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WO2019164283A1 - Nano-vésicules dérivées de bactéries de l'espèce blautia et utilisation associée - Google Patents

Nano-vésicules dérivées de bactéries de l'espèce blautia et utilisation associée Download PDF

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Publication number
WO2019164283A1
WO2019164283A1 PCT/KR2019/002102 KR2019002102W WO2019164283A1 WO 2019164283 A1 WO2019164283 A1 WO 2019164283A1 KR 2019002102 W KR2019002102 W KR 2019002102W WO 2019164283 A1 WO2019164283 A1 WO 2019164283A1
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WIPO (PCT)
Prior art keywords
cancer
vesicles
disease
derived
blautia
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Ceased
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PCT/KR2019/002102
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English (en)
Korean (ko)
Inventor
김윤근
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MD Healthcare Inc
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MD Healthcare Inc
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Priority claimed from KR1020190019742A external-priority patent/KR102122898B1/ko
Application filed by MD Healthcare Inc filed Critical MD Healthcare Inc
Priority to CN201980015198.1A priority Critical patent/CN111936640A/zh
Priority to US16/975,890 priority patent/US20210002707A1/en
Publication of WO2019164283A1 publication Critical patent/WO2019164283A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6851—Quantitative amplification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Blautia genus is an anaerobic Gram-positive bacterium found in the intestine, and it has been reported that mortality due to Graft versus Host disease is reduced when the bacteria increase in the intestine after bone marrow transplantation. However, it has not been reported that Blautia spp. Secrete extracellular vesicles, and there have been no reports of application to diagnosis and treatment of refractory diseases such as cancer or cardiovascular disease.
  • the present invention is to prevent colon disease, liver disease, pancreatic disease, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, heteroangular angina, graft versus host disease
  • Another object is to provide a composition for improvement, treatment or treatment.
  • the present invention comprises the following steps, information for the diagnosis of colorectal cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, or heteroangular angina Provide a way to:
  • the present invention comprises administering to the subject a pharmaceutical composition
  • a pharmaceutical composition comprising a Blautia bacteria-derived vesicle as an active ingredient, colon disease, liver disease, pancreatic disease, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction,
  • a pharmaceutical composition comprising a Blautia bacteria-derived vesicle as an active ingredient, colon disease, liver disease, pancreatic disease, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction.
  • the vesicles may have an average diameter of 10 to 200 nm.
  • the vesicles may be secreted naturally or artificially from the Blautia genus bacteria.
  • the Blautia bacteria-derived vesicles may be Blautia cocoides-derived vesicles.
  • the colon disease may be colitis, irritable growth syndrome or colorectal cancer.
  • the pancreatic disease may be pancreatitis or pancreatic cancer.
  • the present inventors confirmed that intestinal bacteria are not absorbed into the body, but in the case of bacterial-derived vesicles, they are absorbed into the body through epithelial cells, distributed systemically, and excreted in vitro through the kidneys, liver, and lungs.
  • FIG. 6 is a result of comparing the distribution of vesicles derived from Blautia spp. After performing a bacterial-derived vesicle metagenome analysis present in ovarian cancer patients and normal blood.
  • 9 is a result of comparing the distribution of vesicles derived from Blautia spp. After performing a bacterial-derived vesicle metagenome analysis present in patients with atrial fibrillation and normal blood.
  • E. coli EV Escherichia coli vesicles
  • the present invention relates to vesicles derived from Blautia spp. And uses thereof.
  • the present inventors found that vesicles derived from Blautia bacteria were significantly reduced in clinical samples of patients with colorectal cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, and angina in patients with a metagenome analysis. It was confirmed that the disease can be diagnosed.
  • Diagnosis in the broad sense means to determine the actual condition of the patient's disease in all aspects. The content of the judgment is the name of the disease, the etiology, the type of disease, the seriousness, the detailed mode of the condition, the presence or absence of complications, and the prognosis. Diagnosis in the present invention is to determine the incidence and disease level of colon cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, and / or dysplastic angina.
  • the present invention comprises a bladder-derived bacterial vesicles as an active ingredient, colon disease, liver disease, pancreatic disease, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, heteroangular angina or graft
  • a composition for preventing, treating or ameliorating host disease comprises a food composition and a pharmaceutical composition, in the present invention the food composition comprises a nutraceutical composition.
  • the composition of the present invention may be an injection, oral nebulizer, or inhalant formulation.
  • the colon disease may be colitis, irritable growth syndrome or colorectal cancer, but is not limited thereto.
  • the liver disease may be hepatitis, cirrhosis or liver cancer, but is not limited thereto.
  • the pancreatic disease may be pancreatitis or pancreatic cancer, but is not limited thereto.
  • prevention means colon disease, liver disease, pancreatic disease, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, heteroangular angina, and / or graft formation by administration of a composition according to the present invention. It means any action that suppresses or delays the onset of a host disease.
  • treatment refers to colon disease, liver disease, pancreatic disease, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, heteroangular angina and / or graft versus host by administration of a composition according to the present invention. It means any action that improves or beneficially changes the symptoms of illness.
  • the term “improvement” means any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
  • the vesicles were centrifuged, ultra-fast centrifugation, high pressure treatment, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical degradation, chemical treatment, and filter.
  • the separation can be carried out using one or more methods selected from the group consisting of filtration, gel filtration chromatography, pre-flow electrophoresis, and capillary electrophoresis. In addition, it may further include a process for washing to remove impurities, concentration of the obtained vesicles and the like.
  • the pharmaceutical composition according to the invention may comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are conventionally used in the preparation, and include, but are not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • Suitable pharmaceutically acceptable carriers and formulations can be preferably formulated according to the individual components using methods disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, external preparation for skin, oral ingestion, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, skin, nasal, airways) according to the desired method, and the dosage is determined by the condition and weight of the patient, disease Depending on the degree, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug and the drug. Sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
  • the composition according to the present invention may be administered as a separate therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg daily or every other day, per kg of body weight Or divided into 1 to 3 times a day.
  • the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the food composition of the present invention includes a nutraceutical composition.
  • the food composition according to the present invention may be used as it is, or may be used in combination with other foods or food ingredients, or may be appropriately used according to conventional methods.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the compositions of the invention are added in amounts of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the amount may be below the above range.
  • the food composition of the present invention in addition to containing the active ingredient as an essential ingredient in the indicated ratio, there are no particular restrictions on other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract, for example, rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • these components can be used independently or in combination.
  • the proportion of such additives may also be appropriately selected by those skilled in the art.
  • the bacteria and the bacteria-derived vesicles orally administered to evaluate the absorption, distribution, and excretion of the bacteria and vesicles in the body in the case of bacteria is not absorbed through the intestinal vesicles 5 minutes administration It was confirmed that it was absorbed within the body and distributed systemically and excreted through the kidney, liver, and the like (see Example 1).
  • a vesicle isolated from blood or stool of a normal person of age and sex matched in patients with colorectal cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, and dysplastic angina pectoris Bacterial metagenome analysis was performed. As a result, compared to the normal sample, the Blautia bacteria-derived vesicles were significantly reduced in the clinical samples of colon cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, and angina. It was confirmed (see Examples 3 to 11).
  • the Blautia cocoides strain was cultured to evaluate whether the secreted vesicles exhibit immunomodulatory and anti-inflammatory effects. After evaluating the secretion of inflammatory mediators by treating E. coli-derived vesicles, the inflammatory disease-causing factor, it was confirmed that Blautia cocoides-derived vesicles effectively suppressed IL-6 and TNF- ⁇ secretion by E. coli-derived vesicles. (See Example 13).
  • Example 1 Analysis of absorption, distribution, and excretion of intestinal bacteria and bacterial-derived vesicles
  • DNA extracted by the above method was amplified using the above 16S rDNA primers, followed by sequencing (Illumina MiSeq sequencer), and the results were outputted in a Standard Flowgram Format (SFF) file, using GS FLX software (v2.9). After converting the SFF file into a sequence file (.fasta) and a nucleotide qualityscore file, the credit rating of the lead was confirmed, and the window (20 bps) average base call accuracy was less than 99% (Phred score ⁇ 20). . For operational taxonomy unit (OTU) analysis, clustering is performed according to sequence similarity using UCLUST and USEARCH.
  • OFUTU operational taxonomy unit
  • Genus is 94%, family is 90%, order is 85%, and steel ( class is 80% and phylum is clustered based on 75% sequence similarity and the phylum, class, order, family and genus levels of each OTU Sorting was performed, and bacteria with greater than 97% sequence similarity at the genus level were profiled (QIIME) using BLASTN and GreenGenes' 16S RNA sequence database (108,453 sequences).
  • Example 2 the genes were extracted from the vesicles in 29 stool patients and 358 stool patients in normal stool, followed by metagenomic analysis. Evaluated. As a result, it was confirmed that vesicles derived from Blautia bacteria were significantly reduced in the stool of colorectal cancer patients compared to normal stool (see Table 2 and FIG. 2).
  • Example 2 In the method of Example 2, 176 blood of pancreatic cancer patients and 271 blood of normal persons whose age and sex were matched were extracted from the vesicles present in the blood and subjected to metagenome analysis. The distribution of the derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from Blautia bacteria were significantly reduced in the blood of pancreatic cancer patients compared to normal blood (see Table 4 and FIG. 4).
  • Example 2 In the method of Example 2, 137 blood of ovarian cancer patients and 139 normal blood of age and sex matched were extracted from vesicles in the blood and subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that vesicles derived from Blautia bacteria were significantly reduced in blood of ovarian cancer patients compared to normal blood (see Table 6 and FIG. 6).
  • Example 2 the blood of 91 bladder cancer patients and 176 bloods of normal age and gender matched were extracted from vesicles in the blood and subjected to metagenomic analysis. The distribution of the derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from Blautia bacteria were significantly reduced in the blood of bladder cancer patients compared to normal blood (see Table 7 and FIG. 7).
  • Example 2 the blood of 80 patients with angina and 80 normal blood whose age and sex were matched were extracted from the vesicles in the blood and subjected to metagenomic analysis. The distribution of bacterial derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from Blautia bacteria were significantly reduced in blood of patients with heteroangular angina compared with normal blood (see Table 10 and FIG. 10).
  • Blautia cocoides-derived vesicles were collected in raw 264.7 cells. 0.1, 1, 10 ⁇ g / ml), followed by ELISA. More specifically, the Blautia cocooides-derived vesicles of various concentrations containing DMEM (Dulbeco's Modified Eagle's Medium) serum-free medium in 4 ⁇ 10 4 aliquots of 4 ⁇ 10 4 cells in 48-well cell culture plates were treated for 12 hours. Incubated. Then, the cell cultures were collected in a 1.5 ml tube, centrifuged at 3000 g for 5 minutes, the supernatants were collected, stored at -80 ° C, and then subjected to ELISA.
  • DMEM Dynamic microsomal growth factor
  • the capture antibody was diluted in phosphate buffered saline (PBS), and 50 ⁇ l was dispensed into 96 well polystyrene plates according to the working concentration, followed by reaction at 4 ° C. overnight. I was. After washing three times with 100 ⁇ l of PBST (phosphate buffered saline solution containing 0.05% tween-20), 100 ⁇ l of RD (phosphate buffered saline solution containing 1% BSA (bovine serum albumin) solution was dispensed. Blocking for 1 hour at room temperature.
  • PBS phosphate buffered saline
  • RD phosphate buffered saline solution containing 1% BSA (bovine serum albumin
  • Dispense the sample and standard by 50 ⁇ l according to the concentration react for 2 hours at room temperature, wash three times with 100 ⁇ l of PBST, and then dilute the detection antibody in RD and dispense 50 ⁇ l according to the working concentration. The reaction was carried out at room temperature for 2 hours.
  • Blautia cocoides-derived vesicles were treated with a macrophage line ( After pretreatment with Raw 264.7) for 12 hours, 1 ⁇ g / ml of E. coli vesicles derived from Escherichia coli (E. coli EV) were treated, and after 12 hours, the secretion of inflammatory cytokines was measured by ELISA. Lactobacillus plantarum- derived vesicles were used.
  • the extracellular vesicles derived from the Blautia spp. Bacterium according to the present invention are for preventing, improving or treating colon cancer, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation or angina, as well as the above diseases. Since it can be used as a composition for the medical and food industry is expected to be usefully utilized.

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Abstract

La présente invention concerne des vésicules dérivées de bactéries de l'espèce Blautia et une utilisation associée. Les présents inventeurs ont découvert expérimentalement des teneurs significativement réduites des vésicules dans des échantillons cliniques de patients atteints du cancer colorectal, du cancer du foie, du cancer du pancréas, du cholangiocarcinome, du cancer de l'ovaire, du cancer de la vessie, de l'infarctus du myocarde, de la fibrillation auriculaire, et de l'angine de Prinzmetal, par comparaison à des personnes normales, et l'administration des vésicules isolées de la souche a permis de réprimer notablement la sécrétion de médiateurs inflammatoires induite par des vésicules pathogènes telles que des vésicules dérivées d'E. coli. Les vésicules dérivées de bactéries de l'espèce Blautia selon la présente invention peuvent être efficacement utilisées pour développer une méthode de diagnostic du cancer colorectal, du cancer du foie, du cancer du pancréas, du cholangiocarcinome, du cancer de l'ovaire, du cancer de la vessie, de l'infarctus du myocarde, de la fibrillation auriculaire, ou de l'angine de Prinzmetal et une composition pour la prévention, le soulagement ou le traitement d'une maladie colorectale, d'une maladie hépatique, d'une maladie du pancréas, du cholangiocarcinome, du cancer de l'ovaire, du cancer de la vessie, de l'infarctus du myocarde, de la fibrillation auriculaire, de l'angine de Prinzmetal ou de la maladie du greffon contre l'hôte.
PCT/KR2019/002102 2018-02-26 2019-02-21 Nano-vésicules dérivées de bactéries de l'espèce blautia et utilisation associée Ceased WO2019164283A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201980015198.1A CN111936640A (zh) 2018-02-26 2019-02-21 来源于布劳特氏菌种细菌的纳米囊泡及其用途
US16/975,890 US20210002707A1 (en) 2018-02-26 2019-02-21 Nanovesicles derived from blautia bacteria and use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2018-0023210 2018-02-26
KR20180023210 2018-02-26
KR1020190019742A KR102122898B1 (ko) 2018-02-26 2019-02-20 블라우티아 속 세균 유래 나노소포 및 이의 용도
KR10-2019-0019742 2019-02-20

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058094A1 (en) * 2010-08-20 2012-03-08 Dow Global Technologies Llc Compositions and methods for treating obesity and related disorders by characterizing and restoring mammalian bacterial microbiota
WO2012159023A2 (fr) * 2011-05-19 2012-11-22 Virginia Commonwealth University Microflore de l'intestin servant de biomarqueur dans le pronostic de la cirrhose et du dysfonctionnement cérébral
KR20160073157A (ko) * 2014-12-16 2016-06-24 이화여자대학교 산학협력단 세균 유래의 나노소포체를 이용한 세균성 감염질환 원인균 동정방법
KR20180006303A (ko) * 2016-07-08 2018-01-17 주식회사 엠디헬스케어 프로피오니박테리움 속 세균 유래 나노소포 및 이의 용도
KR20180012846A (ko) * 2015-06-15 2018-02-06 4디 파마 리서치 리미티드 박테리아 균주를 함유한 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058094A1 (en) * 2010-08-20 2012-03-08 Dow Global Technologies Llc Compositions and methods for treating obesity and related disorders by characterizing and restoring mammalian bacterial microbiota
WO2012159023A2 (fr) * 2011-05-19 2012-11-22 Virginia Commonwealth University Microflore de l'intestin servant de biomarqueur dans le pronostic de la cirrhose et du dysfonctionnement cérébral
KR20160073157A (ko) * 2014-12-16 2016-06-24 이화여자대학교 산학협력단 세균 유래의 나노소포체를 이용한 세균성 감염질환 원인균 동정방법
KR20180012846A (ko) * 2015-06-15 2018-02-06 4디 파마 리서치 리미티드 박테리아 균주를 함유한 조성물
KR20180006303A (ko) * 2016-07-08 2018-01-17 주식회사 엠디헬스케어 프로피오니박테리움 속 세균 유래 나노소포 및 이의 용도

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