-administration of the target- specific moiety with the bacteria (either in combination or in separate administrations) increases the targeting of the bacteria to the cancer cells.

[0048] In some embodiments, the polymer causes the coated bacteria to acquire an infection profile wherein they localize to and/or infect certain cells, tissues and/or organs. In some embodiments, the polymer-coated bacteria have an infection profile in which they localize to tumors and/or cancer cells. In some embodiments, the polymer-coated bacteria have an infection profile where they localize to a particular organ and/or tissue (e.g., skeletal muscles, cardiac muscles, smooth muscles, bones, joints, ligaments, tendons, salivary glands, stomach, small intestine, large intestine, liver, gallbladder, pancreas, pharynx, larynx, bronchi, lungs, kidneys, ureters, bladder, urethra, ovaries, uterus, vagina, placenta, testes, prostate, brain, spinal cord, peripheral nerves, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, pancreas, heart, arteries, veins, capillaries, lymph nodes, thymus, spleen, bone marrow, eyes and skin). In some embodiments, the polymer-coated bacteria have an infection profile wherein they infect and/or bind to particular cell types. In some embodiments, the polymer-coated bacteria have an infection profile wherein they infect and/or bind to cancer and/or tumor cells. In some embodiments, the bacteria have an infection profile wherein they infect and/or bind to antigen presenting cells (e.g., dendritic cells, macrophages, B cells). In some embodiments, the polymer-coated bacteria have an infection profile wherein they infect and/or bind to tumor-associated macrophages and/or myeloid- derived suppressor cells.

[0049] In some embodiments, the polymers provided herein are bound to a therapeutic agent by a cross-linker. As used herein, the term "cross-linker" broadly refers to compositions that can be used to join various molecules, including proteins, together.

Examples of cross-linkers include, but are not limited to, l,5-difluoro-2,4-dinitrobenzene, 3,3'-dithiobis(succinimidyl propionate), bis(2-succinimidooxycarbonyloxy)ethyl)sulfone, bis(sulfosuccinimidyl)suberate, dimethyl 3,3'-dithiobispropionimidate, dimethyl adipimidate, dimethyl pimelimidate, dimethyl suberimidate, disuccinimidyl glutarate, disuccinimidyl suberate, disuccinimidyl tartrate, dithiobis(succinimidyl propionate), ethylene glycosl bis(succinimidyl succinate) , ethylene glycosl bis(sulfosuccinimidyl succinate) , PEGylated bis(sulfosuccinimidyl)suberate (with PEG5), PEGylated bis(sulfosuccinimidyl)suberate (with PEG9), and tris-(succinimidyl)aminotriacetate, as well as those listed in Table A, below.

Table A: Exemplary Cross-Linkers

DSP Amine-to- Amine

DSS Amine-to- Amine

DST Amine-to- Amine

DTBP Amine-to- Amine

DTSSP Amine-to- Amine

EGS Amine-to- Amine

Sulfo-EGS Amine-to- Amine

TSAT Amine-to- Amine

AMAS Amine-to- Sulfhy dryl

BMPS Amine-to- Sulfhy dryl

EMCS Amine-to- Sulfhy dryl

GMBS Amine-to- Sulfhy dryl

LC-SMCC Amine-to- Sulfhy dryl

LC-SPDP Amine-to- Sulfhy dryl

MBS Amine-to- Sulfhy dryl

PEG12-SPDP Amine-to- Sulfhy dryl

PEG4-SPDP Amine-to- Sulfhy dryl

SBAP Amine-to- Sulfhy dryl

SIA Amine-to- Sulfhy dryl

SIAB Amine-to- Sulfhy dryl

SM(PEG)12 Amine-to- Sulfhy dryl

SM(PEG)2 Amine-to- Sulfhy dryl

SM(PEG)24 Amine-to- Sulfhy dryl

SM(PEG)4 Amine-to- Sulfhy dryl

SM(PEG)6 Amine-to- Sulfhy dryl

SM(PEG)8 Amine-to- Sulfhy dryl

SMCC Amine-to- Sulfhy dryl

SMPH Amine-to- Sulfhy dryl

SMPT Amine-to- Sulfhy dryl

SPDP Amine-to- Sulfhy dryl

Sulfo-EMCS Amine-to- Sulfhy dryl

Sulfo-GMBS Amine-to- Sulfhy dryl

Sulfo-KMUS Amine-to- Sulfhy dryl

Sulfo-LC-SPDP Amine-to- Sulfhy dryl

Sulfo-MBS Amine-to- Sulfhy dryl

Sulfo-SIAB Amine-to- Sulfhy dryl

Sulfo-SMCC Amine-to- Sulfhy dryl

DCC Carboxyl-to-Amine

EDC Carboxyl-to-Amine

NHS Carboxyl-to-Amine

Sulfo-NHS Carboxyl-to-Amine

BMPH Sulfhydryl-to-Carbohydrate EMCH Sulfhydryl-to-Carbohydrate

KMUH Sulfhydryl-to-Carbohydrate

MPBH Sulfhydryl-to-Carbohydrate

PDPH Sulfhydryl-to-Carbohydrate

BM(PEG)2 Sulfhydryl-to-Sulfhydryl

BM(PEG)3 Sulfhydryl-to-Sulfhydryl

BMB Sulfhydryl-to-Sulfhydryl

BMH Sulfhydryl-to-Sulfhydryl

BMOE Sulfhydryl-to-Sulfhydryl

DTME Sulfhydryl-to-Sulfhydryl

TMEA Sulfhydryl-to-Sulfhydryl

A B-NOS Photoreactive

LC-SDA Photoreactive

SDA Photoreactive

SDAD Photoreactive

Sulfo-LC-SDA Photoreactive

Sulfo-SA PAH Photoreactive

Sulfo-SDA Photoreactive

Sulfo-SDAD Photoreactive

[0050] In some embodiments, the polymer described herein is linked to a therapeutic agent through a nucleic acid linker. For example, in some embodiments, the polymers described herein are covalently bonded to a first single-stranded nucleic acid oligonucleotide (e.g., an oligonucleotide of at least 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length and/or no more than 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 nucleotides in length) that can serve binding site for an agent that comprises and/or is linked to second nucleic acid oligonucleotide (e.g., an

oligonucleotide of at least 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length and/or no more than 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 nucleotides in length) that specifically hybridizes to the first nucleic acid oligonucleotide. In some embodiments, the first oligonucleotide has a sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence of the second oligonucleotide. Exemplary methods for linking agents to oligonucleotides are provided, for example, in David A. Rusling & Keith R. Fox, Small Molecule-Oligonucleotide Conjugates, DNA Conjugates and Sensors, 2012, Ch3, 75-102, which is hereby incorporated by reference. In some embodiments, a cancer therapeutic is covalently linked to a single-stranded nucleic acid oligonucleotide that specifically hybridizes to a single-stranded nucleic acid oligonucleotide covalently attached to a polymer described herein. The hybridized oligonucleotides hybridize and the resulting double-stranded nucleic acid duplex is stable for days. In some embodiments, the stability of the duplex is improved by incorporating phosphorothioate bonds (e.g., 1, 2, 3, 4, 5, 6, 7 or more phosphorothioate bonds) on the 5' and/or 3 ' ends of one or both oligonucleotides.

[0051] As used herein, the terms "polynucleotide", and "nucleic acid" are used interchangeably and refer to a polymeric form of nucleotides, whether deoxyribonucleotides, ribonucleotides, or analogs thereof, in any combination and of any length. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides. A polynucleotide "specifically hybridizes" to a target sequence if the oligomer hybridizes to the target under physiological conditions, with a Tm substantially greater than 45 °C, or at least 50 °C, or at least 60 °C-80° C or higher. Such hybridization corresponds to stringent hybridization conditions. At a given ionic strength and pH, the Tm is the temperature at which 50% of a target sequence hybridizes to a

complementary polynucleotide. Such hybridization may occur with "near" or "substantial" complementarity of the oligonucleotide to the target sequence, as well as with exact complementarity.

[0052] In some embodiments, the polymers described herein are linked to a therapeutic agent through a biotin/streptavidin interaction. In some embodiments, the polymers described herein are linked to biotin or to a cancer therapeutic using amine-reactive N-hydroxysuccinimide (NHS) esters or N-hydroxysulfosuccinimide (Sulfo-NHS) esters. NHS esters or Sulfo-NHS esters (Life Technologies can be made of virtually any carboxyl- containing molecule of interest by mixing the NHS or Sulfo-NHS with the carboxyl- containing molecule of interest and a dehydrating agent such as the carbodimide EDC using methods available in the art.

[0053] In some embodiments, functional groups such as ketones, azides, alkynes or other functional groups functionalize the polymers described herein and are used to link the polymer to a therapeutic agent.

[0054] Methods for producing the microbial compositions of the invention may include three main processing steps. The steps are: organism banking, organism production, and preservation. [0055] For banking, the strains included in the microbial composition may be (1) isolated directly from a specimen or taken from a banked stock, (2) optionally cultured on a nutrient agar or broth that supports growth to generate viable biomass, and (3) the biomass optionally preserved in multiple aliquots in long-term storage.

[0056] In embodiments using a culturing step, the agar or broth may contain nutrients that provide essential elements and specific factors that enable growth. An example would be a medium composed of 20 g/L glucose, 10 g/L yeast extract, 10 g/L soy peptone, 2 g/L citric acid, 1.5 g/L sodium phosphate monobasic, 100 mg/L ferric ammonium citrate, 80 mg/L magnesium sulfate, 10 mg/L hemin chloride, 2 mg/L calcium chloride, 1 mg/L menadione. Another examples would be a medium composed of 10 g/L beef extract, 10 g/L peptone, 5 g/L sodium chloride, 5 g/L dextrose, 3 g/L yeast extract, 3 g/L sodium acetate, 1 g/L soluble starch, and 0.5 g/L L-cysteine HC1, at pH 6.8. A variety of microbiological media and variations are well known in the art (e.g., R.M. Atlas, Handbook of Microbiological Media (2010) CRC Press). Culture media can be added to the culture at the start, may be added during the culture, or may be intermittently/continuously flowed through the culture. The strains in the bacterial composition may be cultivated alone, as a subset of the microbial composition, or as an entire collection comprising the microbial composition. As an example, a first strain may be cultivated together with a second strain in a mixed continuous culture, at a dilution rate lower than the maximum growth rate of either cell to prevent the culture from washing out of the cultivation.

[0057] The inoculated culture is incubated under favorable conditions for a time sufficient to build biomass. For microbial compositions for human use this is often at 37°C temperature, pH, and other parameter with values similar to the normal human niche. The environment may be actively controlled, passively controlled (e.g., via buffers), or allowed to drift. For example, for anaerobic bacterial compositions, an anoxic/reducing environment may be employed. This can be accomplished by addition of reducing agents such as cysteine to the broth, and/or stripping it of oxygen. As an example, a culture of a bacterial

composition may be grown at 37°C, pH 7, in the medium above, pre-reduced with 1 g/L cysteine-HCl.

[0058] When the culture has generated sufficient biomass, it may be preserved for banking. The organisms may be placed into a chemical milieu that protects from freezing (adding 'cryoprotectants'), drying ('lyoprotectants'), and/or osmotic shock

('osmoprotectants'), dispensing into multiple (optionally identical) containers to create a uniform bank, and then treating the culture for preservation. Containers are generally impermeable and have closures that assure isolation from the environment. Cryopreservation treatment is accomplished by freezing a liquid at ultra-low temperatures (e.g., at or below - 80°C). Dried preservation removes water from the culture by evaporation (in the case of spray drying or 'cool drying') or by sublimation (e.g., for freeze drying, spray freeze drying). Removal of water improves long-term microbial composition storage stability at temperatures elevated above cryogenic. If the microbial composition comprises, for example, spore forming species and results in the production of spores, the final composition may be purified by additional means such as density gradient centrifugation preserved using the techniques described above. Microbial composition banking may be done by culturing and preserving the strains individually, or by mixing the strains together to create a combined bank. As an example of cryopreservation, a microbial composition culture may be harvested by centrifugation to pellet the cells from the culture medium, the supernatant decanted and replaced with fresh culture broth containing 15% glycerol. The culture can then be aliquoted into 1 mL cryotubes, sealed, and placed at -80°C for long-term viability retention. This procedure achieves acceptable viability upon recovery from frozen storage.

[0059] Microbial production may be conducted using similar culture steps to banking, including medium composition and culture conditions. It may be conducted at larger scales of operation, especially for clinical development or commercial production. At larger scales, there may be several subcultivations of the microbial composition prior to the final cultivation. At the end of cultivation, the culture is harvested to enable further formulation into a dosage form for administration. This can involve concentration, removal of undesirable medium components, and/or introduction into a chemical milieu that preserves the microbial composition and renders it acceptable for administration via the chosen route. For example, a microbial composition may be cultivated to a concentration of 10¹⁰ CFU/mL, then

concentrated 20-fold by tangential flow microfiltration; the spent medium may be exchanged by diafiltering with a preservative medium consisting of 2% gelatin, 100 mM trehalose, and 10 mM sodium phosphate buffer. The suspension can then be freeze-dried to a powder and titrated.

[0060] After drying, the powder may be blended to an appropriate potency, and mixed with other cultures and/or a filler such as microcrystalline cellulose for consistency and ease of handling, and the bacterial composition formulated as provided herein.

[0061] In certain aspects, provided are formulations for administration to subjects. In some embodiments, the microbial compositions are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose format.

[0062] In some embodiments the composition comprises at least one carbohydrate. A

"carbohydrate" refers to a sugar or polymer of sugars. The terms "saccharide,"

"polysaccharide," "carbohydrate," and "oligosaccharide" may be used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on each carbon atom of the molecule. Carbohydrates generally have the molecular formula CnEhnOn. A carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose. Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and polysaccharides include six or more monosaccharide units.

Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified saccharide units such as 2'-deoxyribose wherein a hydroxyl group is removed, 2'-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N- acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2'-fluororibose, deoxyribose, and hexose). Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

[0063] In some embodiments the composition comprises at least one lipid. As used herein a "lipid" includes fats, oils, triglycerides, cholesterol, phospholipids, fatty acids in any form including free fatty acids. Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans). In some embodiments the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16: 1), margaric acid (17:0), heptadecenoic acid (17: 1), stearic acid (18:0), oleic acid (18: 1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20: 1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22: 1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and tetracosanoic acid (24:0). In some embodiments the composition comprises at least one modified lipid, for example a lipid that has been modified by cooking.

[0064] In some embodiments the composition comprises at least one supplemental mineral or mineral source. Examples of minerals include, without limitation: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and combinations thereof.

[0065] In some embodiments the composition comprises at least one supplemental vitamin. The at least one vitamin can be fat-soluble or water soluble vitamins. Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.

[0066] In some embodiments the composition comprises an excipient. Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.

[0067] In some embodiments the excipient is a buffering agent. Non-limiting examples of suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.

[0068] In some embodiments the excipient comprises a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol.

[0069] In some embodiments the composition comprises a binder as an excipient.

Non-limiting examples of suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose,

ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.

[0070] In some embodiments the composition comprises a lubricant as an excipient.

Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.

[0071] In some embodiments the composition comprises a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[0072] In some embodiments the composition comprises a disintegrant as an excipient. In some embodiments the disintegrant is a non-effervescent disintegrant. Non- limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. In some embodiments the disintegrant is an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[0073] In some embodiments, the composition is a food product (e.g., a food or beverage) such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a food or beverage for patients, or an animal feed. Specific examples of the foods and beverages include various beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages; alcoholic beverages such as beers; carbohydrate-containing foods such as rice food products, noodles, breads, and pastas; paste products such as fish hams, sausages, paste products of seafood; retort pouch products such as curries, food dressed with a thick starchy sauces, and Chinese soups; soups; dairy products such as milk, dairy beverages, ice creams, cheeses, and yogurts; fermented products such as fermented soybean pastes, yogurts, fermented beverages, and pickles; bean products; various confectionery products, including biscuits, cookies, and the like, candies, chewing gums, gummies, cold desserts including jellies, cream caramels, and frozen desserts; instant foods such as instant soups and instant soy-bean soups; microwavable foods; and the like. Further, the examples also include health foods and beverages prepared in the forms of powders, granules, tablets, capsules, liquids, pastes, and jellies.

Therapeutic Agents

[0074] In certain aspects, the compositions provided herein include a polymer that is covalently attached to a residue of a therapeutic agent. In certain embodiments, the therapeutic agent is an anti-cancer therapeutic agent. In some embodiments, the therapeutic agent is an anti-inflammatory therapeutic agent.

[0075] In some embodiments, the anti-cancer therapeutic agent is a chemotherapy agent. Examples of such chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine;

acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide,

mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and

calicheamicin omegal l ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related

chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin,

authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti -metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamipnne, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine;

bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine;

elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan;

lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone;

mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;

pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine;

methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO);

retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0076] In some embodiments, the anti-cancer therapeutic agent is a cancer immunotherapy agent. Immunotherapy refers to a treatment that uses a subject's immune system to treat cancer, e.g., checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy. Non-limiting examples of immunotherapies are checkpoint inhibitors include Nivolumab (BMS, anti-PD-1), Pembrolizumab (Merck, anti- PD-1), Ipilimumab (BMS, anti-CTLA-4), MEDI4736 (AstraZeneca, anti-PD-Ll), and MPDL3280A (Roche, anti-PD-Ll). Other immunotherapies may be tumor vaccines, such as Gardail, Cervarix, BCG, sipulencel-T, Gpl00:209-217, AGS-003, DCVax-L, Algenpantucel- L, Tergenpantucel-L, TG4010, ProstAtak, Prostvac-V/R-TRICOM, Rindopepimul, E75 peptide acetate, IMA901, POL-103A, Belagenpumatucel-L, GSK1572932A, MDX-1279, GV1001, and Tecemotide. Immunotherapy may be administered via injection (e.g., intravenously, intratumorally, subcutaneously, or into lymph nodes), but may also be administered orally, topically, or via aerosol. Immunotherapies may comprise adjuvants such as cytokines.

[0077] In some embodiments, the immunotherapy agent is an immune checkpoint inhibitor. Immune Checkpoint inhibition broadly refers to inhibiting the checkpoints that cancer cells can produce to prevent or downregulate an immune response. Examples of immune checkpoint proteins include, but are not limited to, CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA. Immune checkpoint inhibitors can be antibodies or antigen binding fragments thereof that bind to and inhibit an immune checkpoint protein. Examples of immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG- 7446, BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.

[0078] In some embodiments, the immunotherapy agent is an immunostimulatory agent.

[0079] In some embodiments, the immunostimulatory agent is an adjuvant. In certain embodiments, the adjuvant is selected from immune modulatory protein, Adjuvant 65, a- GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG DNA, GPI-0100, lipid A, lipopoly saccharide, Lipovant, Montanide, N-acetyl-muramyl- L-alanyl-D-isoglutamine, Pam3CSK4, quil A and trehalose dimycolate.

[0080] In some embodiments, the immunostimulatory agent is an immune modulatory protein, such as a cytokine.

[0081] In some embodiments, the immunotherapy agent is an antibody or antigen binding fragment thereof that, for example, binds to a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDHlAl, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR- ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3- ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmel l7, GP MB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA- A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE- A10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan-A/MART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, FYC, NY- BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml- RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, R F43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA 17, SSX-2, SSX- 4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2- INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE- 1 b/ GAGED2a. In some embodiments, the antigen is a neo-antigen.

[0082] In some embodiments, the immunotherapy agent is a cancer vaccine and/or a component of a cancer vaccine (e.g., an antigenic peptide and/or protein). The cancer vaccine can be a protein vaccine, a nucleic acid vaccine or a combination thereof. For example, in some embodiments, the cancer vaccine comprises a polypeptide comprising an epitope of a cancer-associated antigen. In some embodiments, the cancer vaccine comprises a nucleic acid (e.g., DNA or RNA, such as mRNA) that encodes an epitope of a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDHIAI, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA,

carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CS K1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gpl00/Pmel l7, GP MB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-Al l, HLA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC 1, KM-HN-1, KMHN1 also known as CCDC1 10, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC 1R, MCSP, mdm-2, ME1, Melan- A/MART- 1 , Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, FYC, NY-BR-1, NY-ESO-l/LAGE-2, OA1, OGT, OS-9, P

polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymo hic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38/NY-MEL- 1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD 1, SOX10, Spl7, SPA 17, SSX-2, SSX-4, STEAPl, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-lb/GAGED2a. In some embodiments, the antigen is a neo-antigen. In some embodiments, the cancer vaccine is administered with an adjuvant. Examples of adjuvants include, but are not limited to, an immune modulatory protein, Adjuvant 65, a-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG DNA, GPI-0100, lipid A, lipopoly saccharide, Lipovant, Montanide, N-acetyl-muramyl-L- alanyl-D-isoglutamine, Pam3CSK4, quil A and trehalose dimycolate.

[0083] In some embodiments, the immunotherapy agent is an immune modulating protein to the subject. In some embodiments, the immune modulatory protein is a cytokine. Examples of immune modulating proteins include, but are not limited to, B lymphocyte chemoattractant ("BLC"), C-C motif chemokine 11 ("Eotaxin-1 "), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G-CSF"), Granulocyte macrophage colony-stimulating factor ("GM-CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM-l "), Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-l alpha"), Interlukin-1 beta ("IL-l beta"), Interleukin 1 receptor antagonist ("IL-l ra"), Interleukin-2 ("IL-2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin-6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ("IL-10"), Interleukin- 11 ("IL-l l "), Subunit beta of Interleukin- 12 ("IL-12 p40" or "IL-12 p70"), Interleukin- 13 ("IL-13"), Interleukin- 15 ("IL-15"), Interleukin- 16 ("IL-16"),

Interleukin- 17 ("IL-17"), Chemokine (C-C motif) Ligand 2 ("MCP-1 "), Macrophage colony- stimulating factor ("M-CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP-1 alpha"), Chemokine (C-C motif) ligand 4 ("MIP-1 beta"), Macrophase inflammatory protein- 1 -delta ("MIP-1 delta"), Platelet-derived growth factor subunit B ("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on Activation, Normal T cell Expressed and Secreted ("RANTES"), TIMP metallopeptidase inhibitor 1 ("TFMP-1 "), TFMP metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF alpha"), Tumor necrosis factor, lymphotoxin-beta ("TNF beta"), Soluble TNF receptor type 1 ("sTNFRI"), sTNFRIIAR, Brain-derived neurotrophic factor ("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BMP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG- VEGF"), Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor

("GD F"), Growth Hormone, Heparin-binding EGF-like growth factor ("FIB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-1 "), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulinlike growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-1 "), Insulin, Macrophage colony-stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NT-3"), Neurotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet-derived growth factor receptors ("PDGF-AA"), Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing comples ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha

("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1 "), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 (" VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO ("Axl"), Betacellulin ("BTC"), Mucosae-associated epithelial chemokine ("CCL28"), Chemokine (C- C motif) ligand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("Eotaxin-3"),

Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand 14 ("HCC-l"), Chemokine (C-C motif) ligand 16 ("HCC-4"), Interleukin-9 ("IL-9"), Interleukin- 17 F ("IL-17F"), Interleukin- 18-binding protein ("IL-18 BPa"), Interleukin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31 "), C-X-C motif chemokine 10 ("IP-10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light,

Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP- 2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte chemoattractant protein 4 ("MCP-4"), Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF-1 "), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1-like 4 ("NAP-2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen ("ALCAM"), Cluster of Differentiation 80 ("B7-1 "), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"), Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM-1 "), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3 ("ErbB3"), Endothelial-leukocyte adhesion molecule 1 ("E- Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, IL-17R, IL-2Rgamma, IL-21R, Lysosome membrane protein 2 ("LFMPII"), Neutrophil gelatinase-associated lipocalin ("Lipocalin-2"), CD62L ("L- Selectin"), Lymphatic endothelium ("LYVE-1 "), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGl-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM-1 "), RAGE, Hepatitis A virus cellular receptor 1 ("TFM-1 "), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein

transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1 "), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"), Angiopoietin 1, Angiostatin, Catheprin S, CD40, Cryptic family protein IB ("Cripto-1 "), DAN, Dickkopf-related protein 1 ("DKK-1 "), E-Cadherin, Epithelial cell adhesion molecule ("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C, FoUistatin, Galectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 Rl, IL-13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1 "), Platelet derived growth factor receptors ("PDGF-AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgpl30, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding immunoglobulin-type lectins ("Siglec-5"), ST2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"),

Triggering receptor expressed on myeloid cells 1 ("TREM-1 "), Vascular endothelial growth factor C ("VEGF-C"), VEGFRlAdiponectin, Adipsin ("AND"), Alpha-fetoprotein ("AFP"), Angiopoietin-like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA125"), Cancer Antigen 15-3 ("CA15- 3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), FoUistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-l sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21, Leptin, Matrix metalloproteinase-1 ("MMP-1 "), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metalloproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP-10"), Matrix metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1 "), Entactin ("Nidogen-1 "), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulin, Metalloproteinase inhibitor 4 ("TIMP- 4"), TSH2B4, Disintegrin and metalloproteinase domain-containing protein 9 ("ADAM-9"), Angiopoietin 2, Tumor necrosis factor ligand superfamily member 13/ Acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP-2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin L, CD200, CD97, Chemerin, Tumor necrosis factor receptor superfamily member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF-19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN-gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin-1 receptor 6 ("IL-1R6"), Interleukin 24 ("IL-24"), Interleukin 33 ("IL-33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1 "), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1, translocation-associated (Drosophila) ("Notch- 1 "), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD-1 "), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"), Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL Rl"), Transferrin ("TRF"), WTF- 1ACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 19-9 ("CA19-9"), CD 163 , Clusterin, CRT AM, Chemokine (C-X-C motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf-related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLL1 "), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha ("FOLR1 "), Furin, GPCR-associated sorting protein 1 ("GASP-1 "), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony-stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"), Interleukin- 17B Receptor ("IL-17B R"), Interleukin 27 ("IL-27"), Lymphocyte-activation gene 3 ("LAG-3"), Apolipoprotein A-V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1 "), Tumor necrosis factor receptor superfamily member 13B ("TACI"), Tissue factor pathway inhibitor ("TFPI"), TSP-1, Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNTl-inducible-signaling pathway protein 1 ("WISP-1 "), and Receptor Activator of Nuclear Factor κ B ("RANK").

[0084] In some embodiments, the immunotherapy agent is an adjuvant. In certain embodiments, the adjuvant is selected from immune modulatory protein, Adjuvant 65, a-

GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide,

CpG DNA, GPI-OlOO, lipid A, lipopoly saccharide, Lipovant, Montanide, N-acetyl-muramyl-

L-alanyl-D-isoglutamine, Pam3CSK4, quil A and trehalose dimycolate.

[0085] In some embodiments, the anti-cancer therapeutic agent is an angiogenesis inhibitor.

[0086] In certain such embodiments, the angiogenesis inhibitor is selected from the group consisting of Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib

(Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

[0087] In some embodiments, the anti-cancer therapeutic agent is a radioactive agent.

[0088] In certain such embodiments, the radioactive agent comprises a radionuclide selected from the group consisting of Cr-51, Cs-131, Ce-134, Se-75, Ru-97, 1-125, Eu-149, Os-189m, Sb-119, 1-123, Ho-161, Sb-117, Ce-139, In-I l l, Rh-103m, Ga-67, Tl-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P-33, Er-169, Ru-103, Yb-169, Au-199, Sn-121, Tm-167, Yb-175, In-113m, Sn-113, Lu-177, Rh-105, Sn-117m, Cu-67, Sc-47, Pt-195m, Ce-141, 1- 131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198, Tm-170, Re-186, Ag-111, Pd-109, Ga-73, Dy-165, Pm-149, Sn-123, Sr-89, Ho-166, P-32, Re-188, Pr-142, Ir- 194, In-114m/In-l 14, and Y-90.

[0089] In some embodiments, the anti-cancer therapeutic agent is an anti-cancer compound. Exemplary anti-cancer compounds include, but are not limited to, Alemtuzumab (Campath®), Alitretinoin (Panretin®), Anastrozole (Arimidex®), Bevacizumab (Avastin®), Bexarotene (Targretin®), Bortezomib (Velcade®), Bosutinib (Bosulif®), Brentuximab vedotin (Adcetris®), Cabozantinib (Cometriq™), Carfilzomib (Kyprolis™), Cetuximab (Erbitux®), Crizotinib (Xalkori®), Dasatinib (Sprycel®), Denileukin diftitox (Ontak®), Erlotinib hydrochloride (Tarceva®), Everolimus (Afinitor®), Exemestane (Aromasin®), Fulvestrant (Faslodex®), Gefitinib (Iressa®), Ibritumomab tiuxetan (Zevalin®), Imatinib mesylate (Gleevec®), Ipilimumab (Yervoy™), Lapatinib ditosylate (Tykerb®), Letrozole (Femara®), Nilotinib (Tasigna®), Ofatumumab (Arzerra®), Panitumumab (Vectibix®), Pazopanib hydrochloride (Votrient®), Pertuzumab (Perjeta™), Pralatrexate (Folotyn®), Regorafenib (Stivarga®), Rituximab (Rituxan®), Romidepsin (Istodax®), Sorafenib tosylate (Nexavar®), Sunitinib malate (Sutent®), Tamoxifen, Temsirolimus (Torisel®), Toremifene (Fareston®), Tositumomab and 1311-tositumomab (Bexxar®), Trastuzumab (Herceptin®), Tretinoin (Vesanoid®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), and Ziv-aflibercept (Zaltrap®).

[0090] Exemplary anti-cancer compounds that modify the function of proteins that regulate gene expression and other cellular functions (e.g., FID AC inhibitors, retinoid receptor ligants) are Vorinostat (Zolinza®), Bexarotene (Targretin®) and Romidepsin (Istodax®), Alitretinoin (Panretin®), and Tretinoin (Vesanoid®).

[0091] Exemplary anti-cancer compounds that induce apoptosis (e.g., proteasome inhibitors, antifolates) are Bortezomib (Velcade®), Carfilzomib (Kyprolis™), and

Pralatrexate (Folotyn®).

[0092] Exemplary anti-cancer compounds that increase anti-tumor immune response

(e.g., anti CD20, anti CD52; anti-cytotoxic T-lymphocyte-associated antigen-4) are

Rituximab (Rituxan®), Alemtuzumab (Campath®), Ofatumumab (Arzerra®), and

Ipilimumab (Yervoy™).

[0093] Exemplary anti-cancer compounds that deliver toxic agents to cancer cells

(e.g., anti-CD20-radionuclide fusions; IL-2-diphtheria toxin fusions; anti-CD30- monomethylauristatin E (MMAE)-fusions) are Tositumomab and 1311-tositumomab

(Bexxar®)and Ibritumomab tiuxetan (Zevalin®), Denileukin diftitox (Ontak®), and

Brentuximab vedotin (Adcetris®).

[0094] Other exemplary anti-cancer compounds are small molecule inhibitors and conjugates thereof of, e.g., Janus kinase, ALK, Bcl-2, PARP, PI3K, VEGF receptor, Braf, MEK, CDK, and HSP90.

[0095] Exemplary platinum-based anti-cancer compounds include, for example, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, Nedaplatin, Triplatin, and

Lipoplatin. Other metal-based drugs suitable for treatment include, but are not limited to ruthenium-based compounds, ferrocene derivatives, titanium-based compounds, and gallium- based compounds.

[0096] In some embodiments, the anti-cancer therapeutic agent is a radioactive moiety that comprises a radionuclide. Exemplary radionuclides include, but are not limited to Cr-51, Cs-131, Ce-134, Se-75, Ru-97, 1-125, Eu-149, Os-189m, Sb-1 19, 1-123, Ho-161, Sb- 1 17, Ce-139, In-1 1 1, Rh-103m, Ga-67, Tl-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P- 33, Er-169, Ru-103, Yb-169, Au-199, Sn-121, Tm-167, Yb-175, In-1 13m, Sn-1 13, Lu-177, Rh-105, Sn-1 17m, Cu-67, Sc-47, Pt-195m, Ce-141 , 1-131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198, Tm-170, Re-186, Ag-1 1 1, Pd-109, Ga-73, Dy-165, Pm- 149, Sn-123, Sr-89, Ho-166, P-32, Re-188, Pr-142, Ir-194, In-1 14m/In-l 14, and Y-90.

[0097] In some embodiments, the cancer therapeutic is an antibiotic. For example, if the presence of a cancer-associated bacteria and/or a cancer-associated microbiome profile is detected according to the methods provided herein, antibiotics can be administered to eliminate the cancer-associated bacteria from the subject. "Antibiotics" broadly refers to compounds capable of inhibiting or preventing a bacterial infection. Antibiotics can be classified in a number of ways, including their use for specific infections, their mechanism of action, their bioavailability, or their spectrum of target microbe (e.g., Gram-negative vs. Gram-positive bacteria, aerobic vs. anaerobic bacteria, etc.) and these may be used to kill specific bacteria in specific areas of the host ("niches") (Leekha, et al 201 1. General

Principles of Antimicrobial Therapy. Mayo Clin Proc. 86(2): 156-167). In certain

embodiments, antibiotics can be used to selectively target bacteria of a specific niche. In some embodiments, antibiotics known to treat a particular infection that includes a cancer niche may be used to target cancer-associated microbes, including cancer-associated bacteria in that niche.

[0098] In some aspects, antibiotics can be selected based on their bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that disrupt the cell wall (e.g., β-lactams), the cell membrane (e.g., daptomycin), or bacterial DNA (e.g., fluoroquinolones). Bacteriostatic agents inhibit bacterial replication and include

sulfonamides, tetracyclines, and macrolides, and act by inhibiting protein synthesis.

Furthermore, while some drugs can be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one skilled in the art to select an antibiotic with the appropriate properties. In certain treatment conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and

bacteriostatic antibiotics are not combined.

[0099] Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti-mycobacterial compounds, and combinations thereof.

[0100] Aminoglycosides include, but are not limited to Amikacin, Gentamicin,

Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin.

Aminoglycosides are effective, e.g., against Gram -negative bacteria, such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria but less effective against obligate/facultative anaerobes. Aminoglycosides are believed to bind to the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[0101] Ansamycins include, but are not limited to, Geldanamycin, Herbimycin,

Rifamycin, and Streptovaricin. Geldanamycin and Herbimycin are believed to inhibit or alter the function of Heat Shock Protein 90.

[0102] Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.

[0103] Carbapenems include, but are not limited to, Ertapenem, Doripenem,

Imipenem/Cilastatin, and Meropenem. Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics. Carbapenems are believed to inhibit bacterial cell wall synthesis.

[0104] Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin,

Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil,and Ceftobiprole.

Selected Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against methicillin-resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[0105] Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and

Telavancin. Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile. Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[0106] Lincosamides include, but are not limited to, Clindamycin and Lincomycin.

Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus, and Streptococcus. Lincosamides are believed to bind to the bacterial 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[0107] Lipopeptides include, but are not limited to, Daptomycin. Lipopeptides are effective, e.g., against Gram -positive bacteria. Lipopeptides are believed to bind to the bacterial membrane and cause rapid depolarization.

[0108] Macrolides include, but are not limited to, Azithromycin, Clarithromycin,

Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, and

Spiramycin. Macrolides are effective, e.g., against Streptococcus and Mycoplasma.

Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[0109] Monobactams include, but are not limited to, Aztreonam. Monobactams are effective, e.g., against Gram -negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[0110] Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

[0111] Oxazolidonones include, but are not limited to, Linezolid, Posizolid,

Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.

[0112] Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin,

Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Ticarcillin. Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[0113] Penicillin combinations include, but are not limited to,

Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, and

Ticarcillin/clavulanate.

[0114] Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and

Polymyxin B and E. Polypeptide Antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.

[0115] Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin,

Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, and Temafloxacin. Quinolones/Fluoroquinolone are effective, e.g., against Streptococcus and Neisseria. Quinolones/Fluoroquinolone are believed to inhibit the bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

[0116] Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide,

Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co- trimoxazole), and Sulfonamidochrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthetase, thereby inhibiting nucleic acid synthesis.

[0117] Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline,

Minocycline, Oxytetracycline, and Tetracycline. Tetracyclines are effective, e.g., against Gram-negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[0118] Anti-mycobacterial compounds include, but are not limited to, Clofazimine,

Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin.

[0119] Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin PI, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JHl 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamicin, rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptogramin A, synergistin, taurolidine, teicoplanin, telithromycin, ticarcillin/clavulanic acid,

triacetyloleandomycin, tylosin, tyrocidin, tyrothricin, vancomycin, vemamycin, and virginiamycin.

[0120] In yet further embodiments of the invention, the therapeutic agent is a prodrug enzyme, such as purine nucleoside phosphorylase.

[0121] In still further embodiments, the composition of the invention further comprises a prodrug, such as 6-methylpurine 2'-deoxyriboside (6MePdR).

[0122] In still further embodiments, the composition of the invention further comprises a prebiotic. The prebiotic may be a fructooligosaccharide, a

galactooligosaccharide, a trans-galactooligosaccharide, a xylooligosaccharide, a chitooligosaccharide, a soy oligosaccharide, a gentiooligosaccharide, an

isomaltooligosaccharide, a mannooligosaccharide, a maltooligosaccharide, a

mannanoligosaccharide, lactulose, lactosucrose, palatinose, glycosyl sucrose, guar gum, gum Arabic, tagalose, amylose, amylopectin, pectin, xylan, or a cyclodextrin.

[0123] In certain embodiments, the therapeutic agent is an anti-inflammatory agent.

[0124] The anti-inflammatory agent may be selected from the group consisting of corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives,

immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, and cytokine inhibitors.

[0125] In some embodiments, the cytokine inhibitor is selected from anti-IL-6 antibodies and TNF inhibitors. Exemplary TNF inhibitors include infliximab, adalimumab, certolizumab pegol, golimumab, and etanercept.

[0126] In some embodiments, the anti-inflammatory agent is a vaccine (e.g., a vaccine used for vaccination where the amount of an allergen is gradually increased).

[0127] In further embodiments of the invention, the therapeutic agent is N-acetyl cysteine, polyethylene glycol, a lectin, a protein antigen, a vitamin, curcumin, quercetin, bromelain, zinc, glutamine, a TLR agonist, a TDO/IDO metabolite, a TDO/IDO inhibitor, a DNA fragment, a prebiotic, or a quorum sensing molecule.

[0128] In some embodiments, the therapeutic agent is N-acetyl cysteine (NAC).

NAC may adhere to or facilitate breaking up or penetrating a mucus layer. Loosening a mucus layer may confer a positive therapeutic effect in disorders such as cystic fibrosis, chronic obstructive pulmonary disorder, or Tylenol overdose.

[0129] In other embodiments, the therapeutic agent is polyethylene glycol (PEG).

PEG is commonly used for protection and delivery, and can function to protect and/or penetrate mucus. In some embodiments, PEG is useful for penetrating mucus and extracellular matrix for cellular uptake.

[0130] In certain embodiments, the therapeutic agent is a lectin, and the lectin is Ulex europaeus agglutinin I, Aleuria aurantia lectin, or wheat germ agglutinin. In some embodiments, Ulex europaeus agglutinin is useful for targeting M cells and/or Peyer' s patches. Ulex europaeus agglutinin-I lectin binds to fucose glycan, which is commonly found on M cells. This agent may target delivery of particles and/or vaccines to Peyer's patches. [0131] Alternatively, the therapeutic agent may be a protein antigen and the protein antigen is a peanut allergen or ovalbumin.

[0132] Alternatively still, the therapeutic agent may be a vitamin, and the vitamin is retinoic acid, vitamin D3, vitamin B6, biotin, or folic acid.

[0133] In further embodiments, the therapeutic agent is a TLR agonist, and the TLR agonist is selected from the group consisting of R848/imiquimod, polyinosinic-polycytidylic acid, Pam3CSK4, and zymosan.

[0134] In yet further embodiments, the therapeutic agent is a TDO inhibitor, and the

TDO inhibitor is selected from the group consisting of tryptophan kynurenine and indole-3- aldehyde.

Bacteria

[0135] In certain embodiments, the compositions provided herein comprise a bacterium.

[0136] As used herein, the term "bacteria" broadly refers to the domain of prokaryotic organisms, including Gram positive and Gram negative organisms. Examples of specific bacteria useful in the compositions and methods provided herein are provided in Table 1 and/or Table 2. In certain embodiments, the bacterial strain used and/or detected in the methods provided herein is a bacterial strain listed in Table 1 and/or Table 2. In some embodiments, the bacterial strain is a bacterial strain having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a strain listed in Table 1 and/or Table 2. In certain embodiments, a combination of bacterial strains are used and/or detected in the methods provided herein. In some embodiments, the combination is a combination of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or 50 bacterial strains. In some embodiments combination includes bacterial strains listed in Table 1 and/or Table 2 and/or bacterial strains having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a strain listed in Table 1 and/or Table 2.

Table 1. Exemplary Bacterial Strains

mm® Public D li Accession

Abiotrophia defectiva ACIN02000016 Abiotrophia para adiacens AB022027

Abiotrophia sp. oral clone P4PA 155 PI AY207063

Acetanaerobacterium elongatum R_042930

Acetivibrio cellulolyticus R_025917

Acetivibrio ethanolgignens FR749897

Acetobacter aceti R_026121

Acetobacter fabarum R_042678

Acetobacter lovaniensis R_040832

Acetobacter malorum R_025513

Acetobacter orientalis R_028625

Acetobacter pasteurianus R_026107

Acetobacter pomorum R_042112

Acetobacter syzygii R_040868

Acetobacter tropicalis R_036881

Acetobacteraceae bacterium AT 5844 AGEZO 1000040

Acholeplasma laidlawii R_074448

Achromobacter denitrificans R_042021

Achromobacter piechaudii ADMS01000149

Achromobacter xylosoxidans ACRC01000072

Acidaminococcus fermentans CP001859

Acidaminococcus intestini CP003058

Acidaminococcus sp. D21 ACGB01000071

Acidilobus saccharovorans AY350586

Acidithiobacillus ferrivorans R_074660

Acidovorax sp. 98 63833 AY258065

Acinetobacter baumannii ACYQ01000014

Acinetobacter calcoaceticus AMI 57426

Acinetobacter genomosp. CI AY278636

Acinetobacter haemolyticus ADMT01000017

Acinetobacter j ohnsonii ACPL01000162

Acinetobacter junii ACPM01000135

Acinetobacter lwoffii ACPN01000204 Acinetobacter parvus AIEBO 1000124

Acinetobacter radioresistens ACVR01000010

Acinetobacter schindleri R_025412

Acinetobacter sp. 56A1 GQ 178049

Acinetobacter sp. CIP 101934 JQ638573

Acinetobacter sp. CIP 102143 JQ638578

Acinetobacter sp. CIP 53.82 JQ638584

Acinetobacter sp. M16_22 HM366447

Acinetobacter sp. RUH2624 ACQF01000094

Acinetobacter sp. SH024 ADCH01000068 macActinobacillus actinomycetemcomitans AY362885

Actinobacillus minor ACFT01000025

Actinobacillus pleuropneumoniae R_074857

Actinobacillus succinogenes CP000746

Actinobacillus ureae AEVG01000167

Actinobaculum massiliae AF487679

Actinobaculum schaalii AY957507

Actinobaculum sp. BM#101342 AY282578

Actinobaculum sp. P2P 19 PI AY207066

Actinomyces cardiffensis GU470888

Actinomyces europaeus R_026363

Actinomyces funkei HQ906497

Actinomyces genomosp. CI AY278610

Actinomyces genomosp. C2 AY278611

Actinomyces genomosp. PI oral clone MB6 C03 DQ003632

Actinomyces georgiae GU561319

Actinomyces israelii AF479270

Actinomyces massiliensis AB545934

Actinomyces meyeri GU561321

Actinomyces naeslundii X81062

Actinomyces nasicola AJ508455

Actinomyces neuii X71862 Actinomyces odontolyticus ACYT01000123

Actinomyces oricola R_025559

Actinomyces orihominis AJ575186

Actinomyces oris BABVO 1000070

Actinomyces sp. 7400942 EU484334

Actinomyces sp. cl09 AB167239

Actinomyces sp. CCUG 37290 AJ234058

Actinomyces sp. ChDC B197 AF543275

Actinomyces sp. GEJ15 GU561313

Actinomyces sp. HKU31 HQ335393

Actinomyces sp. ICM34 HQ616391

Actinomyces sp. ICM41 HQ616392

Actinomyces sp. ICM47 HQ616395

Actinomyces sp. ICM54 HQ616398

Actinomyces sp. M2231_94_l AJ234063

Actinomyces sp. oral clone GU009 AY349361

Actinomyces sp. oral clone GU067 AY349362

Actinomyces sp. oral clone IO076 AY349363

Actinomyces sp. oral clone IO077 AY349364

Actinomyces sp. oral clone IP073 AY349365

Actinomyces sp. oral clone IP081 AY349366

Actinomyces sp. oral clone JA063 AY349367

Actinomyces sp. oral taxon 170 AFBL01000010

Actinomyces sp. oral taxon 171 AECW01000034

Actinomyces sp. oral taxon 178 AEUH01000060

Actinomyces sp. oral taxon 180 AEPP01000041

Actinomyces sp. oral taxon 848 ACUY01000072

Actinomyces sp. oral taxon C55 HM099646

Actinomyces sp. TeJ5 GU561315

Actinomyces urogeni talis ACFH01000038

Actinomyces viscosus ACRE01000096

Adlercreutzia equolifaciens AB306661 Aerococcus sanguinicola AY837833

Aerococcus urinae CP002512

Aerococcus urinaeequi R_043443

Aerococcus viridans ADNTO 1000041

Aeromicrobium marinum R_025681

Aeromicrobium sp. JC14 JF824798

Aeromonas allosaccharophila S39232

Aeromonas enteropelogenes X71121

Aeromonas hydrophila NC_008570

Aeromonas j andaei X60413

Aeromonas salmonicida NC_009348

Aeromonas trota X60415

Aeromonas veronii R_044845

Afipia genomosp. 4 EU117385

Aggregatibacter actinomycetemcomitans CP001733

Aggregatibacter aphrophilus CP001607

Aggregatibacter segnis AEPS01000017

Agrobacterium radiobacter CP000628

Agrobacterium tumefaciens AJ389893

Agrococcus j enensi s R_026275

Akkermansia muciniphila CP001071

Alcaligenes faecalis AB680368

Alcaligenes sp. C014 DQ643040

Alcaligenes sp. S3 HQ262549

Alicyclobacillus acidocaldarius R_074721

Alicyclobacillus acidoterrestns R_040844

Alicyclobacillus contaminans R_041475

Alicyclobacillus cycloheptanicus R_024754

Alicyclobacillus herbarius R_024753

Alicyclobacillus pomorum R_024801

Alicyclobacillus sp. CCUG 53762 HE613268

Alistipes finegoldii R_043064 Alistipes indistinctus AB490804

Ali stipes onderdonkii R_043318

Alistipes putredinis ABFK02000017

Alistipes shahii FP929032

Alistipes sp. HGB5 AENZ01000082

Alistipes sp. JC50 JF824804

Alistipes sp. RMA 9912 GQ 140629

Alkaliphilus metalliredigenes AY137848

Alkaliphilus oremlandii R_043674

Alloscardovia omnicolens R_042583

Alloscardovia sp. OB7196 AB425070

Anaerobaculum hydrogeniformans ACJX02000009

Anaerobiospirillum succiniciproducens R_026075

Anaerobiospirillum thomasii AJ420985

Anaerococcus hydrogenalis ABXAO 1000039

Anaerococcus lactolyticus ABYOO 1000217

Anaerococcus octavius R_026360

Anaerococcus prevotii CP001708

Anaerococcus sp. 8404299 HM587318

Anaerococcus sp. 8405254 HM587319

Anaerococcus sp. 9401487 HM587322

Anaerococcus sp. 9403502 HM587325

Anaerococcus sp. gpacl04 AM176528

Anaerococcus sp. gpacl26 AM176530

Anaerococcus sp. gpacl55 AM176536

Anaerococcus sp. gpacl99 AM176539

Anaerococcus sp. gpac215 AM176540

Anaerococcus tetradius ACGC01000107

Anaerococcus vaginalis ACXU01000016

Anaerofustis stercorihominis ABIL02000005

Anaeroglobus geminatus AGCJ01000054

Anaerosporobacter mobilis R_042953 Anaerostipes caccae ABAX03000023

Anaerostipes sp. 3_2_56FAA ACWB01000002

Anaerotruncus colihominis ABGD02000021

Anaplasma marginale ABORO 1000019

Anaplasma phagocytophilum NC_007797

Aneurinibacillus aneurinilyticus AB101592

Aneurinibacillus danicus R_028657

Aneurinibacillus migulanus R_036799

Aneurinibacillus terranovensis R_042271

Aneurinibacillus thermoaerophilus R_029303

Anoxybacillus contaminans R_029006

Anoxybacillus flavithermus R_074667

Arcanobacterium haemolyticum R_025347

Arcanobacterium pyogenes GU585578

Arcobacter butzleri AEPT01000071

Arcobacter cryaerophilus R_025905

Arthrobacter agilis R_026198

Arthrobacter arilaitensis R_074608

Arthrobacter bergerei R_025612

Arthrobacter globiformis R_026187

Arthrobacter nicotianae R_026190

Atopobium minutum HM007583

Atopobium parvulum CP001721

Atopobium rimae ACFE01000007

Atopobium sp. BS2 HQ616367

Atopobium sp. F0209 EU592966

Atopobium sp. ICM42 0 HQ616393

Atopobium sp. ICM57 HQ616400

Atopobium vaginae AEDQ01000024

Aurantimonas coralicida AY065627

Aureimonas altamirensis FN658986

Auritibacter ignavus FN554542 Averyella dalhousiensis DQ481464

Bacillus aeolius R_025557

Bacillus aerophilus R_042339

Bacillus aestuarii GQ980243

Bacillus alcalophilus X76436

Bacillus amyloliquefaciens R_075005

Bacillus anthracis AAENO 1000020

Bacillus atrophaeus R_075016

Bacillus badius R_036893

Bacillus cereus ABDJO 1000015

Bacillus circulans AB271747

Bacillus clausii FN397477

Bacillus coagulans DQ297928

Bacillus firmus R_025842

Bacillus flexus R_024691

Bacillus fordii R_025786

Bacillus gelatini R_025595

Bacillus halmapalus R_026144

Bacillus halodurans AY144582

Bacillus herbersteinensis R_042286

Bacillus horti R_036860

Bacillus idriensis R_043268

Bacillus lentus R_040792

Bacillus licheniformis NC_006270

Bacillus megaterium GU252124

Bacillus nealsonii R_044546

Bacillus niabensis R_043334

Bacillus niacini R_024695

Bacillus pocheonensis R_041377

Bacillus pumilus R_074977

Bacillus safensis JQ624766

Bacillus simplex R_042136 Bacillus sonorensis R_025130

Bacillus sp. 10403023 MM10403188 CAET01000089

Bacillus sp. 2_A_57_CT2 ACWD01000095

Bacillus sp. 2008724126 GU252108

Bacillus sp. 2008724139 GU252111

Bacillus sp. 7 16AIA FN397518

Bacillus sp. 9 3AIA FN397519

Bacillus sp. AP8 JX101689

Bacillus sp. B27(2008) EU362173

Bacillus sp. BT1B CT2 ACWC01000034

Bacillus sp. GB1.1 FJ897765

Bacillus sp. GB9 FJ897766

Bacillus sp. HU19.1 FJ897769

Bacillus sp. HU29 FJ897771

Bacillus sp. HU33.1 FJ897772

Bacillus sp. JC6 JF824800

Bacillus sp. oral taxon F26 HM099642

Bacillus sp. oral taxon F28 HM099650

Bacillus sp. oral taxon F79 HM099654

Bacillus sp. SRC DSFl GU797283

Bacillus sp. SRC DSFIO GU797292

Bacillus sp. SRC DSF2 GU797284

Bacillus sp. SRC DSF6 GU797288

Bacillus sp. tc09 HQ844242

Bacillus sp. zhl68 FJ851424

Bacillus sphaericus DQ286318

Bacillus sporothermodurans R_026010

Bacillus subtilis EU627588

Bacillus thermoamylovorans R_029151

Bacillus thuringiensis NC_008600

Bacillus weihenstephanensis R_074926

Bacteroidales bacterium ph8 JN837494 Bacteroidales genomosp. PI AY341819

Bacteroidales genomosp. P2 oral clone MB1 G13 DQ003613

Bacteroidales genomosp. P3 oral clone MB1 G34 DQ003615

Bacteroidales genomosp. P4 oral clone MB2 G17 DQ003617

Bacteroidales genomosp. P5 oral clone MB2 P04 DQ003619

Bacteroidales genomosp. P6 oral clone MB3 C19 DQ003634

Bacteroidales genomosp. P7 oral clone MB3 P19 DQ003623

Bacteroidales genomosp. P8 oral clone MB4 G15 DQ003626

Bacteroides acidifaciens R_028607

Bacteroides barnesiae R_041446

Bacteroides caccae EU136686

Bacteroides cellulosilyticus ACCHO 1000108

Bacteroides clarus AFBM01000011

Bacteroides coagulans AB547639

Bacteroides coprocola ABIY02000050

Bacteroides coprophilus ACBW01000012

Bacteroides dorei ABWZO 1000093

Bacteroides eggerthii ACWG01000065

Bacteroides faecis GQ496624

Bacteroides finegoldii AB222699

Bacteroides fluxus AFBN01000029

Bacteroides fragilis AP006841

Bacteroides galacturonicus DQ497994

Bacteroides helcogenes CP002352

Bacteroides heparinolyticus JN867284

Bacteroides intestinalis ABJL02000006

Bacteroides massiliensis AB200226

Bacteroides nordii R_043017

Bacteroides oleiciplenus AB547644

Bacteroides ovatus ACWH01000036

Bacteroides pectinophilus ABVQ01000036

Bacteroides plebeius AB200218 Bacteroides pyogenes R_041280

Bacteroides salanitronis CP002530

Bacteroides salyersiae EU136690

Bacteroides sp. 1 1 14 ACRPO 1000155

Bacteroides sp. 1 1 30 ADCL01000128

Bacteroides sp. 1 1 6 ACICO 1000215

Bacteroides sp. 2_1_22 ACPQ01000117

Bacteroides sp. 2 1 56FAA ACWIO 1000065

Bacteroides sp. 2_2_4 ABZZO 1000168

Bacteroides sp. 20 3 ACRQ01000064

Bacteroides sp. 3 1 19 ADC JO 1000062

Bacteroides sp. 3 1 23 ACRS01000081

Bacteroides sp. 3 1 33FAA ACPS01000085

Bacteroides sp. 3 1 40A ACRT01000136

Bacteroides sp. 3 2 5 ACIB01000079

Bacteroides sp. 315 5 FJ848547

Bacteroides sp. 31 SF15 AJ583248

Bacteroides sp. 31 SF18 AJ583249

Bacteroides sp. 35AE31 AJ583244

Bacteroides sp. 35AE37 AJ583245

Bacteroides sp. 35BE34 AJ583246

Bacteroides sp. 35BE35 AJ583247

Bacteroides sp. 4 1 36 ACTC01000133

Bacteroides sp. 4_3_47FAA ACDR02000029

Bacteroides sp. 9 1 42FAA ACAA01000096

Bacteroides sp. AR20 AF139524

Bacteroides sp. AR29 AF139525

Bacteroides sp. B2 EU722733

Bacteroides sp. Dl ACAB02000030

Bacteroides sp. D2 ACGA01000077

Bacteroides sp. D20 ACPT01000052

Bacteroides sp. D22 ADCK01000151 Bacteroides sp. F_4 AB470322

Bacteroides sp. B 8 AB117565

Bacteroides sp. WH2 AY895180

Bacteroides sp. XB12B AM230648

Bacteroides sp. XB44A AM230649

Bacteroides stercoris ABFZ02000022

Bacteroides thetaiotaomicron R_074277

Bacteroides uniformis AB050110

Bacteroides ureolyticus GQ 167666

Bacteroides vulgatus CP000139

Bacteroides xylanisolvens ADKPO 1000087

Bacteroidetes bacterium oral taxon D27 HM099638

Bacteroidetes bacterium oral taxon F31 HM099643

Bacteroidetes bacterium oral taxon F44 HM099649

Barnesiella intestinihominis AB370251

Barnesiella viscericola R_041508

Bartonella bacilliformis NC_008783

Bartonella grahamii CP001562

Bartonella henselae NC_005956

Bartonella quintana BX897700

Bartonella tamiae EF672728

Bartonella washoensis FJ719017

Bdellovibrio sp. MPA AY294215

Bifidobacteriaceae genomosp. CI AY278612

Bifidobacterium adolescentis AAXD02000018

Bifidobacterium angulatum ABYS02000004

Bifidobacterium animalis CP001606

Bifidobacterium bifidum ABQPO 1000027

Bifidobacterium breve CP002743

Bifidobacterium catenulatum ABXYO 1000019

Bifidobacterium dentium CP001750

Bifidobacterium gallicum ABXB03000004 Bifidobacterium infantis AY151398

Bifidobacterium kashiwanohense AB491757

Bifidobacterium longum ABQQO 1000041

Bifidobacterium pseudocatenulatum ABXX02000002

Bifidobacterium pseudolongum R_043442

Bifidobacterium scardovii AJ307005

Bifidobacterium sp. HM2 AB425276

Bifidobacterium sp. HMLN12 JF519685

Bifidobacterium sp. M45 HM626176

Bifidobacterium sp. MSX5B HQ616382

Bifidobacterium sp. TM 7 AB218972

Bifidobacterium thermophilum DQ340557

Bifidobacterium urinalis AJ278695

Bilophila wadsworthia ADCP01000166

Bisgaard Taxon AY683487

Bisgaard Taxon AY683489

Bisgaard Taxon AY683491

Bisgaard Taxon AY683492

Blastomonas natatoria R_040824

Blautia coccoides AB571656

Blautia glucerasea AB588023

Blautia glucerasei AB439724

Blautia hansenii ABYU02000037

Blautia hydrogenotrophica ACBZ01000217

Blautia luti AB691576

Blautia producta AB600998

Blautia schinkii R_026312

Blautia sp. M25 HM626178

Blautia stercoris HM626177

Blautia wexlerae EF036467

Bordetella bronchiseptica R_025949

Bordetella holmesii AB683187 Bordetella parapertussis R_025950

Bordetella pertussis BX640418

Borrelia afzelii ABCUO 1000001

Borrelia burgdorferi ABGI01000001

Borrelia crocidurae DQ057990

Borrelia duttonii NC_011229

Borrelia garinii ABJV01000001

Borrelia hermsii AY597657

Borrelia hispanica DQ057988

Borrelia persica HM161645

Borrelia recurrentis AF107367

Borrelia sp. E49 AJ224142

Borrelia spielmanii ABKB01000002

Borrelia turicatae NC_008710

Borrelia valaisiana ABCY01000002

Brachybacterium alimentarium R_026269

Brachybacterium conglomeratum AB537169

Brachybacterium tyrofermentans R_026272

Brachyspira aalborgi FM178386

Brachyspira pilosicoli R_075069

Brachyspira sp. HIS3 FM178387

Brachyspira sp. HIS4 FM178388

Brachyspira sp. HIS5 FM178389

Brevibacillus agri R_040983

Brevibacillus brevis R_041524

Brevibacillus centrosporus R_043414

Brevibacillus choshinensis R_040980

Brevibacillus invocatus R_041836

Brevibacillus laterosporus R_037005

Brevibacillus parabrevis R_040981

Brevibacillus reuszeri R_040982

Brevibacillus sp. phR JN837488 Brevibacillus thermoruber R_026514

Brevibactenum aurantiacum R_044854

Brevibacterium casei JF951998

Brevibactenum epidermidis R_029262

Brevibacterium frigoritolerans R_042639

Brevibacterium linens AJ315491

Brevibacterium mcbrellneri ADNUO 1000076

Brevibacterium paucivorans EU086796

Brevibacterium sanguinis R_028016

Brevibacterium sp. HI 5 AB 177640

Brevibacterium sp. JC43 JF824806

Brevundimonas subvibrioides CP002102

Brucella abortus ACBJ01000075

Brucella canis R_044652

Brucella ceti ACJD01000006

Brucella melitensis AE009462

Brucella microti R_042549

Brucella ovis NC_009504

Brucella sp. 83 13 ACBQ01000040

Brucella sp. BOl EU053207

Brucella suis ACBK01000034

Bryantella formatexigens ACCL02000018

Buchnera aphidicola R_074609

Bulleidia extructa ADFR01000011

Burkholderia ambifaria AAUZ01000009

Burkholderia cenocepacia AAHI01000060

Burkholderia cepacia R_041719

Burkholderia mallei CP000547

Burkholderia multivorans NC_010086

Burkholderia oklahomensis DQ108388

Burkholderia pseudomallei CP001408

Burkholderia rhizoxinica HQ005410 Burkholderia sp. 383 CP000151

Burkholderia xenovorans U86373

Burkholderiales bacterium 1 1 47 ADCQO 1000066

Butyricicoccus pullicaecorum HH793440

Butyricimonas virosa AB443949

Butyrivibrio crossotus ABWN01000012

Butyrivibrio fibrisolvens U41172

Caldimonas manganoxidans R_040787

Caminicella sporogenes R_025485

Campylobacter coli AAFL01000004

Campylobacter concisus CP000792

Campylobacter curvus NC_009715

Campylobacter fetus ACLG01001177

Campylobacter gracilis ACYG01000026

Campylobacter hominis NC_009714

Campylobacter j ejuni AL139074

Campylobacter lari CP000932

Campylobacter rectus ACFU01000050

Campylobacter showae ACVQ01000030

Campylobacter sp. FOBRC14 HQ616379

Campylobacter sp. FOBRC15 HQ616380

Campylobacter sp. oral clone BB120 AY005038

Campylobacter sputorum R_044839

Campylobacter upsaliensis AEPU01000040

Candidatus Arthromitus sp. SFB mouse Yit R_074460

Candidatus Sulcia muelleri CP002163

Capnocytophaga canimorsus CP002113

Capnocytophaga genomosp. CI AY278613

Capnocytophaga gingivalis ACLQ01000011

Capnocytophaga granulosa X97248

Capnocytophaga ochracea AEOH01000054

Capnocytophaga sp. GEJ8 GU561335 Capnocytophaga sp. oral clone AH015 AY005074

Capnocytophaga sp. oral clone ASCH05 AY923149

Capnocytophaga sp. oral clone ID062 AY349368

Capnocytophaga sp. oral strain A47ROY AY005077

Capnocytophaga sp. oral strain S3 AY005073

Capnocytophaga sp. oral taxon 338 AEXXO 1000050

Capnocytophaga sp. Sib U42009

Capnocytophaga sputigena ABZVO 1000054

Cardiobacterium hominis ACKY01000036

Cardiobacterium valvarum R_028847

Carnobacterium divergens R_044706

Carnobacterium maltaromaticum NC_019425

Catabacter hongkongensis AB671763

Catenibacterium mitsuokai AB030224

Catonella genomosp. PI oral clone MB5 P12 DQ003629

Catonella morbi ACIL02000016

Catonella sp. oral clone FL037 AY349369

Cedecea davisae AF493976

Cellulosimicrobium funkei AY501364

Cetobacterium somerae AJ438155

Chlamydia muridarum AE002160

Chlamydia psittaci R_036864

Chlamydia trachomatis U68443

Chlamydiales bacterium NS11 JN606074

Chlamydiales bacterium NS13 JN606075

Chlamydiales bacterium NS16 JN606076

Chlamydophila pecorum D88317

Chlamydophila pneumoniae NC_002179

Chlamydophila psittaci D85712

Chloroflexi genomosp. PI AY331414

Christensenella minuta AB490809

Chromobacterium violaceum NC_005085 Chryseobacterium anthropi AM982793

Chryseobacterium gleum ACKQ02000003

Chryseobacterium hominis R_042517

Citrobacter amalonaticus FR870441

Citrobacter braakii R_028687

Citrobacter farmeri AF025371

Citrobacter freundii R_028894

Citrobacter gillenii AF025367

Citrobacter koseri NC_009792

Citrobacter murliniae AF025369

Citrobacter rodentium R_074903

Citrobacter sedlakii AF025364

Citrobacter sp. 30_2 ACDJ01000053

Citrobacter sp. KMSI 3 GQ468398

Citrobacter werkmanii AF025373

Citrobacter youngae ABWL02000011

Cloacibacillus evryensis GQ258966

Clostridiaceae bacterium E D 2 EF451053

Clostridiaceae bacterium JC13 JF824807

Clostridiales bacterium 1_7_47FAA ABQRO 1000074

Clostridiales bacterium 9400853 HM587320

Clostridiales bacterium 9403326 HM587324

Clostridiales bacterium oral clone P4PA 66 PI AY207065

Clostridiales bacterium oral taxon 093 GQ422712

Clostridiales bacterium oral taxon F32 HM099644

Clostridiales bacterium ph2 JN837487

Clostridiales bacterium SY8519 AB477431

Clostridiales genomosp. BVAB3 CP001850

Clostridiales sp. SM4_1 FP929060

Clostridiales sp. SS3_4 AY305316

Clostridiales sp. SSC_2 FP929061

Clostridium acetobutylicum R_074511 Clostridium aerotolerans X76163

Clostridium aldenense R_043680

Clostridium aldrichii R_026099

Clostridium algidicarnis R_041746

Clostridium algidixylanolyticum R_028726

Clostridium aminovalericum R_029245

Clostridium amygdalinum AY353957

Clostridium argentinense R_029232

Clostridium asparagiforme ACCJO 1000522

Clostridium baratii R_029229

Clostridium bartlettii ABEZ02000012

Clostridium beijerinckii R_074434

Clostridium bifermentans X73437

Clostridium bolteae ABCC02000039

Clostridium botulinum NC_010723

Clostridium butyricum ABDT01000017

Clostridium cadaveris AB542932

Clostridium carboxidivorans FR733710

Clostridium carnis R_044716

Clostridium celatum X77844

Clostridium celerecrescens JQ246092

Clostridium cellulosi R_044624

Clostridium chauvoei EU106372

Clostridium citroniae ADLJ01000059

Clostridium clariflavum R_041235

Clostridium clostridiiformes M59089

Clostridium clostridioforme R_044715

Clostridium coccoides EF025906

Clostridium cochlearium R_044717

Clostridium cocleatum R_026495

Clostridium colicanis FJ957863

Clostridium colinum R_026151 Clostridium difficile NC_013315

Clostridium disporicum R_026491

Clostridium estertheticum R_042153

Clostridium fallax R_044714

Clostridium favososporum X76749

Clostridium felsineum AF270502

Clostridium frigidicarnis R_024919

Clostridium gasigenes R_024945

Clostridium ghonii AB542933

Clostridium glycolicum FJ384385

Clostridium glycyrrhizinilyticum AB233029

Clostridium haemolyticum R_024749

Clostridium hathewayi AY552788

Clostridium hiranonis AB023970

Clostridium histolyticum HF558362

Clostridium hylemonae AB023973

Clostridium indolis AF028351

Clostridium innocuum M23732

Clostridium irregulare R_029249

Clostridium isatidis R_026347

Clostridium kluyveri R_074165

Clostridium lactatifermentans R_025651

Clostridium lavalense EF564277

Clostridium leptum AJ305238

Clostridium limosum FR870444

Clostridium magnum X77835

Clostridium malenominatum FR749893

Clostridium mayombei FR733682

Clostridium methylpentosum ACECO 1000059

Clostridium nexile X73443

Clostridium novyi R_074343

Clostridium orbiscindens Y18187 Clostridium oroticum FR749922

Clostridium paraputrificum AB536771

Clostridium perfringens ABDWO 1000023

Clostridium phytofermentans NR_074652

Clostridium piliforme D14639

Clostridium putrefaciens NR_024995

Clostridium quinii NR_026149

Clostridium ramosum M23731

Clostridium rectum NR_029271

Clostridium saccharogumia DQ 100445

Clostridium saccharolyticum CP002109

Clostridium sardiniense NR_041006

Clostridium sartagoforme NR_026490

Clostridium scindens AF262238

Clostridium septicum NR_026020

Clostridium sordellii AB448946

Clostridium sp. 7_2_43FAA ACDK01000101

Clostridium sp. D5 ADBG01000142

Clostridium sp. HGF2 AENW01000022

Clostridium sp. HPB 46 AY862516

Clostridium sp. JC122 CAEV01000127

Clostridium sp. L2 50 AAYW02000018

Clostridium sp. LMG 16094 X95274

Clostridium sp. M62_l ACFX02000046

Clostridium sp. MLG055 AF304435

Clostridium sp. MT4 E FJ159523

Clostridium sp. MBHI l JN093130

Clostridium sp. NML 04A032 EU815224

Clostridium sp. SS2 1 ABGC03000041

Clostridium sp. SY8519 AP012212

Clostridium sp. TM 40 AB249652

Clostridium sp. YIT 12069 AB491207 Clostridium sp. YIT 12070 AB491208

Clostridium sphenoides X73449

Clostridium spiroforme X73441

Clostridium sporogenes ABKW02000003

Clostridium sporosphaeroides R_044835

Clostridium stercorarium R_025100

Clostridium sticklandii L04167

Clostridium straminisolvens R_024829

Clostridium subterminale R_041795

Clostridium sulfidigenes R_044161

Clostridium symbiosum ADLQ01000114

Clostridium tertium Y18174

Clostridium tetani NC_004557

Clostridium thermocellum R_074629

Clostridium tyrobutyricum R_044718

Clostridium viride R_026204

Clostridium xylanolyticum R_037068

Collinsella aerofaciens AAVN02000007

Collinsella intestinalis ABXH02000037

Collinsella stercoris ABXJO 1000150

Collinsella tanakaei AB490807

Comamonadaceae bacterium ML000135 JN585335

Comamonadaceae bacterium ML790751 JN585331

Comamonadaceae bacterium ML910035 JN585332

Comamonadaceae bacterium ML910036 JN585333

Comamonadaceae bacterium oral taxon F47 HM099651

Comamonas sp. NSP5 AB076850

Conchiformibius kuhniae R_041821

Coprobacillus cateniformis AB030218

Coprobacillus sp. 29 1 ADKX01000057

Coprobacillus sp. D7 ACDT01000199

Coprococcus catus EU266552 Coprococcus comes ABVRO 1000038

Coprococcus eutactus EF031543

Coprococcus sp. ART55 1 AY350746

Coriobacteriaceae bacterium BV3Acl JN809768

Coriobacteriaceae bacterium JCl 10 CAEM01000062

Coriobacteriaceae bacterium phi JN837493

Corynebacterium accolens ACGD01000048

Corynebacterium ammoniagenes ADNS01000011

Corynebacterium amycolatum ABZUO 1000033

Corynebacterium appendicis R_028951

Corynebacterium argentoratense EF463055

Corynebacterium atypicum R_025540

Corynebacterium aurimucosum ACLH01000041

Corynebacterium bovis AF537590

Corynebacterium canis GQ871934

Corynebacterium casei R_025101

Corynebacterium confusum Y15886

Corynebacterium coyleae X96497

Corynebacterium diphtheriae NC_002935

Corynebacterium durum Z97069

Corynebacterium efficiens ACLI01000121

Corynebacterium falsenii Y13024

Corynebacterium flavescens R_037040

Corynebacterium genitalium ACL JO 1000031

Corynebacterium glaucum R_028971

Corynebacterium glucuronolyticum ABYP01000081

Corynebacterium glutamicum BA000036

Corynebacterium hansenii AM946639

Corynebacterium imitans AF537597

Corynebacterium j eikeium ACYW01000001

Corynebacterium kroppenstedtii R_026380

Corynebacterium lipophiloflavum ACHJ01000075 Corynebactenum macginleyi AB359393

Corynebacterium mastitidis AB359395

Corynebacterium matruchotii ACSH02000003

Corynebacterium minutissimum X82064

Corynebacterium mucifaciens NR_026396

Corynebacterium propinquum NR_037038

Corynebacterium pseudodiphtheriticum X84258

Corynebacterium pseudogenitalium ABYQ01000237

Corynebacterium pseudotuberculosis NR_037070

Corynebacterium pyruviciproducens FJ185225

Corynebacterium renale NR_037069

Corynebacterium resistens ADGNO 1000058

Corynebacterium riegelii EU848548

Corynebacterium simulans AF537604

Corynebacterium singulare NR_026394

Corynebacterium sp. 1 ex sheep Y13427

Corynebacterium sp. L_2012475 HE575405

Corynebacterium sp. ML 93_0481 GU238409

Corynebacterium sp. NML 97_0186 GU238411

Corynebacterium sp. NML 99_0018 GU238413

Corynebacterium striatum ACGE01000001

Corynebacterium sundsvallense Y09655

Corynebacterium tuberculostearicum ACVP01000009

Corynebacterium tuscaniae AY677186

Corynebacterium ulcerans NR_074467

Corynebacterium urealyticum X81913

Corynebacterium ureicelerivorans AM397636

Corynebacterium variabile NR_025314

Corynebacterium xerosis FN179330

Coxiella burnetii CP000890

Cronobacter malonaticus GU122174

Cronobacter sakazakii NC_009778 Cronobacter turicensis FN543093

Cryptobacterium curtum GQ422741

Cupriavidus metallidurans GU230889

Cytophaga xylanolytica FR733683

Defernbacteres sp. oral clone JVOOl AY349370

Defernbacteres sp. oral clone JV006 AY349371

Defernbacteres sp. oral clone JV023 AY349372

Deinococcus radiodurans AE000513

Deinococcus sp. R 43890 FR682752

Delftia acidovorans CP000884

Dermabacter hominis FJ263375

Dermacoccus sp. Ellinl85 AEIQO 1000090

Desmospora activa AM940019

Desmospora sp. 8437 AFHT01000143

Desulfitobacterium frappieri AJ276701

Desulfitobacterium hafniense R_074996

Desulfobulbus sp. oral clone CH031 AY005036

Desulfotomaculum nigrificans R_044832

Desulfovibrio desulfuricans DQ092636

Desulfovibrio fairfieldensis U42221

Desulfovibrio piger AF192152

Desulfovibrio sp. 3_l_syn3 ADDRO 1000239

Desulfovibrio vulgaris R_074897

Dialister invisus ACIM02000001

Dialister micraerophilus AFBBO 1000028

Dialister microaerophilus AENT01000008

Dialister pneumosintes HM596297

Dialister propionicifaciens R_043231

Dialister sp. oral taxon 502 GQ422739

Dialister succinatiphilus AB370249

Dietzia natronolimnaea GQ870426

Dietzia sp. BBDP51 DQ337512 Dietzia sp. CA149 GQ870422

Dietzia timorensis GQ870424

Dorea formicigenerans AAXA02000006

Dorea longicatena AJ132842

Dysgonomonas gadei ADLVO 1000001

Dysgonomonas mossii ADLW01000023

Edwardsiella tarda CP002154

Eggerthella lenta AF292375

Eggerthella sinensis AY321958

Eggerthella sp. 1_3_56FAA ACWN01000099

Eggerthella sp. HGA1 AEXRO 1000021

Eggerthella sp. YY7918 AP012211

Ehrlichia chaffeensis AAIF01000035

Eikenella corrodens ACEA01000028

Enhydrobacter aerosaccus ACYI01000081

Enterobacter aerogenes AJ251468

Enterobacter asburiae R_024640

Enterobacter cancerogenus Z96078

Enterobacter cloacae FP929040

Enterobacter cowanii R_025566

Enterobacter hormaechei AFHRO 1000079

Enterobacter sp. 247BMC HQ122932

Enterobacter sp. 638 R_074777

Enterobacter sp. JC163 JN657217

Enterobacter sp. SCSS HM007811

Enterobacter sp. TSE38 HM156134

Enterobacteriaceae bacterium 9 2 54FAA ADCU01000033

Enterobacteriaceae bacterium CFOlEnt l AJ489826

Enterobacteriaceae bacterium Smarlab 3302238 AY538694

Enterococcus avium AF133535

Enterococcus caccae AY943820

Enterococcus casseliflavus AEWTO 1000047 Enterococcus durans AJ276354

Enterococcus faecalis AE016830

Enterococcus faecium AM157434

Enterococcus gallinarum AB269767

Enterococcus gilvus AY033814

Enterococcus hawaiiensis AY321377

Enterococcus hirae AF061011

Enterococcus italicus AEPVO 1000109

Enterococcus mundtii R_024906

Enterococcus raffinosus FN600541

Enterococcus sp. BV2CASA2 JN809766

Enterococcus sp. CCRI 16620 GU457263

Enterococcus sp. F95 FJ463817

Enterococcus sp. R£L6 AJ133478

Enterococcus thailandicus AY321376

Eremococcus coleocola AENNO 1000008

Erysipelothrix inopinata R_025594

Erysipelothrix rhusiopathiae ACLK01000021

Erysipelothrix tonsillarum R_040871

Erysipelotrichaceae bacterium 3 1 53 ACTJ01000113

Erysipelotrichaceae bacterium 5 2 54FAA ACZW01000054

Escherichia albertii ABKXO 1000012

Escherichia coli NC_008563

Escherichia fergusonii CU928158

Escherichia hermannii HQ407266

Escherichia sp. 1 1 43 ACID01000033

Escherichia sp. 4 1 40B ACDM02000056

Escherichia sp. B4 EU722735

Escherichia vulneris R_041927

Ethanoligenens harbinense AY675965

Eubacteriaceae bacterium P4P 50 P4 AY207060

Eubacterium barkeri R_044661 Eubacterium biforme ABYTO 1000002

Eubacterium brachy U13038

Eubacterium budayi R_024682

Eubacterium callanderi R_026330

Eubacterium cellulosolvens AY178842

Eubacterium contortum FR749946

Eubacterium coprostanoligenes HM037995

Eubacterium cylindroides FP929041

Eubacterium desmolans R_044644

Eubacterium dolichum L34682

Eubacterium eligens CP001104

Eubacterium fissicatena FR749935

Eubacterium hadrum FR749933

Eubacterium hallii L34621

Eubacterium infirmum U13039

Eubacterium limosum CP002273

Eubacterium moniliforme HF558373

Eubacterium multiforme R_024683

Eubacterium nitritogenes R_024684

Eubacterium nodatum U13041

Eubacterium ramulus AJ011522

Eubacterium rectal e FP929042

Eubacterium ruminantium R_024661

Eubacterium saburreum AB525414

Eubacterium saphenum R_026031

Eubacterium siraeum ABCA03000054

Eubacterium sp. 3 1 31 ACTL01000045

Eubacterium sp. AS 15b HQ616364

Eubacterium sp. OBRC9 HQ616354

Eubacterium sp. oral clone GI038 AY349374

Eubacterium sp. oral clone IR009 AY349376

Eubacterium sp. oral clone JH012 AY349373 Eubacterium sp. oral clone JI012 AY349379

Eubacterium sp. oral clone JN088 AY349377

Eubacterium sp. oral clone JSOOl AY349378

Eubacterium sp. oral clone OH3A AY947497

Eubacterium sp. WAL 14571 FJ687606

Eubacterium tenue M59118

Eubacterium tortuosum R_044648

Eubacterium ventriosum L34421

Eubacterium xylanophilum L34628

Eubacterium yurii AEESO 1000073

Ewingella americana JN175329

Exiguobacterium acetylicum FJ970034

Facklamia hominis Y10772

Faecalibacterium prausnitzii ACOP02000011

Filifactor alocis CP002390

Filifactor villosus R_041928

Finegoldia magna ACHM02000001

Flavobacteriaceae genomosp. CI AY278614

Flavobacterium sp. F2_1 FJ195988

Flavonifractor plautii AY724678

Flexispira rappini AY126479

Flexistipes sinusarabici R_074881

Francisella novicida ABSS01000002

Francisella philomiragia AY928394

Francisella tularensis ABAZ01000082

Fulvimonas sp. ML 060897 EF589680

Fusobacterium canifelinum AY162222

Fusobacterium genomosp. CI AY278616

Fusobacterium genomosp. C2 AY278617

Fusobacterium gonidiaformans ACET01000043

Fusobacterium mortiferum ACDB02000034

Fusobacterium naviforme HQ223106 Fusobactenum necrogenes X55408

Fusobactenum necrophorum AM905356

Fusobactenum nucleatum ADVKO 1000034

Fusobacterium periodonticum ACJY01000002

Fusobacterium russii R_044687

Fusobacterium sp. 1 1 41FAA ADGG01000053

Fusobacterium sp. 11 3 2 ACUO01000052

Fusobacterium sp. 12 1B AGWJ01000070

Fusobacterium sp. 2 1 31 ACDC02000018

Fusobacterium sp. 3 1 27 ADGF01000045

Fusobacterium sp. 3 1 33 ACQE01000178

Fusobacterium sp. 3 1 36A2 ACPU01000044

Fusobacterium sp. 3_1_5R ACDD01000078

Fusobacterium sp. AC 18 HQ616357

Fusobacterium sp. ACB2 HQ616358

Fusobacterium sp. AS2 HQ616361

Fusobacterium sp. CM1 HQ616371

Fusobacterium sp. CM21 HQ616375

Fusobacterium sp. CM22 HQ616376

Fusobacterium sp. D12 ACDG02000036

Fusobacterium sp. oral clone ASCF06 AY923141

Fusobacterium sp. oral clone ASCFl l AY953256

Fusobacterium ulcerans ACDH01000090

Fusobacterium varium ACIE01000009

Gardnerella vaginalis CP001849

Gemella haemolysans ACDZ02000012

Gemella morbillorum R_025904

Gemella morbillorum ACRX01000010

Gemella sanguinis ACRY01000057

Gemella sp. oral clone ASCE02 AY923133

Gemella sp. oral clone ASCF04 AY923139

Gemella sp. oral clone ASCF12 AY923143 Gemella sp. WAL 1945 J EU427463

Gemmiger formicilis GU562446

Geobacillus kaustophilus R_074989

Geobacillus sp. E263 DQ647387

Geobacillus sp. WCH70 CP001638

Geobacillus stearothermophilus R_040794

Geobacillus thermocatenulatus R_043020

Geobacillus thermodenitrificans R_074976

Geobacillus thermoglucosidasius R_043022

Geobacillus thermoleovorans R_074931

Geobacter bemidjiensis CP001124

Gloeobacter violaceus R_074282

Gluconacetobacter azotocaptans R_028767

Gluconacetobacter diazotrophicus R_074292

Gluconacetobacter entanii R_028909

Gluconacetobacter europaeus R_026513

Gluconacetobacter hansenii R_026133

Gluconacetobacter j ohannae R_024959

Gluconacetobacter oboediens R_041295

Gluconacetobacter xylinus R_074338

Gordonia bronchialis R_027594

Gordonia polyisoprenivorans DQ385609

Gordonia sp. KTR9 DQ068383

Gordonia sputi FJ536304

Gordonia terrae GQ848239

Gordonibacter pamelaeae AM886059

Gordonibacter pamelaeae FP929047

Gracilibacter thermotolerans R_043559

Gramella forsetii R_074707

Granulicatella adiacens ACKZO 1000002

Granulicatella elegans AB252689

Granulicatella paradiacens AY879298 Granulicatella sp. M658 99 3 AJ271861

Granulicatella sp. oral clone ASC02 AY923126

Granulicatella sp. oral clone ASCA05 DQ341469

Granulicatella sp. oral clone ASCB09 AY953251

Granulicatella sp. oral clone ASCG05 AY923146

Grimontia hollisae ADAQO 1000013

Haematobacter sp. BC14248 GU396991

Haemophilus aegyptius AFBC01000053

Haemophilus ducreyi AE017143

Haemophilus genomosp. P2 oral clone MB3 C24 DQ003621

Haemophilus genomosp. P3 oral clone MB3 C38 DQ003635

Haemophilus haemolyticus JN175335

Haemophilus influenzae AADP01000001

Haemophilus parahaemolyticus GU561425

Haemophilus parainfluenzae AEWU01000024

Haemophilus paraphrophaemolyticus M75076

Haemophilus parasuis GU226366

Haemophilus somnus NC_008309

Haemophilus sp. 70334 HQ680854

Haemophilus sp. HK445 FJ685624

Haemophilus sp. oral clone ASCA07 AY923117

Haemophilus sp. oral clone ASCG06 AY923147

Haemophilus sp. oral clone BJ021 AY005034

Haemophilus sp. oral clone BJ095 AY005033

Haemophilus sp. oral clone JM053 AY349380

Haemophilus sp. oral taxon 851 AGRK01000004

Haemophilus sputorum AF K01000005

Hafnia alvei DQ412565

Halomonas elongata R_074782

Halomonas j ohnsoniae FR775979

Halorubrum lipolyticum AB477978

Helicobacter bilis ACDN01000023 Helicobacter canadensis ABQS01000108

Helicobacter cinaedi ABQTO 1000054

Helicobacter pullorum ABQU01000097

Helicobacter pylori CP000012

Helicobacter sp. None U44756

Helicobacter winghamensis ACDO01000013

Heliobacterium modesticaldum NR_074517

Herbaspirillum seropedicae CP002039

Herbaspirillum sp. JC206 JN657219

Histophilus somni AF549387

Holdemania filiformis Y11466

Hydrogenoanaerobacterium saccharovorans NR_044425

Hyperthermus butylicus CP000493

Hyphomicrobium sulfonivorans AY468372

Hyphomonas neptunium NR_074092

Ignatzschineria indica HQ823562

Ignatzschinena sp. NML 95_0260 HQ823559

Ignicoccus islandicus X99562

Inquilinus limosus NR_029046

Janibacter limosus NR_026362

Janibacter melonis EF063716

Janthinobacterium sp. SY12 EF455530

Johnsonella ignava X87152

Jonquetella anthropi ACOO02000004

Kerstersia gyiorum NR_025669

Kingella denitrificans AEWV01000047

Kingella genomosp. PI oral cone MB2 C20 DQ003616

Kingella kingae AFHS01000073

Kingella oralis ACJW02000005

Kingella sp. oral clone ID059 AY349381

Klebsiella oxytoca AY292871

Klebsiella pneumoniae CP000647 Klebsiella sp. AS 10 HQ616362

Klebsiella sp. Co9935 DQ068764

Klebsiella sp. enrichment culture clone SRC DSD25 HM195210

Klebsiella sp. OBRC7 HQ616353

Klebsiella sp. SP BA FJ999767

Klebsiella sp. SRC DSDl GU797254

Klebsiella sp. SRC DSDl l GU797263

Klebsiella sp. SRC DSD12 GU797264

Klebsiella sp. SRC DSD15 GU797267

Klebsiella sp. SRC DSD2 GU797253

Klebsiella sp. SRC DSD6 GU797258

Klebsiella variicola CP001891

Kluyvera ascorbata R_028677

Kluyvera cryocrescens R_028803

Kocuria marina GQ260086

Kocuria palustris EU333884

Kocuria rhizophila AY030315

Kocuria rosea X87756

Kocuria varians AF542074

Lachnobacterium bovis GU324407

Lachnospira multipara FR733699

Lachnospira pectinoschiza L14675

Lachnospiraceae bacterium 1 1 57FAA ACTMO 1000065

Lachnospiraceae bacterium 1 4 56FAA ACTN01000028

Lachnospiraceae bacterium 2 1 46FAA ADLB01000035

Lachnospiraceae bacterium 2 1 58FAA ACTO01000052

Lachnospiraceae bacterium 3_1_57FAA_CT1 ACTP01000124

Lachnospiraceae bacterium 4 1 37FAA ADCR01000030

Lachnospiraceae bacterium 5 1 57FAA ACTR01000020

Lachnospiraceae bacterium 5 1 63FAA ACTS01000081

Lachnospiraceae bacterium 6 1 63FAA ACTV01000014

Lachnospiraceae bacterium 8 1 57FAA ACWQ01000079 Lachnospiraceae bacterium 9 1 43BFAA ACTXO 1000023

Lachnospiraceae bacterium A4 DQ789118

Lachnospiraceae bacterium DJF VP30 EU728771

Lachnospiraceae bacterium ICM62 HQ616401

Lachnospiraceae bacterium MSX33 HQ616384

Lachnospiraceae bacterium oral taxon 107 ADDS01000069

Lachnospiraceae bacterium oral taxon F15 HM099641

Lachnospiraceae genomosp. CI AY278618

Lactobacillus acidipiscis R_024718

Lactobacillus acidophilus CP000033

Lactobacillus alimentarius R_044701

Lactobacillus amylolyticus ADNY01000006

Lactobacillus amylovorus CP002338

Lactobacillus antri ACLL01000037

Lactobacillus brevis EU194349

Lactobacillus buchneri ACGH01000101

Lactobacillus casei CP000423

Lactobacillus catenaformis M23729

Lactobacillus coleohominis ACOH01000030

Lactobacillus coryniformis R_044705

Lactobacillus crispatus ACOG01000151

Lactobacillus curvatus R_042437

Lactobacillus delbrueckii CP002341

Lactobacillus dextrinicus R_036861

Lactobacillus farciminis R_044707

Lactobacillus fermentum CP002033

Lactobacillus gasseri ACOZ01000018

Lactobacillus gastricus AICN01000060

Lactobacillus genomosp. CI AY278619

Lactobacillus genomosp. C2 AY278620

Lactobacillus helveticus ACLM01000202

Lactobacillus hilgardii ACGP01000200 Lactobacillus hominis FR681902

Lactobacillus iners AEKJO 1000002

Lactobacillus j ensenii ACQD01000066

Lactobacillus j ohnsonii AE017198

Lactobacillus kalixensis R_029083

Lactobacillus kefiranofaciens R_042440

Lactobacillus kefiri R_042230

Lactobacillus kimchii R_025045

Lactobacillus leichmannii JX986966

Lactobacillus mucosae FR693800

Lactobacillus murinus R_042231

Lactobacillus nodensis R_041629

Lactobacillus oeni R_043095

Lactobacillus oris AEKL01000077

Lactobacillus parabrevis R_042456

Lactobacillus parabuchneri R_041294

Lactobacillus paracasei ABQV01000067

Lactobacillus parakefiri R_029039

Lactobacillus pentosus JN813103

Lactobacillus perolens R_029360

Lactobacillus plantarum ACGZ02000033

Lactobacillus pontis HM218420

Lactobacillus reuteri ACGW02000012

Lactobacillus rhamnosus ABWJ01000068

Lactobacillus rogosae GU269544

Lactobacillus ruminis ACGS02000043

Lactobacillus sakei DQ989236

Lactobacillus salivarius AEBA01000145

Lactobacillus saniviri AB602569

Lactobacillus senioris AB602570

Lactobacillus sp. 66c FR681900

Lactobacillus sp. BT6 HQ616370 Lactobacillus sp. KLDS 1.0701 EU600905

Lactobacillus sp. KLDS 1.0702 EU600906

Lactobacillus sp. KLDS 1.0703 EU600907

Lactobacillus sp. KLDS 1.0704 EU600908

Lactobacillus sp. KLDS 1.0705 EU600909

Lactobacillus sp. KLDS 1.0707 EU600911

Lactobacillus sp. KLDS 1.0709 EU600913

Lactobacillus sp. KLDS 1.0711 EU600915

Lactobacillus sp. KLDS 1.0712 EU600916

Lactobacillus sp. KLDS 1.0713 EU600917

Lactobacillus sp. KLDS 1.0716 EU600921

Lactobacillus sp. KLDS 1.0718 EU600922

Lactobacillus sp. KLDS 1.0719 EU600923

Lactobacillus sp. oral clone HT002 AY349382

Lactobacillus sp. oral clone HT070 AY349383

Lactobacillus sp. oral taxon 052 GQ422710

Lactobacillus tucceti R_042194

Lactobacillus ultunensis ACGU01000081

Lactobacillus vaginalis ACGV01000168

Lactobacillus vini R_042196

Lactobacillus vitulinus R_041305

Lactobacillus zeae R_037122

Lactococcus garvieae AF061005

Lactococcus lactis CP002365

Lactococcus raffinolactis R_044359

Lactonifactor longoviformis DQ 100449

Lanbacter hongkongensis CP001154

Lautropia mirabilis AEQPO 1000026

Lautropia sp. oral clone AP009 AY005030

Legionella hackeliae M36028

Legionella longbeachae M36029

Legionella pneumophila NC_002942 Legionella sp. D3923 JN380999

Legionella sp. D4088 JN381012

Legionella sp. H63 JF831047

Legionella sp. ML 93L054 GU062706

Legionella steelei HQ398202

Leminorella grimontii AJ233421

Leminorella richardii HF558368

Leptospira borgpetersenii NC_008508

Leptospira broomii R_043200

Leptospira interrogans NC_005823

Leptospira licerasiae EF612284

Leptotnchia buccalis CP001685

Leptotnchia genomosp. CI AY278621

Leptotrichia goodfellowii ADAD01000110

Leptotnchia hofstadii ACVB02000032

Leptotrichia shahii AY029806

Leptotrichia sp. neutropenicPatient AF 189244

Leptotrichia sp. oral clone GT018 AY349384

Leptotrichia sp. oral clone GT020 AY349385

Leptotrichia sp. oral clone HE012 AY349386

Leptotrichia sp. oral clone IK040 AY349387

Leptotrichia sp. oral clone P2PB 51 PI AY207053

Leptotrichia sp. oral taxon 223 GU408547

Leuconostoc carnosum R_040811

Leuconostoc citreum AMI 57444

Leuconostoc gasicomitatum FN822744

Leuconostoc inhae R_025204

Leuconostoc kimchii R_075014

Leuconostoc lactis R_040823

Leuconostoc mesenteroides ACKV01000113

Leuconostoc pseudomesenteroides R_040814

Listeria grayi ACCR02000003 Listeria innocua JF967625

Listeria ivanovii X56151

Listeria monocytogenes CP002003

Listeria welshimeri AM263198

Luteococcus sanguinis R_025507

Lutispora thermophila R_041236

Lysinibacillus fusiformis FN397522

Lysinibacillus sphaericus R_074883

Macrococcus caseolyticus R_074941

Mannheimia haemolytica ACZXO 1000102

Marvinbryantia formatexigens AJ505973

Massilia sp. CCUG 43427A FR773700

Megamonas funiformis AB300988

Megamonas hypermegale AJ420107

Megasphaera elsdenii AY038996

Megasphaera genomosp. CI AY278622

Megasphaera genomosp. type l ADGP01000010

Megasphaera micronuciformis AECS01000020

Megasphaera sp. BLPYG 07 HM990964

Megasphaera sp. UPII 199 6 AFIJ01000040

Metallosphaera sedula D26491

Methanobactenum formicicum R_025028

Methanobrevibacter acididurans R_028779

Methanobrevibacter arboriphilus R_042783

Methanobrevibacter curvatus R_044796

Methanobrevibacter cuticularis R_044776

Methanobrevibacter filiformis R_044801

Methanobrevibacter gottschalkii R_044789

Methanobrevibacter millerae R_042785

Methanobrevibacter olleyae R_043024

Methanobrevibacter oralis HE654003

Methanobrevibacter ruminantium R_042784 Methanobrevibacter smithii ABYV02000002

Methanobrevibacter thaueri R_044787

Methanobrevibacter woesei R_044788

Methanobrevibacter wolinii R_044790

Methanosphaera stadtmanae AY196684

Methyl obacterium extorquens NC_010172

Methyl obacterium podarium AY468363

Methyl obacterium radiotolerans GU294320

Methyl obacterium sp. lsub AY468371

Methyl obacterium sp. MM4 AY468370

Methylocella silvestris R_074237

Methylophilus sp. ECd5 AY436794

Microbacterium chocolatum R_037045

Microbactenum flavescens EU714363

Microbacterium gubbeenense R_025098

Microbacterium lacticum EU714351

Microbacterium oleivorans EU714381

Microbacterium oxydans EU714348

Microbacterium paraoxydans AJ491806

Microbacterium phyllosphaerae EU714359

Microbacterium schleiferi R_044936

Microbacterium sp. 768 EU714378

Microbacterium sp. oral strain C24KA AF287752

Microbacterium testaceum EU714365

Micrococcus antarcticus R_025285

Micrococcus luteus R_075062

Micrococcus lylae R_026200

Micrococcus sp. 185 EU714334

Microcystis aeruginosa NC_010296

Mitsuokella j alaludinii R_028840

Mitsuokella multacida ABWK02000005

Mitsuokella sp. oral taxon 521 GU413658 Mitsuokella sp. oral taxon G68 GU432166

Mobiluncus curtisii AEPZO 1000013

Mobiluncus mulieris ACKW01000035

Moellerella wisconsensis JN175344

Mogibacterium diver sum R_027191

Mogibacterium neglectum R_027203

Mogibacterium pumilum R_028608

Mogibacterium timidum Z36296

Mollicutes bacterium pACH93 AY297808

Moorella thermoacetica R_075001

Moraxella catarrhalis CP002005

Moraxella lincolnii FR822735

Moraxella osloensis JN175341

Moraxella sp. 16285 JF682466

Moraxella sp. GM2 JF837191

Morganella morganii AJ301681

Morganella sp. JB T16 AJ781005

Morococcus cerebrosus JN175352

Moryella indoligenes AF527773

Mycobacterium abscessus AGQU01000002

Mycobacterium africanum AF480605

Mycobacterium alsiensis AJ938169

Mycobacterium avium CP000479

Mycobacterium chelonae AB548610

Mycobacterium colombiense AM062764

Mycobacterium elephantis AF385898

Mycobacterium gordonae GU142930

Mycobacterium intracellulare GQ153276

Mycobacterium kansasii AF480601

Mycobacterium lacus R_025175

Mycobacterium leprae FM211192

Mycobacterium lepromatosis EU203590 Mycobacterium mageritense FR798914

Mycobacterium mantenii FJ042897

Mycobacterium marinum NC_010612

Mycobacterium microti R_025234

Mycobacterium neoaurum AF268445

Mycobacterium parascrofulaceum ADNVO 1000350

Mycobacterium paraterrae EU919229

Mycobacterium phlei GU142920

Mycobacterium seoulense DQ536403

Mycobacterium smegmatis CP000480

Mycobacterium sp. 1761 EU703150

Mycobacterium sp. 1776 EU703152

Mycobacterium sp. 1781 EU703147

Mycobacterium sp. 1791 EU703148

Mycobacterium sp. 1797 EU703149

Mycobacterium sp. AQ1GA4 HM210417

Mycobacterium sp. B 10_07.09.0206 HQ 174245

Mycobacterium sp. GN_10546 FJ497243

Mycobacterium sp. GN_10827 FJ497247

Mycobacterium sp. GN_11124 FJ652846

Mycobacterium sp. GN_9188 FJ497240

Mycobacterium sp. GR_2007_210 FJ555538

Mycobacterium sp. HE5 AJ012738

Mycobacterium sp. LA001000736 HM627011

Mycobacterium sp. W DQ437715

Mycobacterium tuberculosis CP001658

Mycobacterium ulcerans AB548725

Mycobacterium vulneris EU834055

Mycoplasma agalactiae AFO 10477

Mycoplasma amphoriforme AY531656

Mycoplasma arthritidis NC_011025

Mycoplasma bovoculi R_025987 Mycoplasma faucium NR_024983

Mycoplasma fermentans CP002458

Mycoplasma flocculare X62699

Mycoplasma genitalium L43967

Mycoplasma hominis AF443616

Mycoplasma orale AY796060

Mycoplasma ovipneumoniae NR_025989

Mycoplasma penetrans NC_004432

Mycoplasma pneumoniae NC_000912

Mycoplasma putrefaciens U26055

Mycoplasma salivarium M24661

Mycoplasmataceae genomosp. PI oral clone

DQ003614 MB 1 G23

Myroides odoratimimus NR_042354

Myroides sp. MY15 GU253339

Neisseria bacilliformis AFAYO 1000058

Neisseria cinerea ACDY01000037

Neisseria elongata ADBF01000003

Neisseria flavescens ACQV01000025

Neisseria genomosp. P2 oral clone MB5 PI 5 DQ003630

Neisseria gonorrhoeae CP002440

Neisseria lactamica ACEQ01000095

Neisseria macacae AFQE01000146

Neisseria meningitidis NC_003112

Neisseria mucosa ACDX01000110

Neisseria pharyngis AJ239281

Neisseria polysaccharea ADBE01000137

Neisseria sicca ACKO02000016

Neisseria sp. KEM232 GQ203291

Neisseria sp. oral clone API 32 AY005027

Neisseria sp. oral clone JC012 AY349388

Neisseria sp. oral strain B33KA AY005028 Neisseria sp. oral taxon 014 ADEAO 1000039

Neisseria sp. SMC_A9199 FJ763637

Neisseria sp. TM10_1 DQ279352

Neisseria subflava ACEO01000067

Neorickettsia risticii CP001431

Neorickettsia sennetsu NC_007798

Nocardia brasiliensis AfflVO 1000038

Nocardia cyriacigeorgica HQ009486

Nocardia farcinica NC_006361

Nocardia puris NR_028994

Nocardia sp. 01_Je_025 GU574059

Nocardiopsis dassonvillei CP002041

Novosphingobium aromaticivorans AAAV03000008

Oceanobacillus caeni NR_041533

Oceanobacillus sp. Ndiop CAER01000083

Ochrobactrum anthropi NC_009667

Ochrobactrum intermedium ACQ AO 1000001

Ochrobactrum pseudintermedium DQ365921

Odoribacter laneus AB490805

Odoribacter splanchnicus CP002544

Okadaella gastrococcus HQ699465

Oligella ureolytica NR_041998

Oligella urethralis NR_041753

Olsenella genomosp. CI AY278623

Olsenella profusa FN178466

Olsenella sp. F0004 EU592964

Olsenella sp. oral taxon 809 ACVE01000002

Olsenella uli CP002106

Opitutus terrae NR_074978

Oribacterium sinus ACKX01000142

Oribacterium sp. ACB1 HM120210

Oribacterium sp. ACB7 HM120211 Oribacterium sp. CM 12 HQ616374

Oribacterium sp. ICM51 HQ616397

Oribacterium sp. OBRC12 HQ616355

Oribacterium sp. oral taxon 078 ACIQ02000009

Oribacterium sp. oral taxon 102 GQ422713

Oribacterium sp. oral taxon 108 AFIH01000001

Orientia tsutsugamushi AP008981

Ornithinibacillus bavariensis R_044923

Ornithinibacillus sp. 7 10AIA FN397526

Oscillibacter sp. G2 HM626173

Oscillibacter valericigenes R_074793

Oscillospira guilliermondii AB040495

Oxalobacter formigenes ACDQ01000020

Paenibacillus barcinonensis R_042272

Paenibacillus barengoltzii R_042756

Paenibacillus chibensis R_040885

Paenibacillus cookii R_025372

Paenibacillus durus R_037017

Paenibacillus glucanolyticus D78470

Paenibacillus lactis R_025739

Paenibacillus lautus R_040882

Paenibacillus pabuli R_040853

Paenibacillus polymyxa R_037006

Paenibacillus popilliae R_040888

Paenibacillus sp. CIP 101062 HM212646

Paenibacillus sp. HGF5 AEXS01000095

Paenibacillus sp. HGF7 AFDHO 1000147

Paenibacillus sp. JC66 JF824808

Paenibacillus sp. oral taxon F45 HM099647

Paenibacillus sp. R 27413 HE586333

Paenibacillus sp. R_27422 HE586338

Paenibacillus timonensis R_042844 Pantoea agglomerans AY335552

Pantoea ananatis CP001875

Pantoea brenneri EU216735

Pantoea citrea EF688008

Pantoea conspicua EU216737

Pantoea septica EU216734

Papillibacter cinnamivorans R_025025

Parabacteroides distasonis CP000140

Parabacteroides goldsteinii AY974070

Parabacteroides gordonii AB470344

Parabacteroides j ohnsonii ABYH01000014

Parabacteroides merdae EU136685

Parabacteroides sp. D13 ACPWO 1000017

Parabacteroides sp. NS31_3 JN029805

Parachlamydia sp. UWE25 BX908798

Paracoccus denitrificans CP000490

Paracoccus marcusii R_044922

Paraprevotella clara AFFY01000068

Paraprevotella xylaniphila AFBR01000011

Parascardovia denticolens ADEB01000020

Parasutterella excrementihominis AFBP01000029

Parasutterella secunda AB491209

Parvimonas micra AB729072

Parvimonas sp. oral taxon 110 AFII01000002

Pasteurella bettyae L06088

Pasteurella dagmatis ACZR01000003

Pasteurella multocida NC_002663

Pediococcus acidilactici ACXB01000026

Pediococcus pentosaceus R_075052

Peptococcus niger R_029221

Peptococcus sp. oral clone JM048 AY349389

Peptococcus sp. oral taxon 167 GQ422727 Peptoniphilus asaccharolyticus D14145

Peptoniphilus duerdenii EU526290

Peptoniphilus harei NR_026358

Peptoniphilus indolicus AY153431

Peptoniphilus ivorii Y07840

Peptoniphilus lacrimalis ADDO01000050

Peptoniphilus sp. gpac007 AM176517

Peptoniphilus sp. gpac018A AM176519

Peptoniphilus sp. gpac077 AM176527

Peptoniphilus sp. gpacl48 AM176535

Peptoniphilus sp. JC140 JF824803

Peptoniphilus sp. oral taxon 386 ADCS01000031

Peptoniphilus sp. oral taxon 836 AEAA01000090

Peptostreptococcaceae bacterium phi JN837495

Peptostreptococcus anaerobius AY326462

Peptostreptococcus micros AM176538

Peptostreptococcus sp. 9succl X90471

Peptostreptococcus sp. oral clone AP24 AB175072

Peptostreptococcus sp. oral clone FJ023 AY349390

Peptostreptococcus sp. P4P 31 P3 AY207059

Peptostreptococcus stomatis ADGQ01000048

Phascolarctobacterium faecium NR_026111

Phascolarctobacterium sp. YIT 12068 AB490812

Phascolarctobacterium succinatutens AB490811

Phenyl obacterium zucineum AY628697

Photorhabdus asymbiotica Z76752

Pigmentiphaga daeguensis JN585327

Planomicrobium koreense NR_025011

Plesiomonas shigelloides X60418

Porphyromonadaceae bacterium NML 060648 EF 184292

Porphyromonas asaccharolytica AENO01000048

Porphyromonas endodontalis ACNN01000021 Porphyron! onas gingivalis AE015924

Porphyromonas levii R_025907

Porphyromonas macacae R_025908

Porphyromonas somerae AB547667

Porphyromonas sp. oral clone BB134 AY005068

Porphyromonas sp. oral clone F016 AY005069

Porphyromonas sp. oral clone P2PB 52 PI AY207054

Porphyromonas sp. oral clone P4GB 100 P2 AY207057

Porphyromonas sp. UQD 301 EU012301

Porphyromonas uenonis ACLR01000152

Prevotella albensis R_025300

Prevotella amnii AB547670

Prevotella bergensis ACKS01000100

Prevotella bivia ADFO01000096

Prevotella brevis R_041954

Prevotella buccae ACRB01000001

Prevotella buccalis JN867261

Prevotella copri ACBX02000014

Prevotella corporis L16465

Prevotella dentalis AB547678

Prevotella denticola CP002589

Prevotella disiens AEDO01000026

Prevotella genomosp. CI AY278624

Prevotella genomosp. C2 AY278625

Prevotella genomosp. P7 oral clone MB2 P31 DQ003620

Prevotella genomosp. P8 oral clone MB3 P13 DQ003622

Prevotella genomosp. P9 oral clone MB7 G16 DQ003633

Prevotella heparinolytica GQ422742

Prevotella histicola JN867315

Prevotella intermedia AF414829

Prevotella loescheii JN867231

Prevotella maculosa AGEK01000035 Prevotella marshii AEEIO 1000070

Prevotella melaninogenica CP002122

Prevotella micans AGWK01000061

Prevotella multiformis AEWX01000054

Prevotella multisaccharivorax AFJEO 1000016

Prevotella nanceiensis JN867228

Prevotella nigrescens AFPXO 1000069

Prevotella oralis AEPE01000021

Prevotella oris ADDV01000091

Prevotella oulorum LI 6472

Prevotella pallens AFP Y01000135

Prevotella ruminicola CP002006

Prevotella salivae AB108826

Prevotella sp. BI 42 AJ581354

Prevotella sp. CM38 HQ610181

Prevotella sp. ICM1 HQ616385

Prevotella sp. ICM55 HQ616399

Prevotella sp. JCM 6330 AB547699

Prevotella sp. oral clone AA020 AY005057

Prevotella sp. oral clone ASCGIO AY923148

Prevotella sp. oral clone ASCG12 DQ272511

Prevotella sp. oral clone AU069 AY005062

Prevotella sp. oral clone CY006 AY005063

Prevotella sp. oral clone DA058 AY005065

Prevotella sp. oral clone FLO 19 AY349392

Prevotella sp. oral clone FU048 AY349393

Prevotella sp. oral clone FW035 AY349394

Prevotella sp. oral clone GI030 AY349395

Prevotella sp. oral clone GI032 AY349396

Prevotella sp. oral clone GI059 AY349397

Prevotella sp. oral clone GU027 AY349398

Prevotella sp. oral clone FIF050 AY349399 Prevotella sp. oral clone ID019 AY349400

Prevotella sp. oral clone IDR CEC 0055 AY550997

Prevotella sp. oral clone IK053 AY349401

Prevotella sp. oral clone IK062 AY349402

Prevotella sp. oral clone P4PB 83 P2 AY207050

Prevotella sp. oral taxon 292 GQ422735

Prevotella sp. oral taxon 299 ACWZ01000026

Prevotella sp. oral taxon 300 GU409549

Prevotella sp. oral taxon 302 ACZK01000043

Prevotella sp. oral taxon 310 GQ422737

Prevotella sp. oral taxon 317 ACQH01000158

Prevotella sp. oral taxon 472 ACZ SO 1000106

Prevotella sp. oral taxon 781 GQ422744

Prevotella sp. oral taxon 782 GQ422745

Prevotella sp. oral taxon F68 HM099652

Prevotella sp. oral taxon G60 GU432133

Prevotella sp. oral taxon G70 GU432179

Prevotella sp. oral taxon G71 GU432180

Prevotella sp. SEQ053 JN867222

Prevotella sp. SEQ065 JN867234

Prevotella sp. SEQ072 JN867238

Prevotella sp. SEQ116 JN867246

Prevotella sp. SG12 GU561343

Prevotella sp. sp24 AB003384

Prevotella sp. sp34 AB003385

Prevotella stercorea AB244774

Prevotella tannerae ACIJ02000018

Prevotella timonensis ADEF01000012

Prevotella veroralis ACVA01000027

Prevotellaceae bacterium P4P 62 PI AY207061

Prochlorococcus marinus CP000551

Propionibacteriaceae bacterium NML 02 0265 EF599122 Propi onib acterium aci dipropi oni ci NC_019395

Propionibacterium acnes ADJMO 1000010

Propionibacterium avidum AJ003055

Propionibacterium freudenreichii R_036972

Propionibacterium granulosum FJ785716

Propionibacterium j ensenii R_042269

Propionibacterium propionicum R_025277

Propionibacterium sp. 434 HC2 AFIL01000035

Propionibacterium sp. H456 AB 177643

Propionibacterium sp. LG AY354921

Propionibacterium sp. oral taxon 192 GQ422728

Propionibacterium sp. S555a AB264622

Propionibacterium thoenii R_042270

Proteus mirabilis ACLE01000013

Proteus penneri ABVPO 1000020

Proteus sp. HS7514 DQ512963

Proteus vulgaris AJ233425

Providencia alcalifaciens ABXWO 1000071

Providencia rettgeri AM040492

Providencia rustigianii AM040489

Providencia stuartii AF008581

Pseudoclavibacter sp. Timone FJ375951

Pseudoflavonifractor capillosus AY136666

Pseudomonas aeruginosa AABQ07000001

Pseudomonas fluorescens AY622220

Pseudomonas gessardii FJ943496

Pseudomonas mendocina AAUL01000021

Pseudomonas monteilii R_024910

Pseudomonas poae GUI 88951

Pseudomonas pseudoalcaligenes R_037000

Pseudomonas putida AF094741

Pseudomonas sp. 2 1 26 ACWU01000257 Pseudomonas sp. G1229 DQ910482

Pseudomonas sp. P522b EU723211

Pseudomonas stutzeri AM905854

Pseudomonas tolaasii AF320988

Pseudomonas viridiflava R_042764

Pseudoramibacter alactolyticus AB036759

Psychrobacter arcticus CP000082

Psychrobacter cibarius HQ698586

Psychrobacter cryohalolentis CP000323

Psychrobacter faecalis HQ698566

Psychrobacter nivimaris HQ698587

Psychrobacter pulmonis HQ698582

Psychrobacter sp. 13983 HM212668

Py rami dob acter piscolens AY207056

Ralstonia pickettii NC_010682

Ralstonia sp. 5_7_47FAA ACUFO 1000076

Raoultella ornithinolytica AB364958

Raoultella planticola AF 129443

Raoultella terrigena R_037085

Rhodobacter sp. oral taxon C30 HM099648

Rhodobacter sphaeroides CP000144

Rhodococcus corynebactenoides X80615

Rhodococcus equi ADNW01000058

Rhodococcus erythropolis ACNO01000030

Rhodococcus fascians R_037021

Rhodopseudomonas palustris CP000301

Rickettsia akari CP000847

Rickettsia conorii AE008647

Rickettsia prowazekii M21789

Rickettsia rickettsii NC_010263

Rickettsia slovaca L36224

Rickettsia typhi AE017197 Robinsoniella peoriensis AF445258

Roseburia cecicola GU233441

Roseburia faecalis AY804149

Roseburia faecis AY305310

Roseburia hominis AJ270482

Roseburia intestinalis FP929050

Roseburia inulinivorans AJ270473

Roseburia sp. 11 SE37 FM954975

Roseburia sp. 11 SE38 FM954976

Roseiflexus castenholzii CP000804

Roseomonas cervicalis ADVL01000363

Roseomonas mucosa R_028857

Roseomonas sp. ML94_0193 AF533357

Roseomonas sp. ML97_0121 AF533359

Roseomonas sp. ML98_0009 AF533358

Roseomonas sp. ML98_0157 AF533360

Rothia aeria DQ673320

Rothia dentocariosa ADDWO 1000024

Rothia mucilaginosa ACVO01000020

Rothia nasimurium R_025310

Rothia sp. oral taxon 188 GU470892

Ruminobacter amylophilus R_026450

Ruminococcaceae bacterium D16 ADDX01000083

Ruminococcus albus AY445600

Ruminococcus bromii EU266549

Ruminococcus callidus R_029160

Ruminococcus champanellensis FP929052

Ruminococcus flavefaciens R_025931

Ruminococcus gnavus X94967

Ruminococcus hansenii M59114

Ruminococcus lactaris ABOU02000049

Ruminococcus obeum AY169419 Ruminococcus sp. 18P13 AJ515913

Ruminococcus sp. 5 1 39BFAA ACIIO 1000172

Ruminococcus sp. 9SE51 FM954974

Ruminococcus sp. ID8 AY960564

Ruminococcus sp. K_l AB222208

Ruminococcus torques AAVP02000002

Saccharomonospora viridis X54286

Salmonella bongori R_041699

Salmonella enterica NC_011149

Salmonella enterica NC_011205

Salmonella enterica DQ344532

Salmonella enterica ABEH02000004

Salmonella enterica ABAK02000001

Salmonella enterica NC_011080

Salmonella enterica EU118094

Salmonella enterica NC_011094

Salmonella enterica AE014613

Salmonella enterica ABFH02000001

Salmonella enterica ABEMO 1000001

Salmonella enterica ABAM02000001

Salmonella typhimurium DQ344533

Salmonella typhimurium AF170176

Sarcina ventriculi R_026146

Scardovia inopinata AB029087

Scardovia wiggsiae AY278626

Segniliparus rotundus CP001958

Segniliparus rugosus ACZIO 1000025

Selenomonas artemidis HM596274

Selenomonas dianae GQ422719

Selenomonas flueggei AF287803

Selenomonas genomosp. CI AY278627

Selenomonas genomosp. C2 AY278628 Selenomonas genomosp. P5 AY341820

Selenomonas genomosp. P6 oral clone MB3 C41 DQ003636

Selenomonas genomosp. P7 oral clone MB5 C08 DQ003627

Selenomonas genomosp. P8 oral clone MB5 P06 DQ003628

Selenomonas infelix AF287802

Selenomonas noxia GU470909

Selenomonas ruminantium R_075026

Selenomonas sp. FOBRC9 HQ616378

Selenomonas sp. oral clone FT050 AY349403

Selenomonas sp. oral clone GI064 AY349404

Selenomonas sp. oral clone GTOIO AY349405

Selenomonas sp. oral clone HU051 AY349406

Selenomonas sp. oral clone IK004 AY349407

Selenomonas sp. oral clone IQ048 AY349408

Selenomonas sp. oral clone JI021 AY349409

Selenomonas sp. oral clone JS031 AY349410

Selenomonas sp. oral clone OH4A AY947498

Selenomonas sp. oral clone P2PA 80 P4 AY207052

Selenomonas sp. oral taxon 137 AENVO 1000007

Selenomonas sp. oral taxon 149 AEEJ01000007

Selenomonas sputigena ACKP02000033

Serratia fonticola R_025339

Serratia liquefaciens R_042062

Serratia marcescens GU826157

Serratia odorifera ADBY01000001

Serratia proteamaculans AAUN01000015

Shewanella putrefaciens CP002457

Shigella boydii AAKA01000007

Shigella dysenteriae NC_007606

Shigella flexneri AE005674

Shigella sonnei NC_007384

Shuttleworthia satelles ACIP02000004 Shuttleworthia sp. MSX8B HQ616383

Shuttleworthia sp. oral taxon G69 GU432167

Simonsiella muelleri ADCYO 1000105

Slackia equolifaciens EU377663

Slackia exigua ACUX01000029

Slackia faecicanis NR_042220

Slackia heliotrinireducens NR_074439

Slackia isoflavomconvertens AB566418

Slackia piriformis AB490806

Slackia sp. NATTS AB505075

Solobacterium moorei AECQ01000039

Sphingobacterium faecium NR_025537

Sphingobacterium mizutaii JF708889

Sphingobacterium multivorum NR_040953

Sphingobacterium spiritivorum ACHA02000013

Sphingomonas echinoides NR_024700

Sphingomonas sp. oral clone FI012 AY349411

Sphingomonas sp. oral clone FZ016 AY349412

Sphingomonas sp. oral taxon A09 HM099639

Sphingomonas sp. oral taxon F71 HM099645

Sphingopyxis alaskensis CP000356

Spiroplasma insolitum NR_025705

Sporobacter termitidis NR_044972

Sporolactobacillus inulinus NR_040962

Sporolactobacillus nakayamae NR_042247

Sporosarcina newyorkensis AFPZ01000142

Sporosarcina sp. 2681 GU994081

Staphylococcaceae bacterium NML 92_0017 AY841362

Staphylococcus aureus CP002643

Staphylococcus auricularis JQ624774

Staphylococcus capitis ACFR01000029

Staphylococcus caprae ACRH01000033 Staphylococcus carnosus R_075003

Staphylococcus cohnii JN175375

Staphylococcus condimenti R_029345

Staphylococcus epidermidis ACHEO 1000056

Staphylococcus equorum R_027520

Staphylococcus fleurettii R_041326

Staphylococcus haemolyticus NC_007168

Staphylococcus hominis AM157418

Staphylococcus lugdunensis AEQA01000024

Staphylococcus pasteuri FJ189773

Staphylococcus pseudintermedius CP002439

Staphylococcus saccharolyticus R_029158

Staphylococcus saprophyticus NC_007350

Staphylococcus sciuri R_025520

Staphylococcus sp. clone bottae7 AF467424

Staphylococcus sp. H292 AB 177642

Staphylococcus sp. H780 AB 177644

Staphylococcus succinus R_028667

Staphylococcus vitulinus R_024670

Staphylococcus warneri ACPZ01000009

Staphylococcus xylosus AY395016

Stenotrophomonas maltophilia AAVZ01000005

Stenotrophomonas sp. FG_6 EF017810

Streptobacillus moniliformis R_027615

Streptococcus agalactiae AAJO01000130

Streptococcus alactolyticus R_041781

Streptococcus anginosus AECT01000011

Streptococcus australis AEQR01000024

Streptococcus bovis AEEL01000030

Streptococcus canis AJ413203

Streptococcus constellatus AY277942

Streptococcus cri status AEVC01000028 Streptococcus downei AEKNO 1000002

Streptococcus dysgalactiae AP010935

Streptococcus equi CP001129

Streptococcus equinus AEVB01000043

Streptococcus gallolyticus FR824043

Streptococcus genomosp. CI AY278629

Streptococcus genomosp. C2 AY278630

Streptococcus genomosp. C3 AY278631

Streptococcus genomosp. C4 AY278632

Streptococcus genomosp. C5 AY278633

Streptococcus genomosp. C6 AY278634

Streptococcus genomosp. C7 AY278635

Streptococcus genomosp. C8 AY278609

Streptococcus gordonii NC_009785

Streptococcus infantarius ABJK02000017

Streptococcus infantis AFNN01000024

Streptococcus intermedius R_028736

Streptococcus lutetiensis R_037096

Streptococcus massiliensis AY769997

Streptococcus milleri X81023

Streptococcus mitis AMI 57420

Streptococcus mutans AP010655

Streptococcus oligofermentans AY099095

Streptococcus oralis ADMV01000001

Streptococcus parasanguinis AEKM01000012

Streptococcus pasteurianus AP012054

Streptococcus peroris AEVF01000016

Streptococcus pneumoniae AE008537

Streptococcus porcinus EF121439

Streptococcus pseudopneumoniae FJ827123

Streptococcus pseudoporcinus AENS01000003

Streptococcus pyogenes AE006496 Streptococcus ratti X58304

Streptococcus salivarius AGBVO 1000001

Streptococcus sanguinis R_074974

Streptococcus sinensis AF432857

Streptococcus sp. 16362 JN590019

Streptococcus sp. 2_1_36FAA ACOI01000028

Streptococcus sp. 2285_97 AJ131965

Streptococcus sp. 69130 X78825

Streptococcus sp. AC 15 HQ616356

Streptococcus sp. ACS2 HQ616360

Streptococcus sp. AS20 HQ616366

Streptococcus sp. BS35a HQ616369

Streptococcus sp. CI 50 ACRI01000045

Streptococcus sp. CM6 HQ616372

Streptococcus sp. CM7 HQ616373

Streptococcus sp. ICM10 HQ616389

Streptococcus sp. ICM12 HQ616390

Streptococcus sp. ICM2 HQ616386

Streptococcus sp. ICM4 HQ616387

Streptococcus sp. ICM45 HQ616394

Streptococcus sp. Ml 43 ACRK01000025

Streptococcus sp. M334 ACRL01000052

Streptococcus sp. OBRC6 HQ616352

Streptococcus sp. oral clone ASB02 AY923121

Streptococcus sp. oral clone ASCA03 DQ272504

Streptococcus sp. oral clone ASCA04 AY923116

Streptococcus sp. oral clone ASCA09 AY923119

Streptococcus sp. oral clone ASCB04 AY923123

Streptococcus sp. oral clone ASCB06 AY923124

Streptococcus sp. oral clone ASCC04 AY923127

Streptococcus sp. oral clone ASCC05 AY923128

Streptococcus sp. oral clone ASCC12 DQ272507 Streptococcus sp. oral clone ASCDOl AY923129

Streptococcus sp. oral clone ASCD09 AY923130

Streptococcus sp. oral clone ASCD10 DQ272509

Streptococcus sp. oral clone ASCE03 AY923134

Streptococcus sp. oral clone ASCE04 AY953253

Streptococcus sp. oral clone ASCE05 DQ272510

Streptococcus sp. oral clone ASCE06 AY923135

Streptococcus sp. oral clone ASCE09 AY923136

Streptococcus sp. oral clone ASCE10 AY923137

Streptococcus sp. oral clone ASCE12 AY923138

Streptococcus sp. oral clone ASCF05 AY923140

Streptococcus sp. oral clone ASCF07 AY953255

Streptococcus sp. oral clone ASCF09 AY923142

Streptococcus sp. oral clone ASCG04 AY923145

Streptococcus sp. oral clone BW009 AY005042

Streptococcus sp. oral clone CHOI 6 AY005044

Streptococcus sp. oral clone GK051 AY349413

Streptococcus sp. oral clone GM006 AY349414

Streptococcus sp. oral clone P2PA 41 P2 AY207051

Streptococcus sp. oral clone P4PA 30 P4 AY207064

Streptococcus sp. oral taxon 071 AEEPO 1000019

Streptococcus sp. oral taxon G59 GU432132

Streptococcus sp. oral taxon G62 GU432146

Streptococcus sp. oral taxon G63 GU432150

Streptococcus sp. SHV515 Y07601

Streptococcus suis FM252032

Streptococcus thermophilus CP000419

Streptococcus uberis HQ391900

Streptococcus urinalis DQ303194

Streptococcus vestibularis AEKOO 1000008

Streptococcus viridans AF076036

Streptomyces albus AJ697941 Streptomyces griseus R_074787

Streptomyces sp. 1 AIP 2009 FJ176782

Streptomyces sp. SD 511 EU544231

Streptomyces sp. SD 524 EU544234

Streptomyces sp. SD 528 EU544233

Streptomyces sp. SD 534 EU544232

Streptomyces thermoviolaceus R_027616

Subdoligranulum variabile AJ518869

Succinatimonas hippei AEVOO 1000027

Sutterella morbirenis AJ832129

Sutterella parvirubra AB300989

Sutterella sanguinus AJ748647

Sutterella sp. YIT 12072 AB491210

Sutterella stercoricanis R_025600

Sutterella wadsworthensis ADMFO 1000048

Synergistes genomosp. CI AY278615

Synergistes sp. RMA 14551 DQ412722

Synergistetes bacterium ADV897 GQ258968

Synergistetes bacterium LBVCM1157 GQ258969

Synergistetes bacterium oral taxon 362 GU410752

Synergistetes bacterium oral taxon D48 GU430992

Syntrophococcus sucromutans R_036869

Syntrophomonadaceae genomosp. PI AY341821

Tannerella forsythia CP003191

Tannerella sp. 6_1_58FAA_CT1 ACWX01000068

Tatlockia micdadei M36032

Tatumella ptyseos R_025342

Tessaracoccus sp. oral taxon F04 HM099640

Tetragenococcus halophilus R_075020

Tetragenococcus koreensis R_043113

Thermoanaerobacter pseudethanolicus CP000924

Thermobifida fusca NC_007333 Thermofilum pendens X14835

Thermus aquaticus R_025900

Tissierella praeacuta R_044860

Trabulsiella guamensis AY373830

Treponema denticola ADECO 1000002

Treponema genomosp. PI AY341822

Treponema genomosp. P4 oral clone MB2 G19 DQ003618

Treponema genomosp. P5 oral clone MB3 P23 DQ003624

Treponema genomosp. P6 oral clone MB4 Gl 1 DQ003625

Treponema lecithinolyticum R_026247

Treponema pallidum CP001752

Treponema parvum AF302937

Treponema phagedenis AEFH01000172

Treponema putidum AJ543428

Treponema refringens AF426101

Treponema socranskii R_024868

Treponema sp. 6:H:D15A 4 AY005083

Treponema sp. clone DDKL 4 Y08894

Treponema sp. oral clone JU025 AY349417

Treponema sp. oral clone JU031 AY349416

Treponema sp. oral clone P2PB 53 P3 AY207055

Treponema sp. oral taxon 228 GU408580

Treponema sp. oral taxon 230 GU408603

Treponema sp. oral taxon 231 GU408631

Treponema sp. oral taxon 232 GU408646

Treponema sp. oral taxon 235 GU408673

Treponema sp. oral taxon 239 GU408738

Treponema sp. oral taxon 247 GU408748

Treponema sp. oral taxon 250 GU408776

Treponema sp. oral taxon 251 GU408781

Treponema sp. oral taxon 254 GU408803

Treponema sp. oral taxon 265 GU408850 Treponema sp. oral taxon 270 GQ422733

Treponema sp. oral taxon 271 GU408871

Treponema sp. oral taxon 508 GU413616

Treponema sp. oral taxon 518 GU413640

Treponema sp. oral taxon G85 GU432215

Treponema sp. ovine footrot AJO 10951

Treponema vincentii ACYH01000036

Tropheryma whipplei BX251412

Trueperella pyogenes R_044858

Tsukamurella paurometabola X80628

Tsukamurella tyrosinosolvens AB478958

Turicibacter sanguinis AF349724

Ureaplasma parvum AE002127

Ureaplasma urealyticum AAYN01000002

Ureibacillus composti R_043746

Ureibacillus suwonensis R_043232

Ureibacillus terrenus R_025394

Ureibacillus thermophilus R_043747

Ureibacillus thermosphaericus R_040961

Vagococcus fluvialis R_026489

Veillonella atypica AEDS01000059

Veillonella dispar ACIK02000021

Veillonella genomosp. PI oral clone MB5 P17 DQ003631

Veillonella montpellierensis AF473836

Veillonella parvula ADFU01000009

Veillonella sp. 3_1_44 ADCV01000019

Veillonella sp. 6_1_27 ADCW01000016

Veillonella sp. ACPI HQ616359

Veillonella sp. AS 16 HQ616365

Veillonella sp. BS32b HQ616368

Veillonella sp. ICM51a HQ616396

Veillonella sp. MSA12 HQ616381 Veillonella sp. NVG lOOcf EF 108443

Veillonella sp. OK11 JN695650

Veillonella sp. oral clone ASCA08 AY923118

Veillonella sp. oral clone ASCB03 AY923122

Veillonella sp. oral clone ASCGOl AY923144

Veillonella sp. oral clone ASCG02 AY953257

Veillonella sp. oral clone OH1A AY947495

Veillonella sp. oral taxon 158 AENU01000007

Veillonellaceae bacterium oral taxon 131 GU402916

Veillonellaceae bacterium oral taxon 155 GU470897

Vibrio cholerae AAUR01000095

Vibrio fluvialis X76335

Vibrio furnissii CP002377

Vibrio mimicus ADAF01000001

Vibrio parahaemolyticus AAWQ01000116

Vibrio sp. RC341 ACZT01000024

Vibrio vulnificus AE016796

Victivallaceae bacterium NML 080035 FJ394915

Victivallis vadensis ABDE02000010

Virgibacillus proomii NR_025308

Weissella beninensis EU439435

Wei s sell a cibaria NR_036924

Weissella confusa NR_040816

Weissella hellenica AB680902

Weissella kandleri NR_044659

Weissella koreensis NR_075058

Weissella paramesenteroides ACKU01000017

Weissella sp. KLDS 7.0701 EU600924

Wolinella succinogenes BX571657

Xanthomonadaceae bacterium NML 03 0222 EU313791

Xanthomonas campestris EF101975

Xanthomonas sp. kmd 489 EU723184 Xenophilus aerolatus JN585329

Yersinia aldovae AJ871363

Yersinia aleksiciae AJ627597

Yersinia bercovieri AF366377

Yersinia enterocolitica FR729477

Yersinia frederiksenii AF366379

Yersinia intermedia AF366380

Yersinia kristensenii ACCAO 1000078

Yersinia mollaretii R_027546

Yersinia pestis AE013632

Yersinia pseudotuberculosis NC_009708

Yersinia rohdei ACCD01000071

Yokenella regensburgei AB273739

Zimmermannella bifida AB012592

Zymomonas mobilis R_074274

[0137] In some embodiments, the bacteria used in the methods described herein are cancer-associated bacteria. Exemplary cancer-associated bacteria are provided in Table 2.

Table 2. Exemplary Cancer-Associated Bacteria

Genera Species 1 umor Association

Mycoplasma hyorhinis Gastric Carcinoma

Propi onib acterium Acnes Prostate Cancer

Mycoplasma genitalium Prostate Cancer

Methylophilus sp. Prostate Cancer

Chlamydia trachomatis Prostate Cancer

Helicobacter pylori Gastric MALT

Listeria welshimeri Renal Cancer

Streptococcus pneumoniae Lymphoma and Leukemia

Haemophilus influenzae Lymphoma and Leukemia

Staphylococcus aureus Breast Cancer

Listeria monocytogenes Breast Cancer Methyl ob acterium radiotolerans Breast Cancer

Shingomonas yanoikuyae breast Cancer

Fusobacterium sp Larynx cancer

Provetelis sp Larynx cancer

streptococcus pneumoniae Larynx cancer

Gemella sp Larynx cancer

Bordetella Pertussis Larynx cancer

Corumebacterium tub er cul o ster an cum Oral squamous cell carcinoma

Micrococcus luteus Oral squamous cell carcinoma

Prevotella melaninogenica Oral squamous cell carcinoma

Exiguobacterium oxidotolerans Oral squamous cell carcinoma

Fusobacterium naviforme Oral squamous cell carcinoma

Veillonella parvula Oral squamous cell carcinoma

Streptococcus salivarius Oral squamous cell carcinoma

Streptococcus mitis/oralis Oral squamous cell carcinoma veillonella dispar Oral squamous cell carcinoma

Peptostreptococcus stomatis Oral squamous cell carcinoma

Streptococcus gordonii Oral squamous cell carcinoma

Gemella Haemolysans Oral squamous cell carcinoma

Gemella morbillorum Oral squamous cell carcinoma

Johnsonella ignava Oral squamous cell carcinoma

Streptococcus parasanguins Oral squamous cell carcinoma

Granulicatella adiacens Oral squamous cell carcinoma

Mycobacteria marinum lung infection

Campylobacter concisus Barrett's Esophagus

Campylobacter rectus Barrett's Esophagus

Orib acterium sp Esophageal adenocarcinoma

Catonella sp Esophageal adenocarcinoma

Peptostreptococcus sp Esophageal adenocarcinoma

Eub acterium sp Esophageal adenocarcinoma

Dialister sp Esophageal adenocarcinoma

Veillonella sp Esophageal adenocarcinoma

Anaeroglobus sp Esophageal adenocarcinoma Megasphaera sp Esophageal adenocarcinoma

Atoppbium sp Esophageal adenocarcinoma

Solobacterium sp Esophageal adenocarcinoma

Rothia sp Esophageal adenocarcinoma

Actinomyces sp Esophageal adenocarcinoma

Fusobacterium sp Esophageal adenocarcinoma

Sneathia sp Esophageal adenocarcinoma

Leptotrichia sp Esophageal adenocarcinoma

Capnocytophaga sp Esophageal adenocarcinoma

Prevotella sp Esophageal adenocarcinoma

Porphyromonas sp Esophageal adenocarcinoma

Campylobacter sp Esophageal adenocarcinoma

Haemophilus sp Esophageal adenocarcinoma

Neisseria sp Esophageal adenocarcinoma

TM7 sp Esophageal adenocarcinoma

Granulicatella sp Esophageal adenocarcinoma

Variovorax sp Psuedomyxoma Peritonei

Escherichia Shigella Psuedomyxoma Peritonei

Pseudomonas sp Psuedomyxoma Peritonei

Tessaracoccus sp Psuedomyxoma Peritonei

Acinetobacter sp Psuedomyxoma Peritonei

Helicobacter hepaticus Breast cancer

Chlamydia psittaci MALT lymphoma

Borrelia burgdorferi B cell lymphoma skin

Escherichia Coli NC101 Colorectal Cancer

Salmonella typhimurium Tool

Eterococcus faecalis blood

Streptococcus mitis blood

Streptococcus sanguis blood

Streptococcus anginosus blood

Streptococcus salvarius blood

Staphylococcus epidermidis blood

Streptococcus gallolyticus Colorectal Cancer Campylobacter showae CC57C Colorectal Cancer

Leptotrichia sp Colorectal Cancer

[0138] In certain embodiments the bacteria used in the methods described herein are systemic anaerobic bacteria. Examples of anaerobic bacteria include gram-negative rods including the genera of Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila and Sutterella spp.), gram -positive cocci (primarily Peptostreptococcus spp.), gram-positive spore-forming (Clostridium spp.), non-spore-forming bacilli (Actinomyces,

Propionibacterium, Eubacterium, Lactobacillus and Bifidobacterium spp.), and gram- negative cocci (mainly Veillonella spp.).

[0139] In some embodiments, the bacteria described herein are spore-forming bacteria. Examples of spore forming bacteria include bacteria of the genus Clostridium (e.g., Clostridium absonum, Clostridium aceticum, Clostridium acetireducens, Clostridium acetobutylicum, Clostridium acidisoli, Clostridium aciditolerans, Clostridium acidurici, Clostridium aerotolerans, Clostridium aestuarii, Clostridium akagii, Clostridium aldenense, Clostridium aldrichii, Clostridium algidicarnis, Clostridium algidixylanolyticum, Clostridium algifaecis, Clostridium algoriphilum, Clostridium alkalicellulosi, Clostridium aminophilum, Clostridium aminovalericum, Clostridium amygdalinum, Clostridium amylolyticum, Clostridium arbusti, Clostridium arcticum, Clostridium argentinense, Clostridium asparagiforme, Clostridium aurantibutyricum, Clostridium baratii, Clostridium barkeri, Clostridium bartlettii, Clostridium beijerinckii, Clostridium bifermentans, Clostridium bolteae, Clostridium bornimense, Clostridium botulinum, Clostridium bowmanii, Clostridium bryantii, Clostridium butyricum, Clostridium cadaveris, Clostridium caenicola, Clostridium caminithermale, Clostridium carboxidivorans, Clostridium carnis, Clostridium cavendishii, Clostridium celatum, Clostridium celerecrescens, Clostridium cellobioparum, Clostridium cellulofermentans, Clostridium cellulolyticum, Clostridium cellulosi, Clostridium

cellulovorans, Clostridium chartatabidum, Clostridium chauvoei, Clostridium

chromiireducens, Clostridium citroniae, Clostridium clariflavum, Clostridium

clostridioforme, Clostridium coccoides, Clostridium cochlearium, Clostridium cocleatum, Clostridium colicanis, Clostridium colinum, Clostridium collagenovorans, Clostridium cylindrosporum, Clostridium difficile, Clostridium diolis, Clostridium disporicum,

Clostridium drakei, Clostridium durum, Clostridium estertheticum, Clostridium e. subsp. estertheticum, Clostridium e. subsp. laramiense, Clostridium fiallax, Clostridium felsineum, Clostridium fervidum, Clostridium fimetarium, Clostridium formicaceticum, Clostridium frigidicarnis, Clostridium rigoris, Clostridium ganghwense, Clostridium gasigenes,

Clostridium ghonii, Clostridium glycolicum, Clostridium glycyrrhizinilyticum, Clostridium grantii, Clostridium haemolyticum, Clostridium halophilum, Clostridium hastiforme, Clostridium hathewayi, Clostridium herbivorans, Clostridium hiranonis, Clostridium histolyticum, Clostridium homopropionicum, Clostridium huakuii, Clostridium hungatei, Clostridium hydrogeniformans, Clostridium ydroxybenzoicum, Clostridium hylemonae, Clostridium jejuense, Clostridium indolis, Clostridium innocuum, Clostridium intestinale, Clostridium irregulare, Clostridium isatidis, Clostridium josui, Clostridium kluyveri, Clostridium lactatifermentans, Clostridium lacusfryxellense, Clostridium laramiense, Clostridium lavalense, Clostridium lentocellum, Clostridium lentoputrescens, Clostridium Upturn, Clostridium limosum, Clostridium litorale, Clostridium lituseburense, Clostridium ljungdahlii, Clostridium lortetii, Clostridium lundense, Clostridium magnum, Clostridium malenominatum, Clostridium mangenotii, Clostridium mayombei, Clostridium

methoxybenzovorans, Clostridium methylpentosum, Clostridium neopropionicum,

Clostridium nexile, Clostridium nitrophenolicum, Clostridium novyi, Clostridium oceanicum, Clostridium orbiscindens, Clostridium oroticum, Clostridium oxalicum, Clostridium papyrosolvens, Clostridium paradoxum, Clostridium paraperfringens, Clostridium paraputrifwum, Clostridium pascui, Clostridium pasteurianum, Clostridium peptidivorans, Clostridium perenne, Clostridium perfringens, Clostridium pfennigii, Clostridium

phytofermentans, Clostridium piliforme, Clostridium polysaccharolyticum, Clostridium populeti, Clostridium propionicum, Clostridium proteoclasticum, Clostridium proteolyticum, Clostridium psychrophilum, Clostridium puniceum, Clostridium purinilyticum, Clostridium putrefaciens, Clostridium putrifwum, Clostridium quercicolum, Clostridium quinii,

Clostridium ramosum, Clostridium rectum, Clostridium roseum, Clostridium

saccharobutylicum, Clostridium saccharogumia, Clostridium saccharolyticum, Clostridium saccharoperbutylacetonicum, Clostridium sardiniense, Clostridium sartagoforme,

Clostridium scatologenes, Clostridium schirmacherense, Clostridium scindens, Clostridium septicum, Clostridium sordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridium sporogenes, Clostridium sporosphaeroides, Clostridium stercorarium, Clostridium s. subsp. leptospartum, Clostridium s. subsp. stercorarium, Clostridium s. subsp. thermolacticum, Clostridium sticklandii, Clostridium straminisolvens, Clostridium subterminale, Clostridium sufflavum, Clostridium sulfidigenes, Clostridium symbiosum, Clostridium tagluense, Clostridium tepidiprofundi, Clostridium termitidis, Clostridium tertium, Clostridium tetani, Clostridium tetanomorphum, Clostridium thermaceticum, Clostridium thermautotrophicum, Clostridium thermoalcaliphilum, Clostridium thermobutyricum, Clostridium thermocellum, Clostridium thermocopriae, Clostridium thermohydrosulfuricum, Clostridium

thermolacticum, Clostridium thermopalmarium, Clostridium thermopapyrolyticum,

Clostridium thermosaccharolyticum, Clostridium thermosuccinogenes, Clostridium thermosulfurigenes, Clostridium thiosulfatireducens, Clostridium tyrobutyricum, Clostridium uliginosum, Clostridium ultunense, Clostridium villosum, Clostridium vincentii, Clostridium viride, Clostridium xylanolyticum and Clostridium xylanovorans), Bacillus (e.g., Bacillus acidiceler, Bacillus acidicola, Bacillus acidiproducens, Bacillus acidocaldarius, Bacillus acidoterrestris, Bacillus aeolius, Bacillus aerius, Bacillus aerophilus, Bacillus

agaradhaerens, Bacillus agri, Bacillus aidingensis, Bacillus akibai, Bacillus alcalophilus, Bacillus algicola, Bacillus alginolyticus, Bacillus alkalidiazotrophicus, Bacillus

alkalinitrilicus, Bacillus alkalisediminis, Bacillus alkalitelluris, Bacillus altitudinis, Bacillus alveayuensis, Bacillus alvei, Bacillus amyloliquefaciens, Bacillus amylolyticus, Bacillus andreesenii, Bacillus aneurinilyticus, Bacillus anthracis, Bacillus aquimaris, Bacillus arenosi, Bacillus arseniciselenatis, Bacillus arsenicus, Bacillus aurantiacus, Bacillus arvi, Bacillus aryabhattai, Bacillus asahii, Bacillus atrophaeus, Bacillus axarquiensis, Bacillus azotofixansvBacillus azotoformans, Bacillus badius, Bacillus barbaricus, Bacillus bataviensis, Bacillus beijingensis, Bacillus benzoevorans, Bacillus beringensis, Bacillus berkeleyi, Bacillus beveridgei, Bacillus bogoriensis, Bacillus boroniphilus, Bacillus borstelensis, Bacillus brevis, Migula, Bacillus butanolivorans, Bacillus canaveralius, Bacillus carboniphilus, Bacillus cecembensis, Bacillus cellulosilyticus, Bacillus

centrosporus, Bacillus cereus, Bacillus chagannorensis, Bacillus chitinolyticus, Bacillus chondroitinus, Bacillus choshinensis, Bacillus chungangensis, Bacillus cibi, Bacillus circulans, Bacillus clarkii, Bacillus clausii, Bacillus coagulans, Bacillus coahuilensis, Bacillus cohnii, Bacillus compostivBacillus curdlanolyticus, Bacillus cycloheptanicus, Bacillus cytotoxicus, Bacillus daliensis, Bacillus decisifrondis, Bacillus decolorationis, Bacillus deserti, Bacillus dipsosauri, Bacillus drentensis, Bacillus edaphicus, Bacillus ehimensis, Bacillus eiseniae, Bacillus enclensis, Bacillus endophyticus, Bacillus endoradicis, Bacillus farraginis, Bacillus fastidiosus, Bacillus fengqiuensis, Bacillus firmus, Bacillus flexus, Bacillus foraminis, Bacillus fordii, Bacillus formosus, Bacillus fortis, Bacillus fumarioli, Bacillus funiculus, Bacillus fusiformis, Bacillus galactophilus, Bacillus

galactosidilyticus, Bacillus galliciensis, Bacillus gelatini, Bacillus gibsonii, Bacillus ginsengi, Bacillus ginsengihumiBacillus ginsengisoli, Bacillus globisporus, Bacillus g. subsp. globisporus, Bacillus g. subsp. marinus, Bacillus glucanolyticus, Bacillus gordonae, Bacillus gottheilii, Bacillus graminis, Bacillus halmapalus, Bacillus haloalkaliphilus, Bacillus halochares, Bacillus halodenitrifwans, Bacillus halodurans, Bacillus halophilus, Bacillus halosaccharovorans, Bacillus hemicellulosilyticus, Bacillus hemicentroti, Bacillus herbersteinensis, Bacillus horikoshii, Bacillus horneckiae, Bacillus horti, Bacillus

huizhouensis, Bacillus humi, Bacillus hwajinpoensis, Bacillus idriensis, Bacillus indicus, Bacillus infantis, Bacillus infernus, Bacillus insolitus, Bacillus invictae, Bacillus iranensis, Bacillus isabeliae, Bacillus isronensis, Bacillus jeotgali, Bacillus kaustophilus, Bacillus kobensis, Bacillus kochii, Bacillus kokeshiiformis, Bacillus koreensis, Bacillus korlensis, Bacillus kribbensis, Bacillus krulwichiae, Bacillus laevolacticus, Bacillus larvae, Bacillus laterosporus, Bacillus lautus, Bacillus lehensis, Bacillus lentimorbus, Bacillus lentus, Bacillus licheniformis, Bacillus ligniniphilus, Bacillus litoralis, Bacillus locisalis, Bacillus luciferensis, Bacillus luteolus, Bacillus luteus, Bacillus macauensis, Bacillus macerans, Bacillus macquariensis, Bacillus macyae, Bacillus malacitensis, Bacillus mannanilyticus, Bacillus marinus, Bacillus marisflavi, Bacillus marismortui, Bacillus marmarensis, Bacillus massiliensis, Bacillus megaterium, Bacillus mesonae, Bacillus methanolicus, Bacillus methylotrophicus, Bacillus migulanus, Bacillus mojavensis, Bacillus mucilaginosus, Bacillus muralis, Bacillus murimartini, Bacillus mycoides, Bacillus naganoensis, Bacillus

nanhaiensis, Bacillus nanhaiisediminis, Bacillus nealsonii, Bacillus neidei, Bacillus neizhouensis, Bacillus niabensis, Bacillus niacini, Bacillus novalis, Bacillus oceanisediminis, Bacillus odysseyi, Bacillus okhensis, Bacillus okuhidensis, Bacillus oleronius, Bacillus oryzaecorticis, Bacillus oshimensis, Bacillus pabuli, Bacillus pakistanensis, Bacillus pallidus, Bacillus pallidus, Bacillus panacisoli, Bacillus panaciterrae, Bacillus pantothenticus, Bacillus parabrevis, Bacillus paraflexus, Bacillus pasteurii, Bacillus patagoniensis, Bacillus peoriae, Bacillus persepolensis, Bacillus persicus, Bacillus pervagus, Bacillus plakortidis, Bacillus pocheonensis, Bacillus polygoni, Bacillus polymyxa, Bacillus popilliae, Bacillus pseudalcaliphilus, Bacillus pseudoflrmus, Bacillus pseudomycoides, Bacillus psychrodurans, Bacillus psychrophilus, Bacillus psychrosaccharolyticus, Bacillus psychrotolerans, Bacillus pulvifaciens, Bacillus pumilus, Bacillus purgationiresistens, Bacillus pycnus, Bacillus qingdaonensis, Bacillus qingshengii, Bacillus reuszeri, Bacillus rhizosphaerae, Bacillus rigui, Bacillus ruris, Bacillus safensis, Bacillus salarius, Bacillus salexigens, Bacillus saliphilus, Bacillus schlegelii, Bacillus sediminis, Bacillus selenatarsenatis, Bacillus selenitireducens, Bacillus seohaeanensis, Bacillus shacheensis, Bacillus shackletonii, Bacillus siamensis, Bacillus silvestris, Bacillus simplex, Bacillus siralis, Bacillus smithii, Bacillus soli, Bacillus solimangrovi, Bacillus solisalsi, Bacillus songklensis, Bacillus sonorensis, Bacillus sphaericus, Bacillus spor other modurans, Bacillus stearothermophilus, Bacillus stratosphericus, Bacillus subterraneus, Bacillus subtilis, Bacillus s. subsp.

inaquosorum, Bacillus s. subsp. spizizenii, Bacillus s. subsp. subtilis, Bacillus taeanensis, Bacillus tequilensis, Bacillus thermantarcticus, Bacillus thermoaerophilus, Bacillus thermoamylovorans, Bacillus thermocatenulatus, Bacillus thermocloacae, Bacillus thermocopriae, Bacillus thermodenitrificans, Bacillus thermoglucosidasius, Bacillus thermolactis, Bacillus thermoleovorans, Bacillus thermophilus, Bacillus thermoruber, Bacillus thermosphaericus, Bacillus thiaminolyticus, Bacillus thioparans, Bacillus thuringiensis, Bacillus tianshenii, Bacillus trypoxylicola, Bacillus tusciae, Bacillus validus, Bacillus vallismortis, Bacillus vedderi, Bacillus velezensis, Bacillus vietnamensis, Bacillus vireti, Bacillus vulcani, Bacillus wakoensis, Bacillus weihenstephanensis, Bacillus xiamenensis, Bacillus xiaoxiensis, Bacillus zhanjiangensis), Sporolactobacillus (e.g., Sporolactobacillus dextrus, Sporolactobacillus inulinus, Sporolactobacillus laevis,

Sporolactobacillus terrae and Sporolactobacillus vineae) and Sporosarcina (e.g.,

Sporosarcina aquimarina, Sporosarcina globispora, Sporosarcina halophila, Sporosarcina koreensis, Sporosarcina luteola and Sporosarcina ureae).

[0140] In some embodiments, the bacteria used in the compositions and methods provided herein have an infection profile wherein they localize to and/or infect certain cells, tissues and/or organs. In some embodiments, the bacteria used in the methods provided herein are selected, at least in part, because of their infection profile. In some embodiments, the bacteria have an infection profile in which they localize to tumors and/or cancer cells. In some embodiments, the bacteria have an infection profile where they localize to a particular organ and/or tissue (e.g., skeletal muscles, cardiac muscles, smooth muscles, bones, joints, ligaments, tendons, salivary glands, stomach, small intestine, large intestine, liver, gallbladder, pancreas, pharynx, larynx, bronchi, lungs, kidneys, ureters, bladder, urethra, ovaries, uterus, vagina, placenta, testes, prostate, brain, spinal cord, peripheral nerves, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, pancreas, heart, arteries, veins, capillaries, lymph nodes, thymus, spleen, bone marrow, eyes and skin. In some embodiments, the bacteria have an infection profile wherein they infect and/or bind to particular cell types. In some embodiments, the bacteria have an infection profile wherein they infect and/or bind to cancer and/or tumor cells. In some embodiments, the bacteria have an infection profile wherein they infect and/or bind to antigen presenting cells (e.g., dendritic cells, macrophages, B cells). In some embodiments, the bacteria have an infection profile wherein they infect and/or bind to tumor-associated macrophages and/or myeloid-derived suppressor cells.

[0141] In certain embodiments, the infection profile of the bacterium of interest is modified by the presence of the polymer in the composition of the invention. In certain embodiments, the polymer enhances the ability of the bacterium to infect the tumor associated macrophage or myeloid-derived suppressor cell, of interest is modified by the presence of the polymer in the composition of the invention. In certain embodiments, the polymer enhances the ability of the bacterium to infect the antigen presenting cells. The antigen presenting cell can be a macrophage, a dendritic cell, or a B cell.

[0142] In some embodiments, the polymer enhances the ability of the bacterium to localize to a tumor.

Administration

[0143] In certain aspects, provided herein is a method of administering to the subject a pharmaceutical composition provided herein (e.g., a composition comprising a bacterium of interest and a polymer).

[0144] In some embodiments of the methods provided herein, the compositions provided herein are administered in conjunction with the administration of a second bacteria that facilitates the penetration of the bacteria of interest into a mammalian target cell. For example, the bacterium Fusobacterium nucleatum can facilitate the penetration of the bacterium of the composition through an endothelial cell monolayer. Thus, in some embodiments, Fusobacterium nucleatum binds to the bacteria of interest, which allows the bacteria of interest to "piggyback" into a mammalian target cell. In some embodiments, the bacteria of interest is co-formulated in a pharmaceutical composition with the second bacteria. In some embodiments, the bacteria of interest is co-administered with the second bacteria. In some embodiments, the second bacteria is administered to the subject before administration of the bacteria of interest {e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,

17, 18, 19, 20, 21, 22 or 23 hours before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before). In some embodiments, the second bacteria is administered to the subject after administration of the bacteria of interest {e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes after, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,

18, 19, 20, 21, 22 or 23 hours after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after). In some embodiments, the cell ratio of the bacteria of interest to the second bacteria is about 1:1. In some embodiments the ratio is about 1000:1, 500:1, 400:1, 300:1, 200:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:200, 1:300, 1:400, 1:500 or 1:1000.

[0145] In some embodiment, the therapeutic agent delivered using the composition provided herein is a prodrug enzyme (e.g., purine nucleoside phosphorylase) and the method further comprises delivery of a prodrug (e.g., 6-methylpurine 2'-deoxyriboside) to the subject. In some embodiments, the prodrug is part of the pharmaceutical composition. In some embodiments, the prodrug is delivered separately from the pharmaceutical composition. In some embodiments, the prodrug is administered to the subject before administration of the pharmaceutical composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before). In some embodiments, the prodrug is administered to the subject after administration of the pharmaceutical composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes after, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after).

[0146] In certain embodiments, the pharmaceutical compositions, dosage forms, and kits described herein can be administered in conjunction with any other conventional anticancer treatment, such as, for example, radiation therapy and surgical resection of the tumor. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the pharmaceutical compositions, dosage forms, and kits described herein.

[0147] The dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors. As is known in the medical arts, dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, for example, tumor size, and other compounds such as drugs being administered concurrently. In addition to the above factors, such levels can be affected by the infectivity of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art. In the present methods, appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate in a tumor or metastasis. The methods of treatment described herein may be suitable for the treatment of a primary tumor, a secondary tumor or metastasis, as well as for recurring tumors or cancers. The dose of the pharmaceutical compositions described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like. For example, the general effective dose of the agents may range between 0.01 mg/kg body weight/day and 1000 mg/kg body

weight/day, between 0.1 mg/kg body weight/day and 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day and 500 mg/kg body weight/day, 1 mg/kg body weight/day and 100 mg/kg body weight/day, or between 5 mg/kg body weight/day and 50 mg/kg body

weight/day. The effective dose may be 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mg/kg body weight/day or more, but the dose is not limited thereto. In some aspects, dosage is determined by CFU per unit area (e.g., square millimeter) of a tumor site. For example, the dose of the microbial component may range between 1x10° CFU/mm², lxlO¹ CFU/mm², lxlO² CFU/mm², lxlO³ CFU/mm², lxlO⁴ CFU/mm², lxlO⁵ CFU/mm², lxlO⁶ CFU/mm², or lxlO⁷ CFU/mm². In other aspects, dosage is determined by CFU per unit volume administered to a patient, such as 1x10° CFU/ml, lxlO¹ CFU/ml, lxlO² CFU/ml, lxlO³ CFU/ml, lxlO⁴ CFU/ml, lxlO⁵ CFU/ml, lxlO⁶ CFU/ml, or lxl 0⁷ CFU/ml.

[0148] For weight-based dosing, exemplary minimum levels for administering a bacterium to a 65 kg human can include at least about 5 x 10⁶ colony forming units (CFU), at least about 1 ^χ 10⁷ CFU, at least about 5 * 10⁷ CFU, at least about 1 ^χ 10⁸ CFU, or at least about l x lO⁹ CFU. In the present methods, appropriate maximum dosage levels of microorganisms can be levels that are not toxic to the host, levels that do not cause splenomegaly of 3 ^χ or more, levels that do not result in colonies or plaques in normal tissues or organs after about 1 day or after about 3 days or after about 7 days.

[0149] The dose administered to a subject should be sufficient to prevent cancer, delay its onset, or slow or stop its progression. One skilled in the art will recognize that dosage will depend upon a variety of factors including the strength of the particular compound employed, as well as the age, species, condition, and body weight of the subject. The size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect.

[0150] Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. An effective dosage and treatment protocol can be determined by routine and conventional means, starting e.g., with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Animal studies are commonly used to determine the maximal tolerable dose ("MTD") of bioactive agent per kilogram weight. Those skilled in the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.

[0151] In accordance with the above, in therapeutic applications, the dosages of the active agents used in accordance with the invention vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and most preferably causing complete regression of the cancer.

[0152] Separate administrations can include any number of two or more administrations, including two, three, four, five or six administrations. One skilled in the art can readily determine the number of administrations to perform or the desirability of performing one or more additional administrations according to methods known in the art for monitoring therapeutic methods and other monitoring methods provided herein. Accordingly, the methods provided herein include methods of providing to the subject one or more

administrations of a microorganism, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations. Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results, including, but not limited to, indication of tumor growth or inhibition of tumor growth, appearance of new metastases or inhibition of metastasis, the subject's anti- microorganism antibody titer, the subject's anti -tumor antibody titer, the overall health of the subject, the weight of the subject, the presence of microorganism solely in tumor and/or metastases, the presence of microorganism in normal tissues or organs.

[0153] The time period between administrations can be any of a variety of time periods. The time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response, the time period for a subject to clear microorganism from normal tissue, or the time period for microorganismal proliferation in the tumor or metastasis. In one example, the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be less than the time period for a subject to mount an immune response, such as less than about one week, less than about ten days, less than about two weeks, or less than about a month. In another example, the time period can be a function of the time period for a subject to clear microorganism from normal tissue; for example, the time period can be more than the time period for a subject to clear microorganism from normal tissue, such as more than about a day, more than about two days, more than about three days, more than about five days, or more than about a week. In another example, the time period can be a function of the time period for microorganismal proliferation in the tumor or metastasis; for example, the time period can be more than the amount of time for a detectable signal to arise in a tumor or metastasis after administration of a microorganism expressing a detectable marker, such as about 3 days, about 5 days, about a week, about ten days, about two weeks, or about a month.

[0154] In some embodiments, the composition is administered in conjunction with a prebiotic. Prebiotics are carbohydrates which are generally indigestible by a host animal and are selectively fermented or metabolized by bacteria. Prebiotics may be short-chain carbohydrates (e.g., oligosaccharides) and/or simple sugars (e.g., mono- and di-saccharides) and/or mucins (heavily glycosylated proteins) that alter the composition or metabolism of a microbiome in the host. The short chain carbohydrates are also referred to as

oligosaccharides, and usually contain from 2 or 3 and up to 8, 9, 10, 15 or more sugar moieties. When prebiotics are introduced to a host, the prebiotics affect the bacteria within the host and do not directly affect the host. In certain aspects, a prebiotic composition can selectively stimulate the growth and/or activity of one of a limited number of bacteria in a host. Prebiotics include oligosaccharides such as fructooligosaccharides (FOS) (including inulin), galactooligosaccharides (GOS), trans-galactooligosaccharides, xylooligosaccharides (XOS), chitooligosaccharides (COS), soy oligosaccharides (e.g., stachyose and raffinose) gentiooligosaccharides, isomaltooligosaccharides, mannooligosaccharides,

maltooligosaccharides and mannanoligosaccharides. Oligosaccharides are not necessarily single components, and can be mixtures containing oligosaccharides with different degrees of oligomerization, sometimes including the parent disaccharide and the monomelic sugars. Various types of oligosaccharides are found as natural components in many common foods, including fruits, vegetables, milk, and honey. Specific examples of oligosaccharides are lactulose, lactosucrose, palatinose, glycosyl sucrose, guar gum, gum Arabic, tagalose, amylose, amylopectin, pectin, xylan, and cyclodextrins. Prebiotics may also be purified or chemically or enzymatically synthesized.

[0155] The effective dose of therapeutic agent described herein is the amount of the therapeutic composition that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, with the least toxicity to the patient. The effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. In general, an effective dose of a therapy will be the amount of the therapeutic agent which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0156] The toxicity of a therapy is the level of adverse effects experienced by the subject during and following treatment. Adverse events associated with cancer therapy toxicity include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylasix, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, gastroesophageal reflux disease, genital pain, granulocytopenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, heart palpitations, heartburn, hematoma, hemorrhagic cystitis, hepatotoxicity, hyperamylasemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipasemia, hypermagnesemia, hypernatremia,

hyperphosphatemia,hyperpigmentation, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, itching, joint pain, kidney failure, leukopenia, liver dysfunction, memory loss, menopause, mouth sores, mucositis, muscle pain, myalgias, myelosuppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, pancytopenia, pericarditis, peripheral neuropathy, pharyngitis, photophobia, photosensitivity, pneumonia, pneumonitis, proteinuria, pulmonary embolus, pulmonary fibrosis, pulmonary toxicity, rash, rapid heart beat, rectal bleeding, restlessness, rhinitis, seizures, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and xerostomia. In general, toxicity is acceptable if the benefits to the subject achieved through the therapy outweigh the adverse events experienced by the subject due to the therapy.

Cancer

[0157] In some embodiments, provided herein is a method of treating cancer in a subject, comprising administering to the subject a composition described herein.

[0158] In some embodiments, any cancer can be treated using the methods described herein. Examples of cancers that may treated by methods and compositions described herein include, but are not limited to, cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp;

adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant;

branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell

adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma;

endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma;

cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma;

infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; and roblastoma, malignant; Sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant;

paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant;

choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma;

osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma;

astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor;

meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas;

malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0159] In some embodiments, the methods and compositions provided herein relate to the treatment of a leukemia. The term "leukemia" is meant broadly progressive, malignant diseases of the hematopoietic organs/sy stems and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Non-limiting examples of leukemia diseases include, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia,

myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, and promyelocytic leukemia.

[0160] In some embodiments, the methods and compositions provided herein relate to the treatment of a carcinoma. The term "carcinoma" refers to a malignant growth made up of epithelial cells tending to infiltrate the surrounding tissues, and/or resist physiological and non-physiological cell death signals and gives rise to metastases. Non-limiting exemplary types of carcinomas include, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma

spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma

tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, and carcinoma scroti.

[0161] In some embodiments, the methods and compositions provided herein relate to the treatment of a sarcoma. The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar, heterogeneous, or homogeneous substance. Sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma,

melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing' s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma. [0162] Additional exemplary neoplasias that can be treated using the methods and compositions described herein include Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer,

rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, and adrenal cortical cancer.

[0163] In some embodiments, the cancer treated is a melanoma. The term

"melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Non-limiting examples of melanomas are Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.

[0164] Particular categories of tumors that can be treated using methods and compositions described herein include lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, cancer of the peripheral nervous system, skin cancer, kidney cancer, as well as metastases of all the above. Particular types of tumors include hepatocellular carcinoma, hepatoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing's tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, pulmonary squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated, poorly differentiated or undifferentiated), bronchioloalveolar carcinoma, renal cell carcinoma, hypernephroma, hypernephroid adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, testicular tumor, lung carcinoma including small cell, non-small and large cell lung carcinoma, bladder carcinoma, glioma, astrocyoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma,

neuroblastoma, colon carcinoma, rectal carcinoma, hematopoietic malignancies including all types of leukemia and lymphoma including: acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin' s lymphoma, non-Hodgkin' s lymphoma.

[0165] Cancers treated in certain embodiments also include precancerous lesions, e.g., actinic keratosis (solar keratosis), moles (dysplastic nevi), acitinic chelitis (farmer's lip), cutaneous horns, Barrett's esophagus, atrophic gastritis, dyskeratosis congenita, sideropenic dysphagia, lichen planus, oral submucous fibrosis, actinic (solar) elastosis and cervical dysplasia.

[0166] Cancers treated in some embodimentsinclude non-cancerous or benign tumors, e.g., of endodermal, ectodermal or mesenchymal origin, including, but not limited to cholangioma, colonic polyp, adenoma, papilloma, cystadenoma, liver cell adenoma, hydatidiform mole, renal tubular adenoma, squamous cell papilloma, gastric polyp, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma,

rhabdomyoma, astrocytoma, nevus, meningioma, and ganglioneuroma.

Autoimmune and Inflammatory Disease

[0167] In certain aspects, provided herein are methods for treating or preventing a disease or disorder associated with a pathological immune response, such as an autoimmune disease, an allergic reaction and/or an inflammatory disease. In some embodiments, the disease or disorder is an inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis).

[0168] In some embodiments, provided herein is a method of treating autoimmune disease in a subject, comprising administering to the subject a composition of the invention. In certain embodiments, the autoimmune disease may be chronic inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, or

Hashimoto's disease.

[0169] In certain embodiments, the autoimmune disease is chronic inflammatory bowel disease. Inflammatory bowel diseases include, for example, certain art-recognized forms of a group of related conditions. Several major forms of inflammatory bowel diseases are known, with Crohn's disease (regional bowel disease, e.g., inactive and active forms) and ulcerative colitis (e.g., inactive and active forms) the most common of these disorders. In addition, the inflammatory bowel disease encompasses irritable bowel syndrome,

microscopic colitis, lymphocytic-plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis and eosinophilic enterocolitis. Other less common forms of IBD include indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel disease, Behcet's disease, sarcoidosis, scleroderma, IBD-associated dysplasia, dysplasia associated masses or lesions, and primary sclerosing cholangitis.

[0170] In some embodiments, provided herein is a method for treating an allergic disease in a subject, comprising administering to the subject a pharmaceutical composition of the invention. Exemplary allergic diseases include a food allergy, pollenosis, and asthma.

[0171] In some embodiments, provided herein is a method for treating an infectious disease in a subject, comprising administering to the subject a pharmaceutical composition of the invention. An exemplary infectious disease is infection with Clostridium difficile.

[0172] In some embodiments, provided herein is a method for treating an

inflammatory disease in a subject, comprising administering to the subject a pharmaceutical composition of the invention.

[0173] In certain embodiments, an inflammatory disease is a TNF-mediated inflammatory disease. The TNF-mediated inflammatory disease may be an inflammatory disease of the gastrointestinal tract, such as pouchitis. Alternatively, the TNF-mediated inflammatory disease may be a cardiovascular inflammatory disease condition, such as atherosclerosis. In still further embodiments, the TNF-mediated inflammatory disease is an inflammatory lung disease, such as chronic obstructive pulmonary disease.

[0174] In some embodiments, administration is in combination with administration of at least one prebiotic substance (e.g., a prebiotic substance that favors the growth of the bacterial species in the composition over the growth of other human commensal bacterial species). In some embodiments, the prebiotic substance is a nondigestible oligosaccharide. In some embodiments, the prebiotic substance is almond skin, inulin, oligofructose, raffinose, lactulose, pectin, hemicellulose, amylopectin, acetyl-Co A, biotin, beet molasses, yeast extracts, and resistant starch.

[0175] In some embodiments, the compositions described herein are administered in combination with an immunosuppressive agent. Examples of immunosuppressive agents include corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, vaccines, anti-TNF inhibitors such as infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept, and combinations thereof. Also described herein is a composition that comprises the bacterial composition and at least one substance selected from the group consisting of corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, vaccines, anti-T F inhibitors such as infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept, and combinations thereof.

[0176] In some embodiments, the methods provided herein include the step of administering at least one antibiotic before or in combination with, the administration of a composition described herein.

[0177] In some embodiments, the methods provided herein include the step of determining the subject's microbiome prior to the administration of a composition described herein. In some embodiments, the selection of the bacteria or combination of bacteria administered to the subject is determined based upon the make-up of the subject's microbiome.

[0178] Actual dosage levels of the bacteria in the compositions described herein may be varied so as to obtain an amount of the bacteria which is effective to achieve the desired therapeutic response for a particular patient. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the composition required.

[0179] The invention also provides a method of suppressing organ transplant rejection, comprising administering to the subject a pharmaceutical composition of the invention.

[0180] In certain embodiments the subject is human. In alternative embodiments, the subject is a non-human mammal, such as a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

EXAMPLES

Example 1: Genomic DNA Extraction

[0181] Genomic DNA is extracted from pure microbial cultures using a hot alkaline lysis method. 1 μΐ of a microbial culture is added to 9 μΐ of Lysis Buffer (25 mM NaOH, 0.2 mM EDTA) and the mixture is incubated for 30 minutes at 95°C. Subsequently, the samples are cooled to 4°C and neutralized by the addition of 10 μΐ of Neutralization Buffer (40 mM Tris-HCl) and then diluted 10-fold in Elution Buffer (10 mM Tris-HCl). Alternatively, genomic DNA is extracted from pure microbial cultures using commercially available kits such as the Mo Bio Ultraclean® Microbial DNA Isolation Kit (Mo Bio Laboratories, Carlsbad, CA) or by standard methods known to one skilled in the art.

Example 2: 16S rDNA Sequencing

[0182] The bacterial 16S rRNA gene is approximately 1500 nucleotides in length and is used in reconstructing the evolutionary relationships and sequence similarity of one bacterial isolate to another using phylogenetic approaches. 16S sequences are used for phylogenetic reconstruction as they are in general highly conserved, but contain specific hypervariable regions that harbor sufficient nucleotide diversity to differentiate genera and species of most microbes. OTUs may be defined either by full 16S sequencing of the rRNA gene, by sequencing of a specific hypervariable region of this gene (i.e., VI, V2, V3, V4, V5, V6, V7, V8, or V9), or by sequencing of any combination of hypervariable regions from this gene (e.g., Vl-3 or V3-5).

[0183] In order to determine the full 16S sequence or the sequence of any

hypervariable region of the 16S rRNA sequence, genomic DNA is extracted from a bacterial sample (as described in Example 1), the 16S rDNA (full region or specific hypervariable regions) amplified using polymerase chain reaction (PCR), the PCR products cleaned, and nucleotide sequences delineated to determine the genetic composition of 16S gene or subdomain of the gene. If full 16S sequencing is performed, the sequencing method used may be, but is not limited to, Sanger sequencing. If one or more hypervariable regions are used, such as the V4 region, the sequencing may be, but is not limited to being, performed using the Sanger method or using a next-generation sequencing method, such as an Illumina (sequencing by synthesis) method using barcoded primers allowing for multiplex reactions.

Example 3: Sequencing other marker genes

[0184] In addition to the 16S rRNA gene, one may define an operational taxonomic unit (OTU) by sequencing a selected set of genes that are known to be marker genes for a given species or taxonomic group of OTUs. These genes may alternatively be assayed using a PCR-based screening strategy. As example, various strains of pathogenic Escherichia coli can be distinguished using DNAs from the genes that encode heat-labile (LTI, LTIIa, and LTIIb) and heat-stable (STI and STII) toxins, verotoxin types 1, 2, and 2e (VT1, VT2, and VT2e, respectively), cytotoxic necrotizing factors (CNFl and CNF2), attaching and effacing mechanisms (eaeA), enteroaggregative mechanisms (Eagg), and enteroinvasive mechanisms (Einv). Example 4: Amplification of 16S Sequences for downstream sequencing & characterization

[0185] To amplify bacterial 16S rDNA, 2 μΐ of extracted gDNA is added to a 20 μΐ final volume PCR reaction. For full-length 16 sequencing the PCR reaction also contains lx HotMasterMix (5PRIME, Gaithersburg, MD), 250 nM of 27f

(AGRGTTTGATCMTGGCTCAG, IDT, Coralville, IA), and 250 nM of 1492r

(TACGGYTACCTTGTTAYGACTT, IDT, Coralville, IA), with sterile water (Mo Bio Laboratories, Carlsbad, CA) to achieve a final volume of 20 μΐ. Alternatively, other universal bacterial primers or thermostable polymerases known to one skilled in the art are used. For example, primers are available to those skilled in the art for the sequencing of the "VI -V9 regions" of the 16S rRNA. A person of ordinary skill in the art can identify the specific hypervariable regions of a candidate 16S rRNA by comparing the candidate sequence in question to the reference sequence and identifying the hypervariable regions based on similarity to the reference hypervariable regions.

[0186] The PCR is performed on commercially available thermocyclers such as a

BioRad MyCycler™ Thermal Cycler (BioRad, Hercules, CA). The reactions are run at 94°C for 2 minutes followed by 30 cycles of 94°C for 30 seconds, 51°C for 30 seconds, and 68°C for 1 minute 30 seconds, followed by a 7 minute extension at 72°C and an indefinite hold at 4°C. Following PCR, gel electrophoresis of a portion of the reaction products is used to confirm successful amplification of a -1500 bp product.

[0187] To remove nucleotides and oligonucleotides from the PCR products, 2 μΐ of

HT ExoSap-IT (Affymetrix, Santa Clara, CA) is added to 5 μΐ of PCR product followed by a 15 minute incubation at 37°C and then a 15 minute inactivation at 80°C.

Example 5: Nucleic Acid Detection

[0188] The prepared library is sequenced on Illumina HiSeq or MiSeq sequencers

(Illumina, San Diego, CA) with cluster generation, template hybridization, isothermal amplification, linearization, blocking and denaturation and hybridization of the sequencing primers performed according to the manufacturer's instructions. Other sequencing technologies can be used such as but not limited to 454, Pacific Biosciences, Helicos, Ion Torrent, and Nanopore using protocols that are standard to someone skilled in the art of genomic sequencing. Example 6: Sequence Annotation and taxonomic characterization

[0189] Nucleic acid sequences are analyzed to define taxonomic assignments using sequence similarity and phylogenetic placement methods or a combination of the two strategies. A similar approach is used to annotate protein names, protein function, transcription factor names, and any other classification schema for nucleic acid sequences. Sequence similarity based methods include BLAST, BLASTx, tBLASTn, tBLASTx, RDP- classifier, DNAclust, and various implementations of these algorithms such as Qiime or Mothur. These methods map a sequence read to a reference database and select the match with the best score and best e-value. Common databases include, but are not limited to the Human Microbiome Project, NCBI non-redundant database, Greengenes, RDP, and Silva for taxonomic assignments. For functional assignments reads are mapped to various functional databases such as but not limited to COG, KEGG, BioCyc, and MetaCyc.

Example 7: Preparation of bacterial suspension

[0190] A human microbiome sample from stool, saliva, or tissue is obtained from healthy, normal subjects or subjects suffering from a particular condition, which enriches their microbiome for certain bacterial species. The sample is diluted to produce a 10-50% slurry in saline and glycerol solution (0.9% (w/v) NaCl, 10% (w/w) glycerol) and placed in a filter membrane-containing stomaching bag. The material is then homogenized and removed from the filtered side of the bag producing the bacterial suspension. Alternatively, a blender is used and filtering is performed after the blending. A low speed centrifugation step is used as an alternative to filtering to remove the large, non-bacterial components of the suspension. The bacterial suspension is titered by producing serial dilutions differing by a log and plating on BBA agar and growing at 37°C in anaerobic conditions. Colonies are considered countable at between 10-400 colonies per plate and triplicates are plated for each dilution. The bacterial suspension is flash frozen and stored at -80°C for future use.

[0191] Isolation of spore formers. To isolate the subpopulation of spore formers, the bacterial slurry is treated with 100%) ethanol to generate a 50% ethanol slurry for 1 hour. Alternatively a heat treatment of 50°C for 30 minutes is added to inactivate the bacteria that are not capable of forming spores. The 50% ethanol suspension is then pelleted by centrifugation and the pellet is washed with equal lOx volume of saline and 10% glycerol 3 times to remove the excess ethanol. The final spore fraction is snap frozen in liquid nitrogen in a solution of injection grade saline and 10% glycerol for subsequent use and stored at - 80°C. Example 8: Sequencing of a bacterial genome

[0192] Prior to sequencing a bacterial genome, the bacterium of interest is isolated, and the bacterial cells are grown in culture. The genomic DNA is then prepared using methods known to one skilled in the art and methods disclosed in the previous examples. Up to three different DNA libraries are generated and sequenced for each bacterial genome determination:

[0193] (1) The isolated bacterial genomic DNA is digested with the Hindlll restriction enzyme and the resulting DNA fragments are cloned into a BAC backbone. The resulting BAC library is sequenced using paired-end sequencing.

[0194] (2+3) Two whole genome shotgun libraries are generated using methods known to one skilled in the art. The first library contains in the order of -25,000 members with an average insert size of 1.5 kbp and the second library contains in the order of -10,000 members with an average insert size of 4 kbp. The libraries are sequenced using paired-end sequencing.

[0195] All DNA sequencing trace files with Q scores greater than 20 (i.e., Q20) are identified using the base-calling software Phred (B. Ewing, L. Hillier, M. Wendl, and P. Green, Genome Res. 8: 175-185 (1998); B. Ewing and P. Green, Genome Res. 8: 186-194 (1998)). These high quality traces files are then assembled into a draft DNA sequence assembly using the Phred-Phrap software package (UW TechTransfer Digital Ventures). The assembly generated by Phrap is checked for assembly problems using the Consed/Autofinish tool (D. Gordon, C. Abajian, and P. Green, Genome Res. 8, 195-202 (1998); D. Gordon, C. Desmarais, and P. Green, Genome Res. 11 :614-625 (2001)).

[0196] The resulting preliminary sequence map is further analyzed and improved using GapFiller (M. Boetzer and W. Pirovano, Genome Biol. 13(6):R56 (2012)) and other software tools known to one skilled in the art. To further improve the quality of the bacterial genome sequence, poor quality regions are identified, PCR-amplified, and sequenced. This is done in an iterative fashion. The final genome assembly aims to achieve in average a lOx sequence coverage with Phred quality values of at least 40 (i.e., Q40). The correctness of the genome assembly is further verified by comparing restriction maps generated in silico with BAC fingerprints. Example 9: Measurement of metabolites and other small molecules by mass spectrometry

[0197] Metabolites and other small molecules are measured by gas chromatography mass spectrometry. Polar metabolites and fatty acids are extracted using monophasic or biphasic systems of organic solvents and an aqueous sample as previously described (Metallo et al, 2012, Fendt et al, 2013). Derivatization of both polar metabolites and fatty acids has been described previously (Metallo et al, 2012). Briefly, polar metabolites are derivatized to form methoxime-tBDMS derivatives by incubation with 2% methoxylamine hydrochloride (MP Biomedicals) in pyridine (or MOX reagent (Thermo Scientific) followed by addition of N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA) with 1% tert- butyldimethylchlorosilane (t-BDMCS) (Regis Technologies). Non-polar fractions, including triacylglycerides and phospholipids are saponified to free fatty acids and esterified to form fatty acid methyl esters either by incubation with 2% H2SO4 in methanol or by using Methyl- 8 reagent (Thermo Scientific). Derivatized samples are analysed by GC-MS using a DB- 35MS column (30 m x 0.25 mm i.d. x 0.25 μπι, Agilent J&W Scientific) installed in an Agilent 7890A gas chromatograph (GC) interfaced with an Agilent 5975C mass spectrometer (MS). Mass isotopomer distributions are determined by integrating metabolite ion fragments and corrected for natural abundance using algorithms adapted from Fernandez et al.

(Fernandez et al., 1996).

[0198] Metabolites and other small molecules are measured by liquid

chromatography mass spectrometry of polar metabolites. After extraction, samples are transferred to a polypropylene vial and samples are analysed using a Q Exactive Benchtop LC-MS/MS (Thermo Fisher Scientific). Chromatographic separation is achieved by injecting 2 μΐ of sample on a SeQuant ZIC-pHTLIC Polymeric column (2.1x150 mm 5 μΜ, EMD Millipore). Flow rate is set to 100 μΐ/min, column compartment is set to 25C, and

autosampler sample tray is set to 4°C. Mobile Phase A consists of 20 mM Ammonium Carbonate, 0.1% Ammonium Hydroxide in 100% Water. Mobile Phase B is 100%

Acetonitrile. The mobile phase gradient (%B) is as follows: 0 min 80%, 5 min 80%, 30 min 20%, 31 min 80%, 42 min 80%. All mobile phase is introduced into the Ion Max source equipped with a FIESI II probe set with the following parameters: Sheath Gas = 40, Aux Gas = 15, Sweep Gas = 1, Spray Voltage = 3.1 kV, Capillary Temperature = 275°C, S-lens RF level = 40, Heater Temp = 350°C. Metabolites are monitored in negative or positive mode using full scan or a targeted selected ion monitoring (tSIM) method. For tSFM methods, raw counts are corrected for quadropole bias by measuring the quadropole bias experimentally in a set of adjacent runs of samples at natural abundance. Quadropole bias is measured for all species by monitoring the measured vs. theoretical ml/mO ratio at natural abundance of all species with m-1, mO, ml, and m2 centred scans. Quadropole bias-corrected counts are additionally corrected for natural abundance to obtain the final mass isotopomer distribution for each compound in each sample.

[0199] Specific quorum sensing molecules are detected using this method. Quorum sensing molecules include dihydroxyacetone phosphate, glyceraldehyde 3 -phosphate, N-Acyl homoserine lactones, N-butanoylhomoserine lactone, N-hexanoyl homoserine lactone, among others.

Example 10: Quantification of the abundance of a bacterium using qPCR

[0200] Standard Curve Preparation. A standard curve is generated from a well on each assay plate containing only the bacterium of interest {e.g., Fusobacterium nucleatum) grown on media known to one skilled in the art. For quantification of Fusobacterium, the bacteria cells are plated on Fastidious Anaerobe Agar (Neogen), supplemented with 5% defibrinated sheep blood and grown overnight in Bacto Tryptic Soy Broth (BD, TSB) supplemented with 5 ug/ml hemin, 1 ug/ml menadione (Sigma) at 37 °C in an anaerobic chamber. Serial dilutions of the culture are performed in sterile phosphate-buffered saline. Genomic DNA is extracted from the standard curve samples along with the other wells. Other bacteria of interest, {e.g., bacterial listed in Tables 1 and 2) are grown following standard protocols known to one skilled in the art.

[0201] Genomic DNA Extraction. Genomic DNA is extracted from 5 μΐ of each sample using a dilution, freeze/thaw, and heat lysis protocol. Five μΐ of thawed samples are added to 45 μΐ of UltraPure water (Life Technologies, Carlsbad, CA) and mixed by pipetting. The plates with diluted samples are frozen at -20 °C until use for qPCR, which includes a heated lysis step prior to amplification. Alternatively the genomic DNA could be isolated using the Mo Bio Powersoil^®-htp 96 Well Soil DNA Isolation Kit (Mo Bio Laboratories, Carlsbad, CA), Mo Bio Powersoil^® DNA Isolation Kit (Mo Bio Laboratories, Carlsbad, CA), or the QIAamp DNA Stool Mini Kit (QIAGEN, Valencia, CA) according to the

manufacturer's instructions.

[0202] qPCR Composition and Conditions. Eight nanograms of DNA are used in each

20μ1 KAPA SYBR® FAST qPCR (Kapa Biosystems, Woburn, MA) reaction, performed in triplicate, and analyzed on the Stratagene Mx3005P (Agilent Technologies, Santa Clara, CA). The following primer sets are used: Fusobacterium spp. (Fwd 5'-

GGATTTATTGGGCGTAAAGC-3 '; Rev 5'- GGC ATTCCTACAAATATCTACGAA-3 '), and universal Eubacteria 16S (Fwd 5 '-GGTGAATACGTTCCCGG-3 '; Rev 5'- TACGGCTACCTTGTTACGACTT-3 '). For the quantification of other bacteria, previously validated primer sets are used (Rinttila, T., et al, Development of an extensive set of 16S rDNA-targeted primers for quantification of pathogenic and indigenous bacteria in faecal samples by real-time PCR, Journal of Applied Microbiology, 2004, 97(6): 1166-77).

[0203] Data Analysis. The Cq value for each well are determined using the CFX

Manager™ 3.0 software. The logio(CFU/ml) of the bacterium of interest (e.g.,

Fusobacterium) is calculated in each experimental sample by inputting a given sample's Cq value into a linear regression model generated from the standard curve and comparing the Cq values of the standard curve wells to the known logio(CFU/ml) values of those samples. The log inhibition is calculated for each sample by subtracting the logio(CFU/ml) of the bacterium of interest in the sample from the logio(CFU/mL) value of the bacterium of interest in the sample on each assay plate used for the generation of the standard curve that has no additional bacteria added. The mean log inhibition is calculated for all replicates.

Example 11: Determining bacterial titer

[0204] Counts of viable bacteria are determined by performing 10-fold serial dilutions in lx PBS and plating on Brucella Blood Agar Petri plates or other applicable solid media known to one skilled in the art (see, e.g., The Manual of Clinical Microbiology ASM Press, 10th Edition or Atlas, Handbook of Microbiological Media, 4th ed, ASM Press, 2010). Plates are incubated at 37 °C for 1-2 days. Colonies are counted from a dilution plate with 50-400 colonies and used to back-calculate the number of viable bacteria in the population. Visual counts are determined by phase contrast microscopy for further morphological identification.

[0205] Alternatively, optical density measurements of bacteria-containing media is used to determine a the concentration of bacteria by comparing to a standard curve of known concentrations of bacteria that have previously measured optical densities in culture.

[0206] Bacteria are isolated and quantified by cell sorting techniques known to one skilled in the art {e.g., as described in Nebe-von-Caron, G., et al, Analysis of bacterial function by multi-color fluorescence flow cytometry and single cell sorting, Journal of Microbiological Methods, 2000, 42(1):97-114 ). Fluorescently labelled antibodies that recognize specific bacterial cell surface proteins are incubated with the bacteria of interest. After the incubation, the bacterial cells are washed with lx PBS to remove the unbound antibody. The cells are then analyzed with flow cytometry to count the number of bacteria in a complex mixture of other bacteria or eukaryotic cells (Example 13). Antibodies are either commercially purchased or raised against a specific antigen of interest using protocols known to one skilled in the art. Instead of using antibody stainings, the bacterium of interest can also be marked with a fluorescent protein reporter (e.g., GFP) to aid cell number quantification (Example 12).

[0207] Spore content is assessed using germination techniques where germinants like bile acids, heat treatment, are used to measure growth of spores after a spore preparation removes non-spore forming bacteria. Additionally Dipicolinic acid (DP A) fluorescence is used when conjugated to terbium (Tb3+) to quantify spores in a solution (e.g., as described in Yung et a/., FEMS, 2007).

Example 12: Labeling of bacterial cells with spectrally-distinct fluorescent protein reporters for ease of detection and quantification of cell numbers

[0208] The bacterium of interest is transformed with a fluorescent protein-expressing plasmid using standard methods known to one skilled in the art. For labeling one bacterium with a fluorescent protein (i.e., single-color experiment), the bacterium of interest is transformed with a plasmid that has a nucleic acid sequence encoding green fluorescent protein (GFP) operably linked to a constitutive promoter. The promoter is chosen such that the promoter causes the active transcription of the operably linked sequence in the respective bacterium. For co-culture experiments such as a competition assay (i.e., a dual-color experiment), the two bacteria of interest are transformed, each with a plasmid that expresses one of two spectrally distinct fluorescent proteins (e.g., CFP and YFP or GFP and REP). Alternatively, the fluorescent protein expression cassettes can also be integrated, in single copy, into the bacterial chromosomes using methods known to one skilled in the art. The fluorescently labelled bacteria are measured and quantified using flow cytometry as previously described (e.g., in Palmer, A. et al, 2010, Chemical decay of an antibiotic inverts selection for resistance, Nat. Chem. Biol, 6(2); 105-107).

Example 13: Detection and isolation of different cell populations using flow cytometry and fluorescence-activated cell sorting (FACS)

[0209] Flow cytometry is used to analyze the cell type, lineage, maturation stage, or activation status of a cell by analyzing the cell surface or intracellular expression of different molecules. Cell populations of various origins are stained with fluorescently labeled probes, including antibodies, that are specific for those molecules. Fluorescent-activated cell sorting (FACS) is an adaptation of flow cytometry that allows separating and isolating cell populations according to which and how much fluorescent probe they bind.

[0210] Prior to flow cytometry analysis, single cell suspensions are prepared using one of the following protocols (see i to vi below) or other methods known to one skilled in the art. All cell clumps are either disrupted or removed prior to flow cytometry to avoid clogging of the machine, (i) Cell preparation of suspension tissue culture cells: Suspension cells grown in a dish are counted and resuspended in lx PBS to a final concentration of 1E6 cells/ml. (ii) Cell preparation of adherent tissue culture cells: Adherent cells are detached from the plate using trypsin, scraping or other methods known to one skilled in the art. The cells are resuspended in lx PBS to a final concentration of 1E6 cells/ml. (iii) Cell preparation from lymphoid tissue: Spleen tissue, thymus tissue or lymph nodes are teased apart using a plunger and then passed through a cell strainer to remove cell debris and clumps. The cells are pelleted by centrifugation (300-400 g, 5 min) and resuspended in lx PBS to a final concentration of 1E6 cells/ml. (iv) Cell preparation from non-lymphoid tissue: The non- lymphoid tissue is minced into 2-4 mm pieces using scissors or a scalpel and then further digested using appropriate enzymes (depending on the tissue) known to one skilled in the art. The cell suspension is then pelleted by centrifugation (300-400 g, 5 min), washed with lx PBS to remove any remaining enzyme solution, and resuspended in lx PBS to a final concentration of 1E6 cells/ml. (v) Cell preparation from tumor-specific tissue: Tumor-bearing regions are identified in tissue via incubation with the dye methylene blue or another method known to the art, and these tissues are excised. The tissue samples are then incubated with a combination of enzymes, including but not limited to collagenase, DNase, and hyaluronidase. Single-cell suspensions are created by straining the cells through a 70 μπι nylon mesh.

Alternatively, tissue samples are rendered a cellular suspension through incubation with Hanks' balanced salt solution enriched with 1 mM ethylenediaminetetraacetic acid, vortexing, and incubation with collagenase, as known to one skilled in the art. (vi) Isolation of peripheral blood mononuclear cell (PBMC) from whole blood: Red blood cells and polymorphonuclear cells are removed using a density gradient centrifugation with Ficoll- Paque (GE Healthcare Ltd.) following established protocols (Fuss I, et al., Isolation of whole mononuclear cells from peripheral blood and cord blood, Curr Protoc Immunol., 2009 Apr;Chapter 7:Unit7.1.). This procedure separates whole blood into two fractions, above and below the density of the Ficoll-Paque, which is a solution of high molecular weight sucrose polymers. Mouse PBMCs are isolated using Ficoll with a density of 1.084 g/ml and human PBMCs can be isolated using Ficoll with a density of 1.077 g/ml. [0211] Prior to flow cytometry analysis, the suspension of single cells is stained with a panel of fluorescently labeled antibodies, which are usually directed against specific cell surface markers. Alternatively, cytoplasmic molecules can be stained by temporarily permeabilizing the cells and permitting the labeled antibodies to enter through the plasma membrane. Cell permeabilization is performed using methods known to one skilled in the art. The antibody staining is used to identify and quantify the presence of a variety of relevant cell types, including immune cells, bacterial cells, and stromal cells. In all flow cytometry and FACS experiments, care is taken to ensure that the fluorescent emission signals do not spectrally overlap, thereby enabling independent measurement of each marker. The stated markers (see below) are used for the identification and isolation of murine cell populations. For human cells, the corresponding human markers known in the art are used.

[0212] To identify the population of CD4⁺ "helper" T cells, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of CD4⁺ Helper T cells, including CD3, CD4, CD8, and CD25. By way of non-limiting example, cells that are CD3⁺, CD4⁺ but CD8^" and CD25^" are generally classified as helper T-cells.

[0213] To identify the population of regulatory T cells (Tregs), also known as suppressor T cells, a cell suspension is incubated with antibodies against markers known in the art to be characteristic of Treg cells, including CD3, CD4, CD25 (IL-2R), CD39,

CD45RA, CD45RO, CD73, CD 101, CD127, CD152 (CTLA-4), CD357 (GITR/AITR), Foxp3, or a combination thereof. Natural Tregs are CD4⁺, and CD25⁺ but alternative Treg subpopulations (e.g., induced Tregs or peripheral Tregs) are identified using marker combinations known to one skilled in the art.

[0214] To identify the population of Thl cells contained within the sample, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of Thl cells, including but not limited to CD3, CD4, CXCR3, CCR5, and CD69.

[0215] To identify the population of Th2 cells contained within the sample, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of Th2 cells, including but not limited to CD3, CD4, CCR3, CCR4, CCR8, and ST2L.

[0216] To identify the population of Thl7 cells contained within the sample, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of Thl7 cells, including but not limited to BTLA, CD4, CD99, CD161, CD 196 (CCR6), CD200, CD212 (IL-12Rp l), CD360 (IL-21R), IL-17A, IL-17F, IL-18Ra, IL-23R, RORy(t), or a combination thereof. [0217] To identify the population of γδ T cells, a given cell suspension is incubated with antibodies against markers known in the art to be characteristic of γδ T cells, which express the γδ T-cell receptor (TCR). The markers include but are not limited to CD3, y5TCR (e.g., using the GL3 antibody from BD), CD4, and CD8, or a combination thereof. Most γδ T cells are y5TCR⁺, CD3⁺, CD4^" and CD8^" although some are CD8⁺.

[0218] To identify the population of natural killer T (NKT) cells, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of NKT cells, including but not limited to apTCR, CD l, CD3, CD4, CD8, CD16 (Fc receptor for IgG), CD56, and CD161 (NK1.1). NKT cells include both NK1.1⁺ and NKl . l^", as well as CD4⁺, CD4^", CD8⁺, and CD8^". NKT cells are typically CD3⁺, CD16⁺, and CD56⁺.

[0219] To identify the population of cytotoxic T cells (CTLs), the cell suspension is incubated with antibodies against markers known in the art to be characteristic of CTLs, including but not limited to CD3, CD4, and CD8, or a combination thereof. Cells that are CD3⁺, CD4^" and CD8⁺ are generally classified as cytotoxic T cells.

[0220] To identify natural killer (NK) cells, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of NK cells, including but not limited to

[0221] CD3, CD16 (Fc receptor for IgG), CD49b+ (DX5), CD56, CD122, and

CD161( NK1.1), or a combination thereof. Typical mouse NK cells are CD3^", CD16⁺, CD49b⁺, and NKl . l⁺.

[0222] To identify follicular B cells (FO B cells), the cell suspension is incubated with antibodies against markers known in the art to be characteristic of FO B cells, including but not limited to CD l, CD5, CD 19, CD21, CD23, IgD, IgM, and MHC class II, or a combination thereof. FO cells are usually CDl ^", CD5^", CD19⁺, CD21 low, CD23⁺, IgD⁺, and IgM⁺.

[0223] To identify marginal zone (MZ) B cells, the cell suspension is incubated with antibodies against markers known in the art to be characteristic of MZ B cells, including but not limited to CDl, CD21, CD23, CD27, IgD, and IgM, or a combination thereof. MZ B cells are typically CD1⁺, CD21^Mgh, CD23^", CD27⁺, IgD^low and IgM⁺.

[0224] To identify dendritic cells (DCs), the cell suspension is incubated with antibodies against markers known in the art to be characteristic of DCs, including but not limited to CDl lc, B220, CD4, CDl lb/Mac- 1, and MHC class II, and a combination thereof. Classical DCs (cDCs) are CDl lb⁺ and CD l lc⁺ and can be further divided into CD8⁺ and CD8^" subpopulations though the CD8⁺ cDCs are also CDl lb^". Mouse plasmacytoid DCs (pDCs) are CD4⁺, CD1 lb^", CD1 lc⁺, and B220⁺. Contaminating NK cells can be removed by negatively selecting against CD49b⁺ and/or CD161⁺ cells.

[0225] To identify the population of macrophages, the cell suspension is incubated with antibodies against markers known in the art to characterize macrophages, including but not limited to CD1 lb/Mac- 1, CD14, CD40, CD64, and F4/80 (Ly71) and a combination thereof. Murine macrophages are generally classified as CD1 lb⁺, CD68⁺, and F4/80⁺ cells.

[0226] To identify the population of neutrophils, the cell suspension is incubated with antibodies against markers known in the art to characterize neutrophils, including but not limited to CD1 lb, GR-1 (Ly6C, Ly6G). Neutrophils are generally classified as CD1 lb⁺ and GR-1⁺.

[0227] To identify the population of myeloid-derived suppressor cells (MDSCs), the cell suspension is incubated with antibodies against markers known in the art to characterize MDSCs, including but not limited to CD33, CD1 lb, CD14, CD15, and a combination thereof. MDSCs are typically negative for CD3, CD19, and CD56. Mouse MDSCs are generally characterized as CD1 lb⁺ and LY6G⁺.

[0228] To identify the population of fibroblasts, the cell suspension is incubated with antibodies against markers known in the art to characterize fibroblasts, including but not limited to PDGFRa. Specific markers for epithelial cells or immune cells should be absent in order to distinguish fibroblasts from these other two cells types.

[0229] To identify the population of endothelial cells, the cell suspension is incubated with antibodies against markers known in the art to characterize endothelial cells, including but not limited to CD31, CD34, VCAM-1, ICAM-1, VE-cadherin, and P-selectin, all of which are typically constitutively expressed in endothelial cells.

[0230] A live/dead viability stain can also be use exclude dead cells from the analysis.

[0231] Fluorescently labeled antibodies against microbial antigens are also used to measure specific bacteria within tissue, within cells, or in fluid (e.g., blood or lymph).

[0232] Besides using fluorescently tagged antibodies or dyes (e.g., DAPI), cell populations can also be labelled in vivo by the expression of transgenes that encode fluorescent proteins, such as green fluorescent protein (GFP).

[0233] As an alternative to FACS, the same antibodies can be attached to magnetic beads to physically isolate cells expressing the specific antigens (see above). The

"immunomagnetic" beads are then added to the cell mixture and the cells of interest are pulled out of the cell suspension using a strong magnet (see, e.g., Wang E.C., et al., Cell sorting using immunomagnetic beads, Methods Mol. Biol. , 1992;80:347-57). Example 14: Determine the infection profile of a polymer-coated bacterium of interest

[0234] Wild-type mice (e.g., C57BL/6 or BALB/c) are infected with the polymer- coated bacterium of interest to determine the in vivo infection profile of the polymer-coated bacterium. A polymer-coated bacterial composition is prepared according to the methods provided herein. Administration of the polymer-coated bacterial composition can be performed orally {e.g., via gavage), intravenously {e.g., via tail vein injection),

intramuscularly, intraperitoneally, or subcutaneously. The mice can receive a single high dose of the polymer-coated bacterium of interest {e.g., lxlO⁹ CFU) or several low doses {e.g., lxlO⁴ CFU). At least four wild-type mice are used for determining the infection profile of the polymer-coated bacterium of interest. The mice, which are used in the experiment, may be started on an antibiotic pre-treatment via instillation of a cocktail of kanamycin (0.4 mg/ml), gentamicin, (0.035 mg/ml), colistin (850 U/ml), metronidazole (0.215 mg/ml) and

vancomycin (0.045 mg/ml) in the drinking water prior to administration of the polymer- coated bacterium of interest. The mice are housed under specific pathogen-free conditions following approved protocols. Blood and stool samples (see, Example 24) can be taken at appropriate time points.

[0235] The mice are humanely sacrificed at various time points {i.e., hours to days) post infection with the polymer-coated bacterium of interest and a full necropsy under sterile conditions is performed. Following standard protocols, lymph nodes, adrenal glands, liver, colon, small intestine, stomach, spleen, kidneys, bladder, pancreas, heart, skin, lungs, brain, and other tissue of interest are harvested and are used directly or snap frozen for further testing. The tissue samples are dissected and homogenized to prepare single-cell suspensions following standard protocols known to one skilled in the art. The number of bacteria present in the sample is then quantified by either plating on agar and colony counting (Example 11) or by qPCR with primers that are specific to the bacterium of interest (Example 10). The number of bacteria present is normalized by the wet weight of the tissue {i.e., CFU/g). The polymer-coated bacterium of interest can also be marked with a fluorescent protein {e.g., GFP) prior to infection of the mice to allow detection by FACS (see, Wang N., et al, Measuring bacterial load and immune responses in mice infected with Listeria

monocytogenes, J. Vis. Exp., 2011, (54) and Example 13) or fluorescence microscopy (Vankelecom H., Fixation and paraffin-embedding of mouse tissues for GFP visualization, Cold Spring Harb. Protoc, 2009, 2009(10). The polymer-coated bacterium of interest can also be detected by antibody staining (Example 13). [0236] The in vitro infection profile of the polymer-coated bacterium of interest is also determined with murine or human cells in culture using an in vitro infection assay like the gentamicin protection assay (Elsinghorst E. A., Measurement of invasion by gentamicin resistance, Methods Enzymol., 1994, 236:405-20) or a modification thereof. In short, the mammalian cells of interest (e.g., epithelial cells or macrophages) are mixed with the polymer-coated bacterium of interest (e.g., Fusobacterium nucleatum, Salmonella, or Listeria monocytogenes) and co-cultured for several hours. The co-culture is then treated with an antibiotic (e.g., gentamicin), which does not penetrate into the eukaryotic cell. Intracellular bacteria are hence protected from the antibiotic and survive whereas extracellular bacteria are rapidly killed. The antibiotic and the dead bacterial cells are washed away and the eukaryotic cells are lysed to release the intracellular bacteria, which are then enumerated as described above for the in vivo infection experiment.

[0237] The assay can be further modified to analyze the adhesion of the polymer- coated bacterium of interest to the mammalian cell of interest (see Letourneau J., et al, In vitro assay of bacterial adhesion onto mammalian epithelial cells, J. Vis. Exp., 2011, (51)). Bacterial adhesion is a critical first step prior to invasion and/or secretion of bacterial toxins. Bacterial adhesion is also an important feature for bacterial drug or antigen delivery (e.g., Example 22). The mammalian cells of interest (e.g., macrophages) are isolated from human donors or mice using FACS (Example 13) or using other standard cell isolation protocols known to one skilled in the art. Mammalian tissue culture cells can also be purchased (e.g., from ATCC).

[0238] The bacterial cells can also be labeled with GFP (Example 12) or a fluorescent dye (e.g., Example 30) to allow detection of invasion and adhesion by fluorescence microscopy (see Bettencourt, P., et al, Application of Confocal Microscopy for

Quantification of Intracellular Mycobacteria in Macrophages, Microscopy: Science,

Technology, Applications and Education, Badajoz: Formatex Research Center, 2010, 1 :614- 621, ISBN: 978-84-614-6189-9).

[0239] The infection profile of the polymer-coated bacterium of interest can also be altered by attaching a molecule (e.g., a bacterial adhesin like FadA, see Xu M., et al, FadA from Fusobacterium nucleatum utilizes both secreted and nonsecreted forms for functional oligomerization for attachment and invasion of host cells, J. Biol. Chem., 2007,

282(34):25000-9) to the bacterial surface using methods described within this application (see, Examples 30-40, and 44). Analysis of the infection profile of the polymer-coated bacterium with and without surface attachment of the molecule of interest (e.g., FadA) shows that in vivo distribution of the bacterium of interest is altered by the surface attachment.

Example 15: Determine the infection profile of a polymer-coated bacterium of interest in a tumor mouse model and isolate mutants with an altered infection profile

[0240] To determine the infection profile of the polymer-coated bacterium of interest in a tumor model, a syngeneic, subcutaneous mouse model of e.g., colorectal cancer (CT-26 cells) or a different cancer model is used. Briefly, CT-26 (CAT# CRL-2638) tumor cells are cultured in vitro as a monolayer in RPMI-1640 or DMEM supplemented with 10% heat inactivated fetal bovine serum at 37 °C in an atmosphere of 5% C02 in air. The

exponentially-growing cells are harvested and counted prior to tumor inoculation. 6 female BALB/c mice are used for this experiment. The mice are 6-8 weeks old and weigh approximately 16-20 g. For the tumor development, each mouse is injected subcutaneously on both flanks with 5xl0⁵ CT-26 tumor cells in 0.1 ml of lx PBS. The mice can receive an antibiotic pre-treatment via instillation of a cocktail of kanamycin (0.4 mg/ml), gentamicin (0.035 mg/ml), colistin (850 U/ml), metronidazole (0.215 mg/ml), and vancomycin (0.045 mg/ml) in the drinking water from day 2 to 5 and an intraperitoneal injection of clindamycin (10 mg/kg) on day 7 after tumor injection. Tumor size, mouse weight, and body temperature are monitored thrice weekly on nonconsecutive days.

[0241] On day 10 after tumor injection or after the tumor volume reaches 100 mm³, the mice are infected with the polymer-coated bacterium of interest as described (see, Example 14). The mice are humanely sacrificed at various time points (i.e., hours to days) post infection with the bacterium of interest and a full necropsy under sterile conditions is performed. Following standard protocols, tumor tissue, metastases, lymph nodes, adrenal glands, liver, colon, small intestine, stomach, spleen, kidneys, bladder, pancreas, heart, skin, lungs, brain, and other tissue of interest are harvested and are used directly or snap frozen for further testing. The tissue samples are processed and analyzed as described above (see, Example 14).

[0242] The infection profile of the polymer-coated bacterium of interest is also determined with tumor cells and non-tumor cells in culture using an in vitro infection assay like the gentamicin protection assay (see, Example 14). Tumor and non-tumor cells can be obtained from a tumor mouse model (see above) following standard protocols known to one skilled in the art. Tumor cell lines (e.g., CT-26) can also be purchased from ATCC. Example 16: Determine how the infection profile of a polymer-coated bacterium of interest can be altered by co-administration of a second bacterium

[0243] The bacterium Fusobacterium nucleatum can facilitate the penetration of other microorganisms, such as the non-pathogenic Escherichia coli lab strain DH5a, through an endothelial cell monolayer in the context of a transwell assay (Fardini Y., et al,

Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity, Mol. Microbiol, 2011, 82(6): 1468-80). Fusobacterium nucleatum may bind to the polymer-coated bacterium of interest, like E. coli, and allows the non-infectious bacterial cells to "piggyback" into the mammalian cell. Hence, the co-administration with Fusobacterium can change the infection profile of the polymer-coated bacterium of interest {e.g., E. coli or Salmonella).

[0244] A binary bacterial composition is prepared by resuspending an invasive bacterium of interest {e.g., Fusobacterium nucleatum) and a polymer-coated bacterium of interest in lx PBS to a final total concentration of 10 CFU/ml. The cell ratio is 1 : 1 but other ratios {e.g., 100: 1, 100: 1, 10: 1, 1 : 10, or 1 : 100, 1 : 1000) can also be used. For a control experiment, a composition of the bacterium of interest alone is also prepared using the same concentration of bacteria as in the respective binary composition.

[0245] Wild-type mice (see, Example 14) or a murine tumor model of e.g., colorectal cancer (see, Example 15) are used to determine the in vivo infection profile. The mice are injected with either the binary composition or the composition of the polymer-coated bacterium of interest alone (see, Examples 14 and 15). The mice are handled, processed, and analyzed as described (see, Examples 14 and 15). The number of bacteria present in the sample is then quantified by either plating on selective agar and colony counting (see, Example 11) or by qPCR with primers that are specific to either the polymer-coated bacterium of interest or to Fusobacterium nucleatum (see, Example 10). The number of bacteria present is normalized by the wet weight of the tissue {i.e., CFU/g).

[0246] The in vitro infection profile of the polymer-coated bacterium of interest is also determined with tumor cells and non-tumor cells in culture in the presence and absence of Fusobacterium nucleatum using an in vitro infection assay (see, Example 14) or a transwell penetration assay (see, Fardini Y., et al, Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity, Mol. Microbiol, 2011, 82(6): 1468-80). Non-tumor and tumor cells can be obtained from wild-type mice or a tumor mouse model respectively following standard protocols known to one skilled in the art. Tumor cell lines (e.g., CT-26) and other murine cell lines can also be purchased from ATCC. Human cells can also be used.

Example 17: Determine how the infection profile of a polymer-coated bacterium of interest can be altered functionalizing the polymer with a molecule of interest

[0247] A bacterial composition is prepared by resuspending a polymer-coated bacterium of interest (e.g., Fusobacterium nucleatum, Salmonella, or Listeria

monocytogenes) in lx PBS to a final concentration of 10 CFU/ml. Wild-type mice (see, Example 14) or mice of a tumor model of e.g., colorectal cancer (see, Example 15) are used to determine the in vivo infection profile as described above (see, Examples 14 and 15) except that the polymer is functionalized with a molecule of interest (e.g., a sugar, a prebiotic, a small molecule, a protein, a peptide, an antibody, a nucleic acid, a lipid).

[0248] Whether the molecules of interest alters the infection profile of the polymer- coated bacterium of interest is also analyzed using an in vitro infection assay as described (see, Example 14). As controls, the bacterium of interest polymer are tested alone.

Example 18: Screen for polymer-coated bacteria that preferentially infect tumor-associated macrophages (TAMs)

[0249] A polymer-coated bacterial composition is prepared by resuspending a polymer-coated bacterium of interest (e.g., Fusobacterium nucleatum, Salmonella, or Listeria monocytogenes) in lx PBS to a final concentration of 10 CFU/ml. Wild-type mice (see, Example 14) or mice of a tumor model of e.g., colorectal cancer (see, Example 15) are infected with the polymer-coated bacterium of interest as described above (see, Examples 14 and 15).

[0250] The mice are humanely sacrificed at various time points post infection (i.e., hours to days) with the polymer-coated bacterium of interest. Macrophages and tumor- associated macrophages (TAMs) are isolated from normal tissue of wild-type mice or from cancerous tissue of the tumor mice respectively (see, Example 13 and Laoui, D., et al, Purification of Tumor- Associated Macrophages (TAM) and Tumor- Associated Dendritic Cells (TADC). Bio-protocol, 2014, 4(22): el294). Bone marrow-derived macrophages can also be isolated from wild-type mice as described (see, Example 22). The isolated

macrophages are transferred to a 6-well tissue culture plate. The cells are washed three times with 0.5 ml lx PBS. After the last wash, the cells are lysed by either adding 0.5 ml of lx PBS with 0.1% Triton-X or 0.5 ml of 4 M guanidine thiocyanate, 0.5% Na N-lauryl sarcosine, 25 mM sodium citrate, and 0.1 M β-mercaptoethanol. The macrophages can also be vortexed and passaged through a 21 gauge needle to shear the cells. The number of intracellular bacteria is then determined by plating serial dilutions on agar plates and colony counting (see, Example 11). The number of intracellular bacteria can also be determined by qPCR (see, Example 10) using a primer set that is specific to the bacterium of interest. The administered polymer-coated bacterium of interest can also be labelled with a fluorescent protein (see, Example 12) to allow quantification with FACS (see, Example 13) or visualization by microscopy.

[0251] This experiment shows that the number of intracellular bacteria can be vary between the macrophages of wild-type mice and TAMs isolated from the tumor mice, depending upon bacterial strain tested.

[0252] A number of bacterial strains and mutants thereof are tested for the ability to infect TAMs using an in vitro infection assay in a 384-well plate format. In short,

approximately 5,000 TAMs/well are seeded in 30 μΐ of an appropriate cell culture medium (e.g., DMEM (HG) + 10% FBS). The plated macrophages are pre-incubated at 37 °C with 5% CO² for at least several hours to allow the cells to adhere before adding the bacteria. The bacterial cells of interest are resuspended in lx PBS to a final OD₆oo of 5E6 CFU/ml. To increase throughput, bacterial strains can also be pooled or administered in defined ratios. The macrophages are infected by adding 10 μΐ of the bacterial suspension (-50,000 bacterial cells) or a multiplicity of infection (MOI) of 10 to each well. Higher or lower MOIs can also be used. The plate is then incubated at 37 °C for 1 h. The plate can also be centrifuged (5 min, 1,000 rpm) using a swinging bucket clinical centrifuge with microtray adapters prior to the 1-h incubation to increase bacterial invasion. Extracellular bacteria are killed by adding an antibiotic {e.g., 50 μg/ml gentamicin) to the infected cells. The plate is incubated for another hour at 37 °C and then washed thrice with lx PBS to remove the dead extracellular bacteria and the antibiotic. Care is taken to not remove the adherent macrophages during the washes. To release the intracellular bacteria, the macrophages are lysed by adding lx PBS with 0.1% Triton-X to the wells.

[0253] To measure the number of live bacteria, serial dilutions of the cell lysate are plated on agar plates and counted for colonies of the bacterium of interest (see, Example 11). The number of cells of the bacterium of interest can also be quantified using qPCR and primers that are specific to the bacterium of interest (see, Example 10). For bacterial identification, -5-10 μΐ of the cell lysate, which contains the live bacteria, is inoculated into appropriate media to culture the bacteria. The bacteria are then identified using 16S rRNA analysis (see, Example 4 and 6). Bacterial genomes can also be sequenced (see, Example 8) to further analyze the mutants.

[0254] The in vitro infection assay is repeated with normal macrophages to show that the bacteria that infect TAMs with a high efficiency (as previously determined) preferentially infect TAMs over normal macrophages. The in vitro infection assay can also be modified to test for bacterial adhesion (see, Example 14) instead of bacterial invasion.

Example 19: Investigation of whether a polymer-coated bacterium of interest can infect myeloid-derived suppressor cells and escape clearance by the immune system

[0255] Myeloid-derived suppressor cells (MDSCs) infiltrate tumors and are associated with poor patient prognosis (Gabitass R.F. et al, Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13, Cancer Immunol Immunother., 2011, 60(10): 1419-30). MDSCs strongly inhibit T cell proliferation and activation, suppress natural killer (NK) cell responses, and can promote angiogenesis and metastases (Schmid M.C. & Varner J.A., Myeloid cells in the tumor microenvironment: modulation of tumor angiogenesis and tumor inflammation, J. Oncol, 2010, 2010:201026). However, MDSCs that are infected with highly attenuated Listeria (Listeria(at)) can protect the Listeria(at) cells from clearance by the immune system and deliver the Listeria(at) predominantly to the microenvironment of metastases and primary tumors where they kill tumor cells (Chandra D., et al, Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice, Br. J. Cancer., 2013, 108(11):2281-90).

[0256] An in vitro infection assay is used to test whether a polymer-coated bacterium of interest, e.g., Fusobacterium nucleatum, can infect MDSCs. Two major groups of MDSCs exits, i.e., granulocytic MDSC (gMDSC) and monocytic MDSC (mMDSC), and both types are analysed using this assay. Listeria(at) cells are used as a positive control. The MDSCs are isolated from normal wild-type mice or a tumor mouse model (e.g., 4T1 tumor-bearing mice) using FACS (see, Example 13) as previously described (Chandra D., et al, Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based

immunotherapy against metastatic breast cancer in young and old mice, Br. J. Cancer, 2013, 108(11):2281-90). The MDSCs are infected with the polymer-coated bacterium of interest in a 1 : 10 ratio and cultured for 1 h in RPMI containing 10% FBS. The infected cells are then treated with gentamicin (50 μg/ml) for 1 h and washed to remove the dead bacteria and the gentamicin. Subsequently, the infected cells are cultured and stopped at various time points. To measure the number of live bacteria, the infected cells are lysed in water, plated on agar, and counted for colonies of the bacterium of interest (see, Example 11). The number of the bacterium of interest can also be quantified using qPCR and primers that are specific to the bacterium of interest (see, Example 10).

Example 20: Analyze the polymer-coated bacterial infection susceptibility of a mammalian cell and how it depends on the genetic makeup of the mammalian cell

[0257] A polymer-coated bacterium with a given infection profile is used to test whether the invasion of the mammalian cell by the polymer-coated bacterium is altered by mutations or other genetic changes of the mammalian cell (e.g., genetic changes that up- or downregulate the expression of proinflammatory chemokines and cytokines). Macrophage cell lines (e.g., RAW 264.7) are purchased from ATCC or purified from transgenic mice strains as described (see, Example 22). Macrophages can also be obtained from cancer patients or healthy donors following published protocols (e.g., Menck K., et al, Isolation of human monocytes by double gradient centrifugation and their differentiation to macrophages in teflon-coated cell culture bags, J. Vis. Exp., 2014, (91):e51554).

[0258] The in vitro macrophage invasion assay is performed as described above (see,

Examples 14 and 18). Macrophage adhesion can similarly be analyzed (see, Example 14). This assay identifies which bacteria are suited for invading the macrophages of patients that harbor certain mutations (e.g., mutations in oncogenes or tumor-suppressor genes).

Example 21: Design of an affinity chromatography column to screen for polymer-coated bacteria that bind to cancer cells

[0259] Cell affinity chromatography is used to analyze the binding of a large collection of polymer-coated bacteria to a cancer cell of interest. The chemically fixed cancer cells are immobilized on a monolithic polyacrylamide cryogel affinity matrix (see, Dainiak M.B., et al, Chromatography of living cells using supermacroporous hydrogels, cryogels, Adv. Biochem. Eng. Biotechnol, 2007;106: 101-27), which forms the stationary phase matrix of the affinity column. The supermacroporous monolithic cryogel is polymerized in a standard column (e.g., length 6.3 cm x diameter 2 cm) at subzero temperature under frozen condition for 12 h. The cryogel is then incubated at room temperature (i.e., 25 °C) and extensively washed to remove unreacted monomers following a published protocol (see Kumar A. & Srivastava A., Cell separation using cryogel -based affinity chromatography, Nat. Protoc, 2010, 5(11): 1737-47). The resulting cryogel column has a continuous matrix with highly interconnected large (10-100 μιη) pores, which allow convective migration of large particles (e.g., bacteria or large aggregates of bacteria) without clogging the column. The cryogel column can be prepared in standard column format (as discussed above) or in a 96-minicolumn plate format (see Dainiak, M.B., et al., Macroporous monolithic hydrogels in a 96-minicolumn plate format for cell surface-analysis and integrated binding/quantification of cells, Enzyme Microb. Technol., 2007, 40(4):688-695).

[0260] For cancer cell attachment to the cryogel column matrix, the cryogel is first functionalized with Staphylococcus aureus protein A, which can bind IgG antibodies. The protein A ligand is covalently coupled to the epoxy-activated cryogel monolith by

functionalization of the epoxy-activated cryogel with ethylenediamine followed by crosslinking using glutaraldehyde (see Kumar A. & Srivastava A., Cell separation using cryogel-based affinity chromatography, Nat. Protoc, 2010, 5(11): 1737-47). Second, the cancer cells of interest are chemically fixed by adding formaldehyde to a final concentration of 4% to the cell culture medium. The cells are then incubated for 10-30 min at room temperature. A fresh 10-ml ampule of 16% aqueous formaldehyde (cat# 18505, Ted Pella) is used to guarantee reproducible fixation conditions. The fixation reaction is quenched by adding glycine to a final concentration of 100-200 mM. The cancer cells are then washed three times with lx PBS. Alternative fixation protocols known to one skilled in the art can also be used. To attach the cancer cells to the protein A-functionalized cryogel, the cancer cells are incubated with an IgG antibody that is specific to a cell surface protein of the cancer cells. The IgG-bound cancer cells are then loaded onto the protein A-functionalized cryogel column. Protein A binds to the Fc region of the IgG antibody and hence tethers the fixed cancer cells to the cryogel column. Non-labeled cells remain unbound and flow through the column when the column is washed with a standard buffer or a bacterial growth medium.

[0261] A solution of the polymer-coated bacterium of interest or a composition of a polymer-coated bacterial mixture is prepared {e.g., 1E7 to 1E9 CFU/ml) and the polymer- coated bacterial solution is run over the column using an experimentally optimized flow rate. Polymer-coated bacterial cells that do not bind to the matrix-immobilized cancer cells are collected in the flow through when the column is washed with a standard buffer or media. After several washes, the bound bacteria are eluted from the affinity cryogel column by either (i) mechanically squeezing the cryogel matrix or (ii) washing the column with a solution of an IgG antibody that has a higher affinity to protein A than the original antibody. This causes displacement and desorption of the matrix-immobilized cancer cells and the bacteria from the cryogel. Bacteria can be identified using 16S rRNA sequencing (see, Example 4) and/or whole genome sequencing (see, Example 8).

[0262] Besides cancer cells, many other cell types can be attached to the cryogel following the protocol described above. For example, cryogel columns with attached macrophages or dendritic cells (DCs) can be used in combination with the cancer cell cryogel column to screen for a polymer-coated bacterium of interest that binds to cancer cells but does not bind to macrophages or DCs. Affinity cell separation allows for positive selection (i.e., cells that bind to the matrix-immobilized cells) and negative selection (i.e., cells that do not bind to the matrix-immobilized cells).

[0263] Instead of attaching entire mammalian cells to the cryogel column, a ligand of interest (e.g., a cancer cell surface protein or an extracellular domain thereof) can be attached to the cryogel using crosslinking with glutaraldehyde. The protocol is analogous to the attachment of protein A to the cryogel as described (see above).

Example 22: Analyze uptake of a polymer-coated bacterium of interest by macrophages and dendritic cells.

[0264] In total, 18 female nude Balb/c mice (Charles River) of age 7-12 weeks are used for this experiment. The mice are divided into 3 groups of 6 mice each. Mice of group A are injected subcutaneously with 100 μΐ of 1E9 CFU/ml of the polymer-coated bacterium of interest (e.g., a bacterium coated with a polymer that is functionalized with an antigen) while group B mice are injected subcutaneously with 100 μΐ of 1E9 CFU/ml of the uncoated bacterium. Bacterial compositions are made by resuspending the bacterium of interest in lx PBS to a final concentration of 1E9 CFU/ml. Group C is injected subcutaneously with 100 μΐ of the vehicle (i.e., lx PBS). Higher or lower bacterial titers can also be used for infecting the mice and the bacteria can be administered via different routes (e.g., PO or via tail vein injection). The mice can receive a single high dose (e.g., 1E9 CFU) of the bacterium of interest or several low doses (e.g., 1E4 CFU) at the same or at different intervals. The mice are housed under specific pathogen-free conditions and used following approved protocols. Blood and stool samples (see, Example 24) can be taken at appropriate time points.

[0265] The mice are humanely sacrificed at various time points (i.e., hours to days) post infection with the bacterium of interest and a full necropsy under sterile conditions is performed (see, Example 14). Macrophages and dendritic cells (DCs) are isolated from tissue using FACS (see, Example 13 and Vremec D. & Shortman K., The isolation and

identification of murine dendritic cell populations from lymphoid tissues and their production in culture, Methods Mol. Biol, 2008, 415: 163-78). The number of bacteria present in the sample is then quantified by either plating on agar and colony counting (see, Example 11) or by qPCR with primers that are specific to the bacterium of interest (see, Example 10). The number of bacteria present is normalized by the wet weight of the tissue {i.e., CFU/g). The bacterium of interest can also be marked with a fluorescent protein {e.g., GFP) prior to infection of the mice to allow detection of the cells by FACS (see, Example 12).

[0266] Bone marrow-derived macrophages are isolated from C57BL/6 mice and grown in DMEM supplemented with 10% FCS, 20% L cell conditioned medium, penicillin, and streptomycin. Murine macrophages can also be purchased from ATCC. At least one day prior to infecting the macrophages with the bacterium of interest the macrophages are grown in the absence of penicillin and streptomycin. The bacterium of interest is declumped by passaging the bacteria through a 21 gauge needle. The bacteria are resuspended in DMEM with 5% fetal calf serum, 10 mM HEPES, pH 7.4. Confluent monolayers of macrophages are then infected with a mid-log phase culture of the bacterium of interest using a multiplicity of infection (MOI) of 20 in standing 75 cm² vented tissue culture flasks. Infections are initiated by centrifugation (1,000 g, 10 min) of the bacterium of interest onto the macrophage monolayers, followed by incubation at 37 °C for 2, 4, 6, or 24 hours.

[0267] After the incubations, the bacteria are washed away or killed using antibiotics

{e.g., 50 μg/ml gentamicin for 1 h) and the macrophages are specifically lysed in 4 M guanidine thiocyanate, 0.5% Na N-lauryl sarcosine, 25 mM sodium citrate, and 0.1 M β- mercaptoethanol. The macrophages are vortexed and passaged through a 21 gauge needle to shear the cells. The intracellular bacteria are then recovered by centrifugation at 3,500 rpm for 30 min (see, Rohde, K. H., et al, Mycobacterium tuberculosis Invasion of Macrophages: Linking Bacterial Gene Expression to Environmental Gene Cues, Cell Host & Microbe, 2007, 2(5):352-364). The recovered bacteria are tested for viable CFU by plating (see, Example 11). The number of recovered bacteria can also be determined using qPCR with primers specific to the bacterium of interest (see, Example 10). Depending on the attached antigen, the bacterium of interest that displays the antigen invades the macrophages to the same, lower, or greater extent than the unmodified bacterium.

[0268] The same experiment is also performed with DCs, which are isolated from bone marrow or blood according to standard methods or protocols of kits {e.g., Inaba, K., et al, Isolation of dendritic cells, Current Protocols in Immunology, 2001, Chapter 3 :Unit 3.7). DCs can also be obtained from the ATCC. Example 23: Deliver an antigen of interest attached to a polymer-coated bacterium of interest to macrophages or DCs

[0269] Macrophages or DCs are isolated and infected with the polymer-coated bacterium of interest as described above (see, Example 22). The polymer-coated bacterium of interest has an antigen of interest chemically attached the coating polymer.

[0270] The uptake of the polymer-coated bacterium of interest by the macrophages or the DCs is confirmed as described (see, Example 22). To show that the macrophages and/or DCs display the antigen that is delivered by the polymer-coated bacterium, the MHC class II complexes of the macrophages and/or DCs are further analyzed. The MHC class II ligandome, i.e the entirety of peptides presented on MHC class II molecules on a cell, is analyzed by liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) based peptide sequencing (see, e.g., Kowalewski D., et al, HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL), Proc. Natl. Acad. Sci. USA, 2015, 112(2):E166-75). The MHC class II ligands can be isolated from the cell surface by i) treating the cells with a mild acid (see, Storkus W., et al, Identification of T-cell epitopes: rapid isolation of class I-presented peptides from viable cells by mild acid elution, J. Immunother. Emphasis. Tumor Immunol, 1993, 14(2):94-103) or by ii) isolating the peptide:MHC II complexes from cell lysates using immunoaffinity purification with MHC class Il-specific monoclonal antibodies as described (see, Adamopoulou E., et al, Exploring the MHC-peptide matrix of central tolerance in the human thymus, Nat. Commun., 2013, 4:2039; Kowalewski D.J. & Stevanovic S.,

Biochemical large-scale identification of MHC class I ligands, Methods Mol. Biol, 2013, 960: 145-57).

[0271] This analysis reveals that a polymer-coated bacterium, which has an antigen attached to the coating polymer can deliver this antigen to macrophages and DCs, which display the antigen or fragments thereof on their MHC class II complexes.

Example 24: Determining the excretion route of administered polymer-coated bacteria

[0272] The excretion of the polymer-coated bacterium of interest is monitored at different time points after the mouse is infected with the polymer-coated bacterium of interest. Excretion is measured by monitoring the number of bacteria in, including but not limited to, the stool and body fluids such as urine, tear fluid, saliva, milk, mucus,

bronchoalveolar lavage fluid, and sweat. Healthy wild-type mice that are not infected with the polymer-coated bacterium of interest are used as a negative control. [0273] Stool samples are obtained by placing the mouse in an empty, sterilized 43- cm-long, 21-cm-wide cage for 1.5 to 2 h to collect individual fecal samples. To minimize sample contamination, the mouse has no access to food and water during this time and sterile forceps are used for sample handling. On average, a mouse produces between 100 and 200 mg of sample during each collection period. Immediately after collection, the stool sample is frozen at -80°C. Genomic DNA (gDNA) is isolated from fecal samples using the PowerSoil DNA isolation kit (MO BIO Laboratories, Inc.) according to the manufacturer's instructions. The concentration of gDNA is determined using UV spectrophotometry as known to one skilled in the art. The number of the administered bacteria is then determined by qPCR using primers specific for the bacterium of interest (Example 10). The number of the administered bacteria in the stool sample can also be determined by plating serial dilutions on agar and colony counting (see, Example 11 and Matsuda K., et al, Sensitive quantitative detection of commensal bacteria by rRNA-targeted reverse transcription-PCR, Appl. Environ. Microbiol, 2007, 73(l):32-9).

[0274] Urine samples are obtained in the morning by applying slight pressure on the bladder of the mouse and using a pipette to take up the liquid. A metabolic cage (Tecniplast, USA) can also be used. The bacterial concentration is measured in the urine by plating serial dilutions on agar and colony counting (see, Example 11). The number of the administered bacteria in the urine can also be determined using qPCR with primers that are specific to the bacterium of interest (see, Example 10). Bacterial urine excretion rates can also be measured since they are reportedly more accurate for diagnosing bacterial counts in urine (Lampert I. & Berlyne G.M., Bacterial excretion-rates in the diagnosis of urinary-tract infections, Lancet, 1971, l(7689):51-2).

[0275] To obtain a tear sample, the mice are anesthetized with e.g., tribromoethanol

(500 μg/g body weight) and intraperitoneally injected with pilocarpine (0.5 μg/g body weight) to induce tearing. The tear fluid is collected using a microcapillary pipet. The number of the administered bacteria in the tear fluid is determined by qPCR using primers specific for the bacterium of interest (see, Example 10) or by plating serial dilutions on selective agar plates and colony counting (see, Example 11).

[0276] Salivation is induced by injecting the mice with pilocarpine as described above. The saliva is then collected with a microcapillary pipet or with a cotton ball that is inserted into the animal's mouth. Saliva can also be obtained by weaning mice following a published protocol (see e.g., Irwin M.H., et al, Identification of transgenic mice by PCR analysis of saliva, Nat. BiotechnoL, 1996, 14(9): 1146-8). The number of the administered bacteria in the saliva sample is determined by qPCR or by plating on selective agar plates.

[0277] A nasal mucus sample is obtained from the nasal mucosa by scraping with a cotton swab. The number of the administered bacteria in the nasal mucus sample is determined by qPCR or by plating on selective agar plates.

[0278] Milk samples are taken from female lactating mice that are infected with the bacterium of interest and from female control mice that are not infected. The dam and her litter are separated for at least 2 hours before milking. The female mouse is intraperitoneally injected with 0.1 ml (2 IU) of oxytocin and milking is initiated 1 min after the injection as described (see, DePeters E.J. & Hovey R.C., Methods for collecting milk from mice, J.

Mammary. Gland. Biol. Neoplasia, 2009, 14(4):397-400). The number of the administered bacteria in the milk sample is determined by qPCR or by plating on selective agar plates.

[0279] The belly of the mouse is shaved with razor to remove the hair. Care is taken to not damage the skin of the mouse. On the next day, a sweat sample is obtained by rinsing a hairless 1 cm² area on the belly of the mouse with lx PBS using a microcapillary pipet and cotton swab. The number of the administered bacteria in the sample is determined by qPCR or by plating on selective agar plates.

[0280] To analyze the skin microbiota of the infected mice and the control mice, the mice are euthanized and a skin sample is taken following a recently published protocol (Garcia-Garcera M., et al, A new method for extracting skin microbes allows metagenomic analysis of whole-deep skin, PLoS One, 2013, 8(9):e74914). The number of the administered bacteria can be quantified by qPCR (see, Example 10). The skin microbiota can also be further analyzed using 16S rRNA analysis (see, Examples 4 and 6).

[0281] Bronchoalveolar lavage (BAL) fluid is obtained from a mouse as described

(Daubeuf, F. & Frossard, N., Performing Bronchoalveolar Lavage in the Mouse, Curr.

Protoc. Mouse Biol, 2012, 2(2): 167-75). The number of the administered bacteria in the BAL fluid is determined by qPCR or by plating on selective agar plates.

[0282] These detection methods are applied at several time points using the same mouse to obtain time-course data on the excretion routes of the administered bacterium of interest. This experiment illustrates that different bacteria are excreted by preferred routes.

Example 25: Screen for polymer-coated bacteria that are excreted via a defined route

[0283] The excretion routes of different polymer-coated bacteria of interest are analyzed systematically as described (see, Example 24). These analyses identify bacterial strains that are mainly excreted by one route but not by a second route (e.g., major route of excretion is the urine and no significant excretion is observed via stool, tear, saliva, milk, or sweat).

Example 26: Labeling bacterial peptidoglycan with fluorescent markers (for in vitro and in vivo tracking)

[0284] The polymeric component of the compositions provided herein are labeled with fluorescent markers to track the biodistribution of the composition. To carry forth the labeling, TSB+ broth containing 0.8 mM 3-azido-D-alanine (from 100 mM DMSO stock) are inoculated with 100 uL of bacteria overnight culture. The mixture is grown 16-24 h in anaerobic chamber (10% H₂, 5% C0₂, 85% N₂) at 37 °C, then the culture was diluted culture with PBS and spun at 5k x g 3 min. Next, the supernatant is decanted, resuspended in 1 mL PBS, transfered to 1.5 mL Eppendorf and spun at 5k x g 3 min. The supernatant is decanted and washed one more time in 900 uL 1% BSA in PBS.

[0285] Next, bacteria are resuspended in 1/100 original culture mL (100 uL per 1 mL culture) of 10 uM dibenzo-aza-cyclooctyne (DIBAC)-fluorescent dye in 1% BS A/PBS (dyes include Cy5, TAMRA, Rhodamine-green, and Cy7). The mixture is incubated 1 h in anaerobic chamber (10% H₂, 5% C0₂, 80% N₂) at 37 °C, then diluted and washed 2x with 1%BSA/PBS and lx with PBS. The mixtures are resuspended in PBS for analysis.

[0286] An exemplary biodistribution of the composition of the invention is shown in

Figure 3. Specifically, Figure 3 shows that PEI-NAc polymer-coated Lactococcus lactis ssp. Cremoris exhibits increased retention at 24 h after administration as compared to the uncoated bacteria.

Example 27: Coating bacteria with polymer materials

[0287] Bacteria (~lxlO^A9) were resuspended in 100 uL of 1 mg/mL chitosan or 0.1 mg/mL PEI in 25 mM KOAc. The suspension was incubated at room temp for 30 min in the anaerobic chamber (10% H₂, 5% C0₂, 85% N₂). Next, the solution was diluted in 25 mM KOAc, spun down (5k x g 3 min) and washed once more in PBS before use. The mixtures were then resuspended in desired amount PBS for analysis. The coated bacteria are analyzed via FACS and fluorescent microscopy. As seen in Figure 1, the bacteria were successfully coated by the fluorescently labeled polymer. Fluorescent microscopy analysis yielded similar results. Example 28: Linking molecules of interest to polymer materials

HS-ester of small molecule (fluorescent probe, peptide, immune agonist, antigen, etc.) in 100 uL of DMSO is added to 1 mL of a 10 mg/mL solution of polymer and incubated at room temperature for 1 h. Reaction is quenched with the addition of 100 uL 1M Tris. The reaction solution is added to a dialysis bag and dialyzed against distilled water for 2 days. The polymer conjugate is frozen in liquid nitrogen and lyophilized to collect the dry polymer conjugate.

Example 29: Improve an adoptive cellular therapy (ACT) using a polymer-coated bacterial composition in which the polymer is functionalized with an antigen that is recognized by the modified T cells

[0288] A subcutaneous B16 mouse melanoma model or a different cancer model is used to show that an adoptive cellular therapy (ACT) with engineered T cells can be improved by administration of a composition provided herein that includes a polymer that is functionalized with an antigen that is recognized by co-administered modified T cells. The improved ACT further reduces tumor growth and the spread of metastases compared to the normal ACT. This experiment can be performed with modified T cells that express an engineered T cell receptor (TCR) or a chimeric antigen receptor (CAR). The antigen that is recognized by the CAR (e.g., human gpl00₂09-2i7 antigen) or the modified TCR (e.g., human gpl00₂5-33 antigen) is covalently attached to the polymer of the composition of the invention.

[0289] Preparation of the T-cell therapeutic. The pmel-1 mouse is obtained from The

Jackson Laboratory. This is a CD8+ T-cell receptor transgenic model, which is derived from the C57BL/6 background and whose CD8⁺ T cells express the Val νβ13 T cell receptor that specifically recognizes the H-2D^b -restricted mouse and human gpl00₂5-33 epitopes (Overwijk W., et al, Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells, J. Exp. Med, 2003, 198:569-80). The pmel-1 transgenic mouse serves as the donor for the preparation of the tumor-reactive CD8⁺ T cells for the adoptive cell transfer (ACT). Splenocytes are isolated from pmel-1 mice using standard protocols known to one skilled in the art. The splenocytes are then pulsed in vitro with 1 μπιοΐ/ΐ of human gpl00₂5-33, and expanded for one week in the presence of culture medium

supplemented with 4 ng/ml of recombinant human IL-2. CD8⁺ νβ13⁺ pmel-1 T cells are isolated by FACS or with magnetic beads following protocols known to one skilled in the art. Freshly made T cell preparations are used for the intravenous administration (see below). [0290] The CAR-T cells (GPA7-28z) are made by lentiviral transduction of peripheral blood mononuclear cells (PBMC) from healthy donors as described (see, Zhang, G., et al., Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor, Sci. Rep., 2014, 4:3571).

[0291] Preparation of mice for tumor development. The mouse cell line B 16 (H-2^b), which is a gpl00⁺ spontaneous melanoma, is obtained from ATCC. The cells are cultured in vitro as a monolayer in RPMI medium, supplemented with 10% heat-inactivated fetal bovine serum and 1% penicillin/streptomycin at 37 °C in an atmosphere of 5% CO² in air. The exponentially growing tumor cells are harvested by trypsinization, washed three times with cold lx PBS, and a suspension of 5E6 cells/ml is prepared for administration. 24 female C57BL/6 mice are used for this experiment. The mice are 6-8 weeks old and weigh approximately 16-20 g. For tumor development, each mouse is injected subcutaneously with 100 μΐ of the B 16 (H-2^b) cell suspension. The mice are assigned to either one of three treatment groups {i.e., groups 1-3) or the control group {i.e., group 4) with 6 mice per group.

[0292] One day 7, a composition is prepared by resuspending the polymer-coated bacterial composition in which the polymer is functionalized with an antigen that is recognized by the modified T cells {e.g., the gplOO antigen), in lx PBS to a final

concentration of 1 xlO¹⁰ CFU/ml. The mice of group 1 and group 3 receive 100 μΐ of the bacterial composition via gavage. The mice of group 2 and group 4 receive 100 μΐ of lx PBS {i.e., vehicle control) via gavage. The same treatment with the bacterial composition is repeated on day 14 using a freshly made preparation of the bacterial composition and the mice of group 2 and group 4 receive again lx PBS. Also on day 14, the mice of group 2 and group 3 receive an intravenous injection of 2E6 freshly prepared CD8+ νβ13+ pmel-1 T cells and a subcutaneous injection of 2 xlO⁷ plaque-forming units of a recombinant fowlpox virus expressing mouse or human gplOO. Mice of group 2 and group 3 may also receive a sublethal irradiation {i.e., 500 cGy) prior to the intravenous T cell administration to destroy existing lymphocytes and T cells. In addition to the adoptive cellular transfer (ACT) treatment and the vaccination, the mice of group 2 and group 3 also receive human recombinant IL-2 (Novartis) twice daily by intraperitoneal injection. Mice of group 1 and group 4 are intravenously administered a vehicle control {e.g., lx PBS).

[0293] Primary tumor size, mouse weight, and body temperature are monitored every

3-4 days and the mice are humanely sacrificed after 6 weeks or when the primary tumor volume reaches 1000 mm³. Blood draws are taken weekly and a full necropsy under sterile conditions is performed at the termination of the protocol. [0294] The number of micro- and macro-metastases is quantified as described (see

Bobek V., et al, Syngeneic lymph-node-targeting model of green fluorescent protein- expressing Lewis lung carcinoma, Clin. Exp. Metastasis, 2004;21(8):705-8). Samples of tumor tissue, non-tumor tissue, and micro- and macro-metastases can be analyzed by mass spectrometry, 16S rRNA sequence analysis, qPCR, ELISA for cytokine levels, and FACS. Mice of the control group (i.e., group 4) have a large primary tumor and many micro- and macro-metastases after six weeks. Mice of group 1, which receive the antigen-containing bacterial composition, and mice of group 2, which receive the ACT, have a significantly smaller primary tumor and also significantly less micro- and macro-metastases. Mice of group 3, which receive the combined treatment of antigen-containing bacterial composition and ACT, have no primary tumor and no micro- or macro-metastases.

[0295] The CAR-T cells are evaluated in vitro in a cytotoxicity assay with human melanoma cells and in the context of a xenograft mouse model (see Zhang, G., et al, Anti- melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor, Sci. Rep., 2014, 4:3571). The treatment with CAR-T cells and the bacterial composition shows an enhanced tumor cell killing compared to treatment with the CAR-T cells alone.

Example 30: Delivering an antigen to a tumor to target tumors for CAR-T therapy

[0296] An adoptive cellular therapy (ACT) with T cells that express a chimeric antigen receptor (CAR) is performed using mice with B16 melanoma as described, with the exception that the composition includes a bacterial antigen and that the CAR-modified T cells recognize this bacterial antigen and not the tumor antigen. The polymer-coated bacteria localize to the tumor and recruit the CAR-T cells to the tumor. The bacterial antigen can be an endogenous antigen.

[0297] This modified CAR-T cell therapy reduces tumor growth and the spread of metastases compared to treating the mice with the bacteria alone.

Example 31: Reduce dosing of chemotherapeutic by using bacterial composition for localized delivery and drug release in the tumor microenvironment

[0298] Compared to systemic administration of an anticancer drug of interest {e.g., taxol or doxorubicin), the administration of a polymer-coated bacterial composition for delivery of the anticancer drug to the tumor microenvironment allows reducing the concentration of the drug to achieve the same degree of tumor cell killing. The localized drug delivery to and release in the tumor microenvironment reduces the administered concentration of the drug, which decreases the risk of side effects.

[0299] The anticancer drug is tested in in vivo using a syngeneic, subcutaneous mouse model of e.g., colorectal cancer (CT-26 cells). The mice are prepared for tumor development as described herein. On day 10 after tumor injection or after the tumor volume reaches 100 mm³, the mice are either infected with the polymer-coated bacterial composition in which the polymer is functionalized with the anticancer drug or the mice receive the free form of the drug {e.g., by subcutaneous injection). The drug concentration, administration routes, and treatment cycles are based on standard protocols that are known to one skilled in the art. Methods for controlling the drug release from the bacterial composition can also be used. As a negative control experiment, the mice are also treated with the bacterial composition that does not include the drug residue and with vehicle control {e.g., subcutaneous injection of lx PBS). Several different drug concentrations are tested and the bacterial drug delivery method is compared to the administration of the free drug and to no treatment. Survival curves are assessed and the mice are humanely sacrificed when they become moribund or when the tumor volume reaches 1000 mm³.

[0300] This experiment shows that tumor growth inhibition or shrinkage is achieved with a lower drug concentration when the drug is delivered directly to the tumor cells using polymer-coated bacterial compositions as delivery agents.

Example 32: Polymer-coated bacteria in a mouse model of delayed-type hypersensitivity (DTH)

[0301] Delayed-type hypersensitivity (DTH) is an animal model of atopic dermatitis

(or allergic contact dermatitis), as reviewed by Petersen et al. (In vivo pharmacological disease models for psoriasis and atopic dermatitis in drug discovery. Basic & Clinical Pharm & Toxicology. 2006. 99(2): 104-115; see also Irving C. Allen (ed.) Mouse Models of Innate Immunity: Methods and Protocols, Methods in Molecular Biology, 2013. vol. 1031, DOI 10.1007/978-l-62703-481-4_13). It can be induced in a variety of mouse and rat strains using various haptens or antigens, for example an antigen emulsified with an adjuvant. DTH is characterized by sensitization as well as an antigen-specific T cell-mediated reaction that results in erythema, edema, and cellular infiltration - especially infiltration of antigen presenting cells (APCs), eosinophils, activated CD4+ T cells, and cytokine-expressing Th2 cells. [0302] Generally, mice are primed with an antigen administered in the context of an adjuvant (e.g. Complete Freund's Adjuvant) in order to induce a secondary (or memory) immune response measured by swelling and antigen-specific antibody titer.

[0303] Polymer-coated bacteria are tested for their efficacy in the mouse model of

DTH, with or without the addition of other anti-inflammatory treatments. For example, 6-8 week old C57B1/6 mice are obtained from Taconic (Germantown, NY), or other vendor. Groups of mice will be administered four subcutaneous (s.c.) injections at four sites on the back (upper and lower) of antigen (e.g. Ovalbumin (OVA)) in an effective dose (50ul total volume per site). For a DTH response, animals will be injected intradermally (i.d.) in the ears under ketamine/xylazine anesthesia (approximately 50mg/kg and 5 mg/kg, respectively). Some mice will serve as control animals. Some groups of mice will be challenged with lOul per ear (vehicle control (0.01% DMSO in saline) in the left ear and antigen (21.2 ug (12nmol) in the right ear) on day 8. To measure ear inflammation, the ear thickness of manually restrained animals will be measured using a Mitutoyo micrometer. The ear thickness will be measured before intradermal challenge as the baseline level for each individual animal.

Subsequently, the ear thickness will be measured two times after intradermal challenge, at approximately 24 hours and 48 hours (i.e. days 9 and 10).

[0304] Treatment with polymer-coated bacteria is initiated at some point, either around the time of priming or around the time of DTH challenge. For example, polymer- coated bacteria may be administered at the same time as the subcutaneous injections (day 0), or they may be administered prior to, or upon, intradermal injection, polymer-coated bacteria are administered at varied doses and at defined intervals. For example, some mice are intravenously injected with polymer-coated bacteria at 15, 20, or 15 ug/mouse. Other mice may receive 25, 50, or 100 mg of polymer-coated bacteria per mouse. While some mice will receive polymer-coated bacteria through i.v. injection, other mice may receive polymer- coated bacteria through intraperitoneal (i.p.) injection, subcutaneous (s.c.) injection, nasal route administration, oral gavage, topical administration, intradermal (i.d.) injection, or other means of administration. Some mice may receive polymer-coated bacteria every day (e.g. starting on day 0), while others may receive polymer-coated bacteria at alternative intervals (e.g. every other day, or once every three days). The bacterial cells may be live, dead, or weakened. The bacterial cells may be harvested fresh (or frozen) and administered, or they may be irradiated or heat-killed prior to administration.

[0305] For example, some groups of mice may receive between lxlO⁴ and 5xl0⁹ polymer-coated bacteria in an administration. [0306] Some groups of mice may be treated with anti-inflammatory agent(s) (e.g. anti-CD 154, blockade of members of the TNF family, or other treatment), and/or an appropriate control (e.g. vehicle or control antibody) at various timepoints and at effective doses.

[0307] In addition, some mice are treated with antibiotics prior to treatment. For example, vancomycin (0.5g/L), ampicillin (l .Og/L), gentamicin (l .Og/L) and amphotericin B (0.2g/L) are added to the drinking water, and antibiotic treatment is halted at the time of treatment or a few days prior to treatment. Some immunized mice are treated without receiving antibiotics.

[0308] At various timepoints, serum samples are taken. Other groups of mice are sacrificed and lymph nodes, spleen, mesenteric lymph nodes (MLN), the small intestine, colon, and other tissues may be removed for histology studies, ex vivo histological, cytokine and/or flow cytometric analysis using methods known in the art. Some mice are

exsanguinated from the orbital plexus under 02/C02 anesthesia and ELISA assays performed.

[0309] Tissues may be dissociated using dissociation enzymes according to the manufacturer's instructions. Cells are stained for analysis by flow cytometry using techniques known in the art. Staining antibodies can include anti-CD 1 lc (dendritic cells), anti-CD80, anti-CD86, anti-CD40, anti -MHCII, anti-CD8a, anti-CD4, and anti-CD 103. Other markers that may be analyzed include pan-immune cell marker CD45, T cell markers (CD3, CD4, CD8, CD25, Foxp3, T-bet, Gata3, Roryt, Granzyme B, CD69, PD-1, CTLA-4), and macrophage/myeloid markers (CDl lb, MHCII, CD206, CD40, CSFIR, PD-Ll, Gr-1, F4/80). In addition to immunophenotyping, serum cytokines are analyzed including, but not limited to, TNFa, IL-17, IL-13, IL-12p70, IL12p40, IL-10, IL-6, IL-5, IL-4, IL-2, IL-lb, IFNy, GM- CSF, G-CSF, M-CSF, MIG, IP10, MlPlb, RANTES, and MCP-1. Cytokine analysis may be carried out on immune cells obtained from lymph nodes or other tissue, and/or on purified CD45+ infiltrated immune cells obtained ex vivo. Finally, immunohistochemistry is carried out on various tissue sections to measure T cells, macrophages, dendritic cells, and checkpoint molecule protein expression.

[0310] In order to examine the impact and longevity of DTH protection, rather than being sacrificed, some mice may be rechallenged with the challenging antigen (e.g. OVA). Mice will be analyzed for susceptibility to DTH and severity of response.

[0311] Polyethyleneimine and N-acetyl cysteine (PEI-NAc) coated Lactococcus lactis ssp. Cremoris (Strain A) bacteria were studied in the DTH model described herein. Relative to the uncoated (powdered) bacteria, the PEI-NAc coated bacteria retained their in vivo efficacy in the DTH model. See Figure 2 for results.

Incorporation by Reference

[0312] All publications patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

[0313] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

What is claimed is:

1. A composition comprising a bacterium and a polymer.

2. The composition of claim 1 , wherein the polymer partially coats the bacterium.

3. The composition of claim 1 , wherein the polymer fully coats the bacterium.

4. The composition of any preceding claims, comprising a plurality of bacteria.

5. The composition of claim 4, wherein the polymer partially coats a plurality of

bacteria.

6. The composition of claim 4, wherein the polymer fully coats a plurality of bacteria.

7. The composition of any preceding claim, wherein the polymer is bound to a surface of the bacterium.

8. The composition of claim 7, wherein the polymer is bound to a surface of the

bacterium through electrostatic interaction.

9. The composition of claim 7, wherein the polymer is bound to a surface of the

bacterium through one or more covalent bonds.

10. The composition of any preceding claim, wherein the polymer is positively charged.

1 1. The composition of any preceding claim, wherein the polymer is selected from the group consisting of polycarbonates, polysaccharides, polyurethanes, polyamides, polyesters, polyethers, polyimides, polyimines, polyorganosiloxanes, polysulfides, polysulfones, polytetrafluoroethylene, polysiloxanes, polyvinylarenes, polyacrylates, and oligosaccharides (e.g., cyclic oligosaccharides).

12. The composition of any one of claims 1 -1 1 , wherein the polymer is selected from the group consisting of chitosan, alginate, polyethyleneimine, poly-y-glutamic acid, poly(beta-amino ester), polyglycolic acid, polylysine, cyclodextrin, collagen, polybrene, diethylaminoethyl-dextran, polyamidoamine, polyethylene glycol, propylene glycol, polystyrene, and polyvinylacetate.

13. The composition of claim 12, wherein the polymer is selected from the group

consisting of chitosan, alginate, polyethyleneimine, poly-y-glutamic acid, poly(beta- amino ester), polyglycolic acid, polylysine, cyclodextrin, collagen, polybrene, diethylaminoethyl-dextran, and polyamidoamine.

14. The composition of claim 13, wherein the polymer is selected from the group consisting of chitosan, alginate, polyethyleneimine, polyglycolic acid, and po!y(beta- amino ester).

15. The composition of claim 14, wherein the polymer is selected from the group

consisting of chitosan, alginate, and polyethyleneimine.

16. The composition of claim 15, wherein the polymer is chitosan.

1 7. The composition of claim 15, wherein the polymer is alginate.

1 8. The composition of claim 1 5, wherein the polymer is polyethyleneimine.

19. The composition of any one of claims 1 -9, wherein the polymer comprises two or more crosslinked polymers.

20. The composition of claim 19, wherein each crosslinked polymer is selected from the group consisting of polyurethanes, polyamides, polyesters, polyethers,

polyorganosiloxanes, polysulfones, polytetrafluoroethylene, polysiloxanes, polyvinylarenes, and polyacrylates.

21. The composition of claim 19, wherein each crosslinked polymer is selected from the group consisting of chitosan, alginate, polyethyleneimine, poly-y-glutamic acid, poly(beta-amino ester), polyglycolic acid, polylysine, cyclodextrin, collagen, polybrene, diethylaminoethyl-dextran, polyamidoamine, polyethylene glycol, propylene glycol, polystyrene, and polyvinylacetate.

22. The composition of any preceding claim, wherein the polymer is covalently attached to a residue of a therapeutic agent.

23. The composition of claim 22, wherein the therapeutic agent is an anti-cancer

therapeutic agent.

24. The composition of claim 23, wherein the anti-cancer therapeutic agent is a

chemotherapy agent.

25. The composition of claim 24, wherein the chemotherapy agent is selected from the group consisting of thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, cally statin, CC-1065, cryptophycin 1 , cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, dynemicin, clodronate, esperamicin; neocarzinostatin chromophore, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, 5-fluorouracil (5-FU), denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, eliiptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, PSK polysaccharide complex, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone; 2,2',2"- trichlorotriethylamine, trichothecene, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxcl, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin, oxaliplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan, RFS 2000,

difluoromethylomithine, retinoic acid and capecitabine.

26. The composition of claim 23, wherein the anti-cancer therapeutic agent is an immunotherapy agent.

27. The composition of claim 26, wherein the immunotherapy agent is an immune

checkpoint inhibitor.

28. The composition of claim 27, wherein the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to an immune checkpoint protein.

29. The composition of claim 28, wherein the immune checkpoint protein is selected from the group consisting of CTLA4, PD-1 , PD-Ll , PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA.

30. The composition of claim 27, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1 1 10, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB- 0020718C, AUR-012 and STI-A 1010.

31. The composition of claim 26, wherein the immunotherapy agent is a cancer-specific antibody or antigen-binding fragment thereof.

32. The composition of claim 31 , wherein the cancer-specific antibody or antigen-binding fragment thereof binds specifically to a cancer-associated antigen.

33. The composition of claim 31 , wherein the cancer-associated antigen is selected from the group consisting of adipophilin, ΑΓΜ-2, ALDH1A1 , alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTC l , B-RAF, BAGE-1 , BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BI G-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1 , CPSF, CSNK1 A 1 , CTAG1 , CTAG2, cyclin Dl, Cyclin-Al , dek-can fusion protein, DKK1 , EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1 , G250 MN/CAIX, GAGE-1 ,2,8, GAGE-3,4,5,6,7, GAS7, glypican- 3, GnTV, gpl OO/Pmein, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A1 1 , HLA-A2, HLA-DOB, hsp70-2, IDOl , IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1 , KKLC1 , KM-HN-1, KMHN1 also known as CCDC1 10, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-A1 , MAGE- A 10, MAGE-A 12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- AMART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO-l/LAGE-2, OAl, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/N Y-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Spl7, SPA 17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/G AGED2a.

34. The composition of claim 31, wherein the cancer-associated antigen is a neo-antigen.

35. The composition of claim 26, wherein the immunotherapy agent is a cancer- associated antigen.

36. The composition of claim 35, wherein the cancer-associated antigen is selected from the group consisting of adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha- fetoprotein ("AFP"), ARTCl, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta- atenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin Dl, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican- 3, GnTV, gpl00/Pmell7, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, IILA-A2, HLA-DOB, hsp70-2, IDOl, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1 , LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan- A/MART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY- BR-1, NY-ESO- l/LAGE-2, OA1 , OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPR , RAB38/NY-MEL- 1 , RAGE-1 , RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1 , SIRT2, SNRPD1 , SOX 10, Spl 7, SPA 17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRlI, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1 and XAGE- 1 b/GAGED2a.

37. The composition of claim 35, wherein the cancer-associated antigen is a neo-antigen.

38. The composition of claim 26, wherein the immunotherapy agent is an

immunostimulatory agent.

39. The composition of claim 38, wherein the immunostimulatory agent is an immune checkpoint inhibitor.

40. The composition of claim 39, wherein the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to an immune checkpoint protein.

41. The composition of claim 40, wherein the immune checkpoint protein is selected from the group consisting of CTLA4, PD-1 , PD-Ll , PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA.

42. The composition of claim 39, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1 1 10, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB- 0020718C, AUR-012 and STI-A1010.

43. The composition of claim 38, wherein the immunostimulatory agent is an adjuvant.

44. The composition of claim 43, wherein the adjuvant is selected from the group

consisting of is selected from the group consisting of an immune modulatory protein, Adjuvant 65, a-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG DNA, GPI-0100, lipid A, lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl-D-isoglutamine, Pam3CSK4, quil A, diperose, EP67 peptide, and trehalose dimycolate.

45. The composition of claim 38, wherein the immunostimulatory agent is an immune modulatory protein.

46. The composition of claim 45, wherein the immune modulatory protein is a cytokine.

47. The composition of claim 45, wherein the immune modulatory protein is selected from the group consisting of B lymphocyte chemoattractant ("BLC"), C-C motif chemokine 1 1 ("Eotaxin-1 "), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G-CSF"), Granulocyte macrophage colony- stimulating factor ("GM-CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM- 1 "), Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-1 alpha"), Interlukin-1 beta ("IL-1 beta"), Interleukin 1 receptor antagonist ("IL-1 ra"), Interleukin-2 ("IL- 2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin- 6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ('TL-10"), Interleukin- 1 1 ("IL-1 1 "), Subunit beta of Interleukin- 12 ("IL-12 p40" or "IL- 12 p70"), Interleukin- 13 ("IL-13"), Interleukin- 15 ("IL- 15"), Interleukin- 16 ("1L-16"), Interleukin- 17 ("IL-17"), Chemokine (C-C motif) Ligand 2 ("MCP-1 "), Macrophage colony-stimulating factor ("M-CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP- 1 alpha"), Chemokine (C-C motif) ligand 4 ("MIP-1 beta"), Macrophase inflammatory protein-

1 -delta ("MIP-1 delta"), Platelet-derived growth factor subunit B ("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on Activation, Normal T cell Expressed and Secreted ("RANTES"), TIMP metallopcptidase inhibitor 1 ("TIMP-1 "), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF alpha"), Tumor necrosis factor, lymphotoxin-beta ("TNF beta"), Soluble TNF receptor type 1 ("sTNFRI"), sTNFRIIAR, Brain-derived neurotrophic factor ("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BMP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG-VEGF"), Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor ("GDNF"), Growth Hormone, Heparin-binding EGF-like growth factor ("HB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-1 "), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulin-like growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-l "), Insulin, Macrophage colony-stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NT-3"), Neurotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet-derived growth factor receptors ("PDGF-AA"), Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing complex ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha ("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1"), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 ("VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO ("Axl"), Betacellulin ("BTC"), Mucosae- associated epithelial chemokine ("CCL28"), Chemokine (C-C motif) ligand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif ohemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("F,otaxin-3"),

Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand 14 ("HCC-1"), Chemokine (C-C motif) ligand 16 ("HCC-4"), Interleukin-9 ("IL-9"), Interleukin-17 F ("IL-17F"), Interleukin- 18-binding protein ("IL-18 BPa"),

Interleukin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31 "), C-X- C motif chemokine 10 ("IP- 10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light, Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte chemoattractant protein 4 ("MCP-4"), Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF-1 "), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1 -like 4 ("NAP-2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen

("ALCAM"), Cluster of Differentiation 80 ("B7-1 "), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD 14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"), Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM-1 "), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3 ("ErbB3"), Endothelial-leukocyte adhesion molecule 1 ("E-Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, IL-17R, IL-2Rgamma, IL-21R, Lysosome membrane protein 2 ("LIMPII"), Neutrophil gelatinase-associated lipocalin ("LipocaIin-2"), CD62L ("L- Selectin"), Lymphatic endothelium ("LYVE-1 "), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGl-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM-1 "), RAGE, Hepatitis A virus cellular receptor 1 ("TIM-1"), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1 "), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"), Angiopoietin 1 , Angiostatin, Catheprin S, CD40, Cryptic family protein IB ("Cripto- 1 "), DAN, Dickkopf-related protein 1 ("DKK-1 "), E-Cadherin, Epithelial cell adhesion molecule ("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C,

FoUistatin, Galectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 Rl, IL- 13R2, IL- 17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1 "), Platelet derived growth factor receptors ("PDGF-AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgpBO, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding

immunoglobulin-type lectins ("SigIec-5"), ST2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"), Triggering receptor expressed on myeloid cells 1 ("TREM- 1 "), Vascular endothelial growth factor C ("VEGF-C"),

VEGFRlAdiponectin, Adipsin ("AND"), Alpha-fetoprotein ("AFP"), Angiopoietin- like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA 125"), Cancer Antigen 15-3 ("CA15-3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), Follistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-1 sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21 , Leptin, Matrix metalloproteinase-1 ("MMP- 1 "), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metalloproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP- 10"), Matrix metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1 "), Entactin ("Nidogen-1 "), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulin, Metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, Disintegrin and metalloproteinase domain-containing protein 9 ("ADAM- 9"), Angiopoietin 2, Tumor necrosis factor ligand superfamily member 13/ Acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP-2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin I ,, CD200, CD97, Chemerin, Tumor necrosis factor receptor superfamily member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF- 19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN- gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin-1 receptor 6 ("IL-1R6"), Interleukin 24 ("IL-24"), Interleukin 33 ("IL-33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1 "), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1 , translocation-associated

(Drosophila) ("Notch-1 "), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD- 1 "), N-acetylmuramoyl-L-alanine amidase ("FGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"),

Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL Rl"), Transferrin ("TRF"), WIF-lACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 1 -9 ("CA19-9"), CD 163 , Clusterin, CRT AM, Chemokine (C-X-C motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf-related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLL1 "), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha ("FOLRl "), Furin, GPCR-associated sorting protein 1 ("GASP-1 "), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony- stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"),

Interleukin-17B Receptor ("IL-17B R"), Interleukin 27 ("IL-27"), Lymphocyte- activation gene 3 ("LAG-3"), Apolipoprotein A-V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1 "), Tumor necrosis factor receptor superfamily member 13B ("TACI"), Tissue factor pathway inhibitor ("TFPI"), TSP- 1, Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNTl-inducible-signaling pathway protein 1 ("WISP- 1 "), and Receptor Activator of Nuclear Factor κ B ("RANK").

48. The composition of claim 26, wherein the immunotherapy agent is an immune

modulatory protein.

49. The composition of claim 48, wherein the immune modulatory protein is a cytokine.

50. The composition of claim 48, wherein the immune modulatory protein is selected from the group consisting of B lymphocyte chemoattractant ("BLC"), C-C motif chemokine 1 1 ("Eotaxin-1 "), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G-CSF"), Granulocyte macrophage colony- stimulating factor ("GM-CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM- 1 "), Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-1 alpha"), Interlukin-1 beta ("IL-1 beta"), Interleukin 1 receptor antagonist ("IL-1 ra"), Interleukin-2 ("IL- 2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin- 6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ("IL-10"), Interleukin- 1 1 ("IL-1 1 "), Subunit beta of Interleukin- 12 ("IL-12 p40" or "IL-12 p70"), Interleukin- 13 ("IL-13"), Interleukin- 15 ("IL-15"), Interleukin- 16 ("IL- 16"), Interleukin- 17 ("IL-17"), Chemokine (C-C motif) Ligand 2 ("MCP-1 "), Macrophage colony-stimulating factor ("M-CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP-1 alpha"), Chemokine (C-C motif) ligand 4 ("MIP-1 beta"), Macrophase inflammatory protein-

1 -delta ("MIP- 1 delta"), Platelet-derived growth factor subunit B ("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on Activation, Normal T cell Expressed and Secreted ("RANTES"), TIMP metallopeptidase inhibitor 1 ("TIMP-1 "), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF alpha"), Tumor necrosis factor, lymphotoxin-beta ("TNF beta"), Soluble TNF receptor type 1 ("sTNFPvI"), sTNFRIIAR, Brain-derived neurotrophic factor

("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BMP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG-VEGF"), Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor ("GDNF"), Growth Hormone, Heparin-binding EGF-like growth factor ("HB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-1 "), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulin-like growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-1 "), Insulin, Macrophage colony-stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NT-3"), Neiirotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet-derived growth factor receptors ("PDGF-AA"), Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing complex ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha ("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1 "), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 ("VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO ("Axl"), Betacellulin ("BTC"), Mucosae- associated epithelial chemokine ("CCL28"), Chemokine (C-C motif) ligand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("Eotaxin-3"),

Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand 14 ("HCC-1"), Chemokine (C-C motif) ligand 16 ("HCC-4"), Interleukin-9 ("IL-9"), Interleukin-17 F ("IL-17F"), Interleukin- 18-binding protein ("IL- 18 BPa"),

Interleiikin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31 "), C-X- C motif chemokine 10 ("IP- 10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light, Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte chemoattractant protein 4 ("MCP-4"), Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF- l "), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1 -like 4 ("NAP-2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen ("ALCAM"), Cluster of Differentiation 80 ("B7-1 "), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD 14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"), Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM-1 "), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3 ("ErbB3"), Endothalial-leukocyte adhesion mnle.nnle 1 ("E-Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, 1L-17R, IL-2Rgamma, IL-21R, Lysosome membrane protein 2 ("LIMPII"), Neutrophil gelatinase-associated lipocalin ("Lipocalin-2"), CD62L ("L- Selectin"), Lymphatic endothelium ("LYVE-1 "), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGI-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM-1 "), RAGE, Hepatitis A virus cellular receptor 1 ("TIM-1 "), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1 "), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"), Angiopoietin 1 , Angiostatin, Catheprin S, CD40, Cryptic family protein IB ("Cripto- 1 "), DAN, Dickkopf-related protein 1 ("DKK-1 "), E-Cadherin, Epithelial cell adhesion molecule ("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C,

FoUistatin, GaIectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 Rl, IL- 13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1 "), Platelet derived growth factor receptors ("PDGF-AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgpl30, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding

immunoglobulin-type lectins ("Siglec-5"), ST2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamiiy member 10D ("TRAIL R4"), Triggering receptor expressed on myeloid cells 1 ("TREM-1 "), Vascular endothelial growth factor C ("VEGF-C"),

VEGFRlAdiponectin, Adipsin ("AND"), Alpha-fetoprotein ("AFP"), Angiopoietin- like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA125"), Cancer Antigen 15-3 ("CA15-3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), Follistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-1 sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21 , Leptin, Matrix metalloproteinase-1 ("MMP- 1 "), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metal loproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP-10"), Matrix metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1 "), Entactin ("Nidogen-1 "), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procal ilonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulin, Metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, Disintegrin and metalloproteinase domain-containing protein 9 ("ADAM- 9"), Angiopoietin 2, Tumor necrosis factor ligand superfamiiy member 13/ Acidic Ieucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP-2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin L, CD200, CD97, Chcmerin, Tumor necrosis factor receptor superfamiiy member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF- 19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN- gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin- 1 receptor 6 ("IL-1R6"), Interleukin 24 ("IL-24"), Interleukin 33 ("IL-33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1 "), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1 , translocation-associated

(Drosophila) ("Notch-1 "), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD-1 "), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"),

Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL Rl"), Transferrin ("TRF"), WIF-lACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 19-9 ("CA19-9"), CD 163 , Clusterin, CRT AM, Chemokine (C-X-C motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf-related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLLl "), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha ("FOLRI "), Furin, GPCR-associated sorting protein 1 ("GASP-1 "), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony- stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"),

Interleukin-17B Receptor ("IL-17B R"), Interleukin 27 ("IL-27"), Lymphocyte- activation gene 3 ("LAG-3"), Apolipoprotein A-V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1 "), Tumor necrosis factor receptor superfamily member 13B ("TACI"), Tissue factor pathway inhibitor ("TFPI"), TSP-1 , Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNTl-inducible-signaling pathway protein 1 ("WISP-1 "), and Receptor Activator of Nuclear Factor κ B ("RANK").

51. The composition of claim 26, immunotherapy agent is an adjuvant.

52. The composition of claim 51 , wherein the adjuvant is selected from the group

consisting of an immune modulatory protein, Adjuvant 65, a-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-Glucan Peptide, CpG DNA, GPI-0100, lipid A, lipopoly saccharide, Lipovant, Montanide, N-acetyl-muramyl-L- alanyl-D-isoglutamine, Pam3CSK4, quil A, diperose, EP67 peptide, and trehalose dimycolate.

53. The composition of claim 23, wherein the anti-cancer therapeutic agent is an

angiogenesis inhibitor,

54. The composition of claim 53, wherein the angiogenesis inhibitor is selected from the group consisting of Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

55. The composition of claim 23, wherein the anti-cancer therapeutic agent is a

radioactive agent.

56. The composition of claim 55, wherein the radioactive agent comprises a radionuclide selected from the group consisting of Cr-51, Cs-131 , Ce-134, Se-75, Ru-97, 1-125, Eu- 149, Os- 189m, Sb- 1 19, 1- 123 , Ho- 161 , Sb- 1 17, Ce- 139, In- 1 1 1 , Rh- 103m, Ga-67, Tl-201 , Pd-103, Au-195, Hg-197, Sr-87m, Pt-191 , P-33, Er-169, Ru-103, Yb- 169, Au-199, Sn-121 , Tm-167, Yb-175, In-1 13m, Sn-1 13, Lu-177, Rh-105, Sn-1 17m, Cu- 67, Sc-47, Pt-195m, Ce-141 , 1-131, Tb- 161 , As-77, Pt-197, Sm-153, Gd-159, Tm- 173, Pr-143, Au- 198, Tm- 170, Re- 186, Ag- 1 1 1 , Pd-109, Ga-73, Dy- 165, Pm-149, Sn- 123, Sr-89, Ho- 166, P-32, Re- 188, Pr-142, Ir-194, In-1 14m/In-l 14, and Y-90.

57 The composition of claim 23, wherein the anti-cancer agent is an antibiotic.

58. The composition of claim 57, wherein the antibiotic is selected from the group

consisting of aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, anti-mycobacterial compounds and combinations thereof.

59. The composition of claim 22, wherein the therapeutic agent is a prodrug enzyme.

60. The composition of claim 59, wherein the prodrug enzyme is purine nucleoside

phosphorylase.

61. The composition of claim 59 or 60, further comprising a prodrug.

62. The composition of clam 61 , wherein the prodrug is 6-methylpurine 2'-deoxyriboside (6MePdR).

63. The composition of any one of claims 1 -62, further comprising a prebiotic.

64. The composition of claim 63, wherein the prebiotic is a fructooligosaccharide, a galactooligosaccharide, a trans-galactooligosaccharide, a xylooligosaccharide, a chitooligosaccharide, a soy oligosaccharide, a gentiooligosaccharide, an isomaltooligosaccharide, a mannooligosaccharide, a maltooligosaccharide, a mannanoligosaccharide, lactulose, lactosucrose, palatinose, glycosyl sucrose, guar gum, gum Arabic, tagalose, amylose, amylopectin, pectin, xylan, or a cyclodextrin.

65. The composition of claim 22, wherein the therapeutic agent is an anti-inflammatory agent.

66. The composition of claim 65, wherein the anti-inflammatory agnet is selected from the group consisting of corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, and cytokine inhibitors.

67. The composition of claim 66, wherein the anti-inflammatory agent is a cytokine

inhibitor selected from anti-IL-6 antibodies and TNF inhibitors.

6b. The composition of claim 6, wlieieiu Ihc cytokin inhibitor i3 a TNF inhibitor

selected from infliximab, adalimumab, certolizumab pegol, golimumab, and etanercept.

69. The composition of claim 65, wherein the anti-inflammatory agent is a vaccine (e.g., a vaccine used for vaccination where the amount of an allergen is gradually increased).

70. The composition of claim 22, wherein the therapeutic agent is N-acetyl cysteine, polyethylene glycol, a lectin, a protein antigen, a vitamin, curcumin, quercetin, bromelain, zinc, glutamine, a TLR agonist, a TDO/IDO metabolite, a TDO/IDO inhibitor, a DNA fragment, a prebiotic, or a quorum sensing molecule.

71. The composition of claim 70, wherein the therapeutic agent is a lectin, and the lectin is Ulex europaeus agglutinin I, Aleuria aurantia lectin, or wheat germ agglutinin.

72. The composition of claim 70, wherein the therapeutic agent is a protein antigen and the protein antigen is a peanut allergen or ovalbumin.

73. The composition of claim 70, wherein the therapeutic agent is a vitamin, and the vitamin is retinoic acid, vitamin D3, vitamin B6, biotin, or folic acid.

74. The composition of claim 70, wherein the therapeutic agent is a TLR agonist, and the TLR agonist is selected from the group consisting of R848/imiquimod, polyinosinic- polycytidylic acid, Pam3CSK4, and zymosan.

75. The composition of claim 70, wherein the therapeutic agent is a TDO inhibitor, and the TDO inhibitor is selected from the group consisting of tryptophan kynurenine and indole-3-aldehyde.

76. The composition of claim 70, wherein the therapeutic agent is a prebiotic, and the prebiotic is selected from the group consisting of mannan oligosaccharides, inulin, xylooligosaccharides.

77. The composition of any preceding claim, wherein the bacterium is a cancer-associated bacterium.

78. The composition of any preceding claim, wherein the bacterium is able to infect a tumor associated macrophage.

79. The composition of claim 78, wherein the polymer enhances the ability of the

bacterium to infect the tumor associated macrophage.

80. The composition of any preceding claim, wherein the bacterium is able to infect a myeloid-derived suppressor cell (MDSC).

81. The composition of claim 80, wherein the polymer enhances the ability of the

bacterium to infect the MDSC.

82. The composition of any preceding claim, wherein the bacterium is able to infect an antigen presenting cell.

83. The composition of claim 82, wherein the polymer enhances the ability of the

bacterium to infect the antigen presenting cell.

84. The composition of claim 82 or 83, wherein the antigen-presenting cell is a

macrophage, a dendritic cell or a B cell.

85. The composition of any preceding claim, wherein the bacterium preferentially adheres to a cancer cell.

86. The composition of claim 85, wherein the polymer enhances the ability of the

bacterium to adhere to a cancer cell.

87. The composition of any preceding claim, wherein the bacterium localizes to a tumor.

88. The composition of claim 87, wherein the polymer enhances the ability of the bacterium to localize to a tumor.

89. The composition of any preceding claim, wherein the bacterium is selected from the group consisting of the bacteria listed in Table 1.

90. The composition of any preceding claim, wherein the bacterium is selected from the group consisting of the bacteria listed in Table 2.

91. The composition of any preceding claim, wherein the bacterium is a spore-forming bacterium.

92. The composition of claim 91, wherein the spore-forming bacterium is selected from the group consisting of Clostridium absonum, Clostridium aceticum, Clostridium acetireducens, Clostridium acetobutylicum, Clostridium acidisoli, Clostridium aciditolerans, Clostridium acidurici, Clostridium aerotolerans, Clostridium aestuarii, Clostridium akagii, Clostridium aldenense, Clostridium aldrichii, Clostridium algidicarnis, Clostridium algidixylanolyticum, Clostridium algifaecis, Clostridium algoriphilum, Clostridium alkulic llulosi, Clostridium aminophilum, Clostridium aminovalericum, Clostridium amygdalinum, Clostridium amylolyticum, Clostridium arbusti, Clostridium arcticum, Clostridium argentinense, Clostridium asparagiforme, Clostridium aurantibutyricum, Clostridium baratii, Clostridium barkeri, Clostridium bartlettii, Clostridium beijerinckii, Clostridium bifermentans, Clostridium bolteae, Clostridium bornimense, Clostridium botulinum, Clostridium bowmanii, Clostridium bryantii, Clostridium butyricum, Clostridium cadaveris, Clostridium caenicola, Clostridium caminithermale, Clostridium carboxidivorans, Clostridium carnis, Clostridium cavendishii, Clostridium celatum, Clostridium celerecrescens,

Clostridium cellobioparum, Clostridium cellulofermentans, Clostridium

cellulolyticum, Clostridium cellulosi, Clostridium cellulovorans, Clostridium chartatabidum, Clostridium chauvoei, Clostridium chromiireducens, Clostridium citroniae, Clostridium clariflavum, Clostridium clostridioforme, Clostridium coccoides, Clostridium cochlearium, Clostridium cocleatum, Clostridium colicanis, Clostridium colinum, Clostridium collagenovorans, Clostridium cylindrosporum, Clostridium difficile, Clostridium diolis, Clostridium disporicum, Clostridium drakei, Clostridium durum, Clostridium estertheticum, Clostridium e. subsp. estertheticum, Clostridium e. subsp. laramiense, Clostridium fallax, Clostridium felsineum, Clostridium fervidum, Clostridium fimetarium, Clostridium formicaceticum, Clostridium frigidicarnis, Clostridium rigoris, Clostridium ganghwense, Clostridium gasigenes, Clostridium ghonii, Clostridium glycolicum, Clostridium

glycyrrhizinilyticum, Clostridium grantii, Clostridium haemolyticum, Clostridium halophilum, Clostridium hastiforme, Clostridium hathewayi, Clostridium

herbivorans, Clostridium hiranonis, Clostridium histolyticum, Clostridium homopropionicum, Clostridium huakuii, Clostridium hungatei, Clostridium hydrogeniformans, Clostridium hydroxybenzoicum, Clostridium hylemonae,

Clostridium jejuense, Clostridium indolis, Clostridium innocuum, Clostridium intestinale, Clostridium irregulare, Clostridium isatidis, Clostridium josui,

Clostridium kluyveri, Clostridium lactatifermentans, Clostridium lacusfryxellense, Clostridium laramiense, Clostridium lavalense, Clostridium lentocellum, Clostridium lentoputrescens, Clostridium leptum, Clostridium limosum, Clostridium litorale, Clostridium lituseburense, Clostridium ljungdahlii, Clostridium lortetii, Clostridium lundense, Clostridium magnum, Clostridium malenominatum, Clostridium mangenotii, Clos 'idium mayombei, Clostridium methoxybenzovorans, Clostridium methylpentosum, Clostridium neopropionicum, Clostridium nexile, Clostridium nitrophenolicum, Clostridium novyi, Clostridium oceanicum, Clostridium

orbiscindens, Clostridium oroticum, Clostridium oxalicum, Clostridium

papyrosolvens, Clostridium paradoxum, Clostridium paraperfringens, Clostridium paraputrificum, Clostridium pascui, Clostridium pasteurianum, Clostridium peptidivorans, Clostridium perenne, Clostridium perfringens, Clostridium pfennigii, Clostridium phytofermentans, Clostridium piliforme, Clostridium

polysaccharolyticum, Clostridium populeti, Clostridium propionicum, Clostridium proteoclasticum, Clostridium proteolyticum, Clostridium psychrophil m, Clostridium puniceum, Clostridium purinilyticum, Clostridium putrefaciens, Clostridium putrificum, Clostridium quercicolum, Clostridium quinii, Clostridium ramosum, Clostridium rectum, Clostridium roseum, Clostridium saccharobutylicum,

Clostridium saccharogumia, Clostridium saccharolyticum, Clostridium

saccharoperbutylacetonicum, Clostridium sardiniense, Clostridium sartagoforme, Clostridium scatologenes, Clostridium schirmacherense, Clostridium scindens, Clostridium septicum, Clostridium sordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridium sporogenes, Clostridium sporosphaeroides, Clostridium stercorarium, Clostridium s. subsp. leptospartum, Clostridium s. subsp. stercorarium, Clostridium s. subsp. thermolacticum, Clostridium sticklandii, Clostridium straminisolvens, Clostridium subterminale, Clostridium sufflavum, Clostridium sulfidigenes, Clostridium symbiosum, Clostridium tagluense, Clostridium

tepidiprofundi, Clostridium termitidis, Clostridium tertium, Clostridium tetani, Clostridium tetanomorphum, Clostridium thermaceticum, Clostridium

thermautotrophicum, Clostridium thermoalcaliphilum, Clostridium thermobutyricum, Clostridium ther ocellum, Clostridium thermocopriae, Clostridium

thermohydrosulfuricum, Clostridium thermolacticum, Clostridium thermopalmarium, Clostridium thermopapyrolyticum, Clostridium thermosaccharolyticum, Clostridium thermosuccinogenes, Clostridium thermosulfurigenes, Clostridium

thiosulfatireducens, Clostridium tyrobutyricum, Clostridium uliginosum, Clostridium ultunense, Clostridium villosum, Clostridium vincentii, Clostridium viride,

Clostridium xylanolyticum, Clostridium xylanovorans, Bacillus acidiceler, Bacillus acidicola, Bacillus acidiproducens, Bacillus acidocaldarius, Bacillus acidoterrestris, Bacillus aeolius, Bacillus aerius, Bacillus aerophilus, Bacillus agar adhaer ens, Bacillus agri, Bacillus aidingensis, Bacillus akibai, Bacillus alcalophilus, Bacillus algicola, Bacillus alginolyticus, Bacillus alkalidiazotrophicus, Bacillus

alkalinitrilicus, Bacillus alkalisediminis, Bacillus alkalitelluris, Bacillus altitudinis, Bacillus alveayuensis, Bacillus alvei, Bacillus amyloliquefaciens, Bacillus amylolyticus, Bacillus andreesenii, Bacillus aneurinilyticus, Bacillus unlhracis, Bacillus aquimaris, Bacillus arenosi, Bacillus arseniciselenatis, Bacillus arsenicus, Bacillus aurantiacus, Bacillus arvi, Bacillus aryabhattai, Bacillus asahii, Bacillus atrophaeus, Bacillus axarquiensis, Bacillus azotofixansvBacillus azotoformans, Bacillus badius, Bacillus barbaricus, Bacillus bataviensis, Bacillus beijingensis, Bacillus benzoevorans, Bacillus beringensis, Bacillus berkeleyi, Bacillus beveridgei, Bacillus bogoriensis, Bacillus boroniphilus, Bacillus borstelensis, Bacillus brevis, Migula, Bacillus butanolivorans, Bacillus canaver alius, Bacillus carboniphilus, Bacillus cecembensis, Bacillus cellulosilyticus, Bacillus centrosporus, Bacillus cereus, Bacillus chagannorensis, Bacillus chitinolyticus, Bacillus chondroitinus, Bacillus choshinensis, Bacillus chungangensis, Bacillus cibi, Bacillus circulans, Bacillus clarkii, Bacillus clausii, Bacillus coagulans, Bacillus coahuilensis, Bacillus cohnii, Bacillus compostivBacillus curdlanolyticus, Bacillus cycloheptanicus, Bacillus cytotoxicus, Bacillus daliensis, Bacillus decisifrondis, Bacillus decolor ationis, Bacillus deserti, Bacillus dipsosauri, Bacillus drentensis, Bacillus edaphicus, Bacillus ehimensis, Bacillus eiseniae, Bacillus enclensis, Bacillus endophyticus, Bacillus endoradicis, Bacillus farraginis, Bacillus fastidiosus, Bacillus fengqiuensis, Bacillus firmus, Bacillus flexus, Bacillus foraminis, Bacillus fordii, Bacillus formosus, Bacillus fortis, Bacillus fumarioli, Bacillus funiculus, Bacillus fusiformis, Bacillus galactophilus, Bacillus galactosidilyticus, Bacillus galliciensis, Bacillus gelatini, Bacillus gibsonii, Bacillus ginsengi, Bacillus ginsengihumiBacillus ginsengisoli, Bacillus globisporus, Bacillus g. subsp. globisporus, Bacillus g. subsp. marinus, Bacillus glucanolyticus, Bacillus gordonae, Bacillus gottheilii, Bacillus graminis, Bacillus halmapalus, Bacillus haloalkaliphilus, Bacillus halochares, Bacillus halodenitrificans, Bacillus halodurans, Bacillus halophilus, Bacillus

halosaccharovorans, Bacillus hemicellulosilyticus, Bacillus hemicentroti, Bacillus herbersteinensis, Bacillus horikoshii, Bacillus horneckiae, Bacillus horti, Bacillus huizhouensis, Bacillus humi, Bacillus hwajinpoensis, Bacillus idriensis, Bacillus indicus, Bacillus infantis, Bacillus infernus, Bacillus insolitus, Bacillus ihvictae, Bacillus iranensis, Bacillus isabeliae, Bacillus isronensis, Bacillus jeotgali, Bacillus kaustophilus, Bacillus kobensis, Bacillus kochii, Bacillus kokeshiiformis, Bacillus koreensis, Bacillus korlensis, Bacillus kribbensis, Bacillus krulwichiae, Bacillus laevolacticus, Bacillus larvae, Bacillus laterosporus, Bacillus lautus, Bacillus lehensis, Bacillus lentimorbus, Bacillus lentus, Bacillus licheniformis, Bacillus ligniniphilus, Bacillus litoralis, Bacillus locisalis, Bacillus luciferensis, Bacillus luteolus, Bacillus luteus, Bacillus macauensis, Bacillus macerans, Bacillus macquariensis, Bacillus macyae, Bacillus malacitensis, Bacillus mannanilyticus, Bacillus marinus, Bacillus marisflavi, Bacillus marismortui, Bacillus marmarensis, Bacillus massiliensis, Bacillus megaterium, Bacillus mesonae, Bacillus methanolicus, Bacillus methylotrophicus, Bacillus migulanus, Bacillus mojavensis, Bacillus mucilaginosus, Bacillus muralis, Bacillus murimartini, Bacillus mycoides, Bacillus naganoensis, Bacillus nanhaiensis, Bacillus nanhaiisediminis, Bacillus nealsonii, Bacillus neidei, Bacillus neizhouensis, Bacillus niabensis, Bacillus niacini, Bacillus novalis, Bacillus oceanisediminis, Bacillus odysseyi, Bacillus okhensis, Bacillus okuhidensis, Bacillus oleronius, Bacillus oryzaecorticis, Bacillus oshimensis, Bacillus pabuli, Bacillus pakistanensis, Bacillus pallidus, Bacillus pallidus, Bacillus panacisoli, Bacillus panaciterrae, Bacillus pantothenticus, Bacillus parabrevis, Bacillus paraflexus, Bacillus pasteurii, Bacillus patagoniensis, Bacillus peoriae, Bacillus persepolensis, Bacillus persicus, Bacillus pervagus, Bacillus plakortidis, Bacillus pocheonensis, Bacillus polygoni, Bacillus polymyxa, Bacillus popilliae, Bacillus pseudalcaliphilus, Bacillus pseudofirmus, Bacillus pseudomycoides, Bacillus psychrodurans, Bacillus psychrophilus, Bacillus psychrosaccharolyticus, Bacillus psychrotolerans, Bacillus pulvifaciens, Bacillus pumilus, Bacillus purgationiresistens, Bacillus pycnus, Bacillus qingdaonensis, Bacillus qingshengii, Bacillus reuszeri, Bacillus rhizosphaerae, Bacillus rigui, Bacillus ruris, Bacillus safensis, Bacillus salarius, Bacillus salexigens, Bacillus saliphilus, Bacillus schlegelii, Bacillus sediminis, Bacillus selenatarsenatis, Bacillus selenitireducens, Bacillus

seohaeanensis, Bacillus shacheensis, Bacillus shackletonii, Bacillus siamensis, Bacillus silvestris, Bacillus simplex, Bacillus siralis, Bacillus smithii, Bacillus soli, Bacillus solimangrovi, Bacillus solisalsi, Bacillus songklensis, Bacillus sonorensis, Bacillus sphaericus, Bacillus sporothermodurans, Bacillus stearothermophilus, Bacillus stratosphericus, Bacillus subterraneus, Bacillus subtilis, Bacillus s. subsp. inaquosorum, Bacillus s. subsp. spizizenii, Bacillus s. subsp. subtilis, Bacillus taeanensis, Bacillus tequilensis, Bacillus thermantarcticus, Bacillus

thermoaerophilus, Bacillus thermoamylovorans, Bacillus thermocatenulatus, Bacillus thermocloacae, Bacillus thermocopriae, Bacillus thermodenitrificans, Bacillus thermoglucosidasius, Bacillus thermolactis, Bacillus thermoleovorans, Bacillus thermophilus, Bacillus thermoruber, Bacillus thermosphaericus, Bacillus

thiaminolyticus, Bacillus thioparans, Bacillus thuringiensis, Bacillus lianshenii, Bacillus trypoxylicola, Bacillus tusciae, Bacillus validus. Bacillus vallismortis, Bacillus vedderi, Bacillus velezensis, Bacillus vietnamensis, Bacillus vireti, Bacillus vulcani, Bacillus wakoensis, Bacillus weihenstephanensis, Bacillus xiamenensis, Bacillus xiaoxiensis, Bacillus zhanjiangensis, Sporolactobacillus dextrus,

Sporolactobacillus inulinus, Sporolactobacillus laevis, Sporolactobacillus terrae, Sporolactobacillus vineae, Sporosarcina aquimarina, Sporosarcina globispora, Sporosarcina halophila, Sporosarcina koreensis, Sporosarcina luteola and

Sporosarcina ureae.

93. The composition of any preceding claim, wherein the bacterium is a systemic

anaerobic bacterium.

94. The composition of claim 93, wherein the systemic anaerobic bacterium is selected from the group consisting of bacteria of the Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila, S tterella, Peptostreptococcus, Clostridium, Actinomyces, Propionib cterium, Eubacterium, Lactobacillus, Bifidobacterium and Veillonella.

95. A method of treating cancer in a subject, comprising administering to the subject a pharmaceutical composition of any one of claims 1-94.

96. The method of claim 95, wherein the cancer is selected from the group consisting of acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,jnegakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large- cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, chondrosarcoma, fibrosarcoma,

lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing' s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, telangiectaltic sarcoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, Harding- Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.

97. A method of treating an autoimmune disease in a subject, comprising administering to the subject a pharmaceutical composition of any one of claims 1 -94.

98. The method of claim 97, wherein the autoimmune disease is chronic inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease.

99. The method of claim 98, wherein the autoimmune disease is chronic inflammatory bowel disease.

100. The method of claim 99, wherein the chronic inflammatory bowel disease is Crohn's disease (regional bowel disease, e.g. , inactive and active forms), Ulcerative colitis {e.g. , inactive and active forms), irritable bowel syndrome, microscopic colitis, lymphocytic-plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis, eosinophilic enterocolitis, indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel di3C03c, Bohoet'c disease, sarcoidosis, scleroderma, IBD-associated dysplasia, dysplasia associated masses or lesions, or primary sclerosing cholangitis.

101. A method of treating an allergic disease in a subject, comprising administering to the subject a pharmaceutical composition of any one of claims 1 -94.

102. The method of claim 101 , wherein the allergic disease is a food allergy, pollenosis, or asthma.

103. A method of treating an infectious disease in a subject, comprising administering to the subject a pharmaceutical composition of any one of claims 1 -94.

104. The method of claim 103, wherein the infectious disease is infection with Clostridium difficile.

105. A method of treating an inflammatory disease in a subject, comprising administering to the subject a pharmaceutical composition of any one of claims 1 -94.

106. The method of claim 105, wherein the inflammatory disease is a TNF-mediated inflammatory disease.

107. The method of claim 106, wherein the TNF-mediated inflammatory disease is an inflammatory disease of the gastrointestinal tract.

108. The method of claim 107, wherein the inflammatory disease of the gastrointestinal tract is pouchitis.

109. The method of claim 106, wherein the TNF-mediated inflammatory disease is a cardiovascular inflammatory condition.

1 10. The method of claim 109, wherein the cardiovascular inflammatory condition is atherosclerosis.

1 1 1. The method of claim 106, wherein the TNF-mediated inflammatory disease is an inflammatory lung disease.

1 12. The method of claim 1 1 1 , wherein the inflammatory lung disease is chronic

obstructive pulmonary disease.

1 13. A method of suppressing organ transplant rejection, comprising administering to the subject a pharmaceutical composition of any one of claims 1 -94.

1 14. The method of any one of claims 95-1 13, wherein the subject is a human.

1 15. The method of any one of claims 95- 1 13, wherein the subject is a non-human mammal.

1 16. The method of claim 1 15, wherein the mammal is selected from the group consisting of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla, and a chimpanzee.

1 17. The composition of any one of claims 1 to 93, wherein the polymer is stable through passage of the GI tract.

1 18. The composition of any one of claims 1 to 93 and 1 17, wherein the polymer improves viability of the bacterium.

1 19. The composition of any one of claims 1 to 93 and 1 17 to 1 18, wherein the polymer modulates the biodistribution of the bacterium.

120. The composition of any one of claims 1 to 93 and 1 17 to 1 19, wherein the polymer modulates the exposure time of the bacterium in a host. A method obtaining a polymer-coated bacterium comprising purifying the poly coated bacterium out of a complex biological mixture.