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WO2025197951A1 - Composition permettant de favoriser la prolifération de cellules immunitaires - Google Patents

Composition permettant de favoriser la prolifération de cellules immunitaires

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Publication number
WO2025197951A1
WO2025197951A1 PCT/JP2025/010645 JP2025010645W WO2025197951A1 WO 2025197951 A1 WO2025197951 A1 WO 2025197951A1 JP 2025010645 W JP2025010645 W JP 2025010645W WO 2025197951 A1 WO2025197951 A1 WO 2025197951A1
Authority
WO
WIPO (PCT)
Prior art keywords
cells
composition
lactic acid
acid bacteria
proliferation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2025/010645
Other languages
English (en)
Japanese (ja)
Inventor
啓誠 川鍋
岳大 横尾
舒宜 唐
真梨枝 中村
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Meiji Co Ltd
Meiji Holdings Co Ltd
Original Assignee
Meiji Co Ltd
Meiji Holdings Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meiji Co Ltd, Meiji Holdings Co Ltd filed Critical Meiji Co Ltd
Publication of WO2025197951A1 publication Critical patent/WO2025197951A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • 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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition for promoting the proliferation of immune cells.
  • T cells play an important role in the immune system. In response to various extracellular stimuli, they differentiate from immature states into various effector T cells with diverse functions, and are known to contribute to the elimination of pathogenic microorganisms, virus-infected cells, cancer cells, and other pathogens.
  • CD4 + T cells (Th7R cells), a type of effector T cell, with a cell surface marker expression pattern of CXCR3 + /CCR4 low /CCR6 high , can be used as a biomarker to predict the response rate of immune checkpoint inhibitors to cancer (Non-Patent Document 1).
  • Patent Document 1 describes a method for determining the relative amount of Th7R cell subpopulation in a CD4 + T cell population in a sample from a subject, comprising the steps of selecting a CXCR3 ⁇ cell subpopulation from the CD4 + T cell population, establishing a boundary between a CCR4 ⁇ cell subpopulation and a CCR4 + cell subpopulation in the CXCR3 ⁇ cell subpopulation, and measuring the relative amount of the CCR4 ⁇ CCR6 + cell subpopulation in the CD4 + T cell population using the boundary.
  • Th7R cells are also known to contribute to the suppression of cancer recurrence after surgical removal (Non-Patent Document 2).
  • MAIT cells and NKT cells which are types of effector T cells, contribute to adaptive immunity, but also possess rapid effector activity and are characterized by their contribution to innate immunity.
  • MAIT cells and NKT cells are known to contribute to cancer prevention and suppression of cancer metastasis (Non-Patent Documents 3 and 4).
  • lactic acid bacteria, their fermentation products, and lactic acid bacteria-derived exopolysaccharides are known to have several physiological activities. These physiological activities include, for example, prevention of autoimmune diseases (Patent Document 2), NK cell activation (Patent Document 3), antiviral activity (Patent Document 4), prevention of pneumococcal infection (Patent Document 5), suppression of acquired immune decline (Patent Document 6), prevention and/or treatment of influenza (Patent Document 7), suppression of cytokine production (Patent Document 8), activation of cellular immunity (Patent Document 9), suppression of cancer cachexia (Patent Document 10), promotion of immune checkpoint inhibitor therapy (Patent Document 11), prevention of secondary infections after viral infection or reduction of the risk of onset (Patent Document 12), anti-human coronavirus activity (Patent Document 13), suppression of viral proliferation (Patent Document 14), regulation of immune balance (Patent Document 15), promotion of interferon- ⁇ production (Patent Document 16), activation of
  • the present invention aims to provide a means for promoting the proliferation of one or more of CD4 + T cells, MAIT cells, and NKT cells, which are types of effector T cells and have a cell surface marker expression pattern of CXCR3 + /CCR4 low /CCR6 high.
  • composition according to [2], wherein the improved sensitivity to immune checkpoint inhibitor therapy is achieved by changing a subject who is resistant to immune checkpoint inhibitor therapy into a subject who is susceptible to immune checkpoint inhibitor therapy, or by enabling a subject who has become resistant to immune checkpoint inhibitor therapy over time to once again benefit from the therapy.
  • composition described in [4], wherein the treatment of a disease or condition that is improved by promoting the proliferation of CD4 + T cells having a cell surface marker expression pattern of CXCR3 + /CCR4 low /CCR6 high is improving sensitivity to immune checkpoint inhibitor therapy, and the composition is intended to be ingested by a subject who is not undergoing immune checkpoint inhibitor therapy.
  • the composition according to any one of [1] to [11] which is a pharmaceutical composition.
  • composition according to any one of [1] to [11] which is a food composition.
  • an exopolysaccharide of lactic acid bacteria or use of a composition comprising exopolysaccharides of lactic acid bacteria, in the manufacture of a composition for promoting the growth of either or both of (i) and (ii).
  • (i) CD4 + T cells with a cell surface marker expression pattern of CXCR3 + / CCR4low / CCR6high and
  • MAIT cells and NKT cells are examples of CD4 + T cells with a cell surface marker expression pattern of CXCR3 + / CCR4low / CCR6high.
  • a method for improving sensitivity to immune checkpoint inhibitor therapy or a non-therapeutic method for suppressing cancer recurrence after excision surgery comprising administering to a subject exocytosaccharides of lactic acid bacteria or a composition comprising exocytosaccharides of lactic acid bacteria.
  • a lactic acid bacterial exocytosaccharide or a composition comprising exocytosaccharides of lactic acid bacteria for use in a method for improving sensitivity to immune checkpoint inhibitor therapy or a method for suppressing cancer recurrence after excision surgery.
  • lactic acid bacterial exopolysaccharides or use of a composition comprising lactic acid bacterial exopolysaccharides in the manufacture of a composition for either or both of improving sensitivity to immune checkpoint inhibitor therapy and suppressing cancer recurrence after excision surgery.
  • Use or non-therapeutic use of exopolysaccharides of lactic acid bacteria, or use or non-therapeutic use of a composition comprising exopolysaccharides of lactic acid bacteria for improving sensitivity to immune checkpoint inhibitor therapy or for suppressing cancer recurrence after excision surgery.
  • a method or non-therapeutic method for treating a disease or condition that is ameliorated by promoting the proliferation of CD4 + T cells having a cell surface marker expression pattern of CXCR3 + / CCR4low / CCR6high comprising administering to a subject exopolysaccharides of lactic acid bacteria or a composition comprising exopolysaccharides of lactic acid bacteria.
  • a lactic acid bacterial exopolysaccharide or a composition comprising exopolysaccharides of lactic acid bacteria for use in a method for treating a disease or condition that is ameliorated by promoting the proliferation of CD4 + T cells having a cell surface marker expression pattern of CXCR3 + / CCR4low / CCR6high .
  • exopolysaccharides of lactic acid bacteria or use of a composition comprising exopolysaccharides of lactic acid bacteria, in the manufacture of a composition for treating a disease or condition that is ameliorated by promoting the proliferation of CD4 + T cells having a cell surface marker expression pattern of CXCR3+/CCR4low/CCR6high.
  • the lactic acid bacterial exopolysaccharide or composition comprising the lactic acid bacterial exopolysaccharide according to [16], wherein the treatment of a disease or condition that can be improved by promoting the proliferation of CD4 + T cells having a cell surface marker expression pattern of CXCR3 + /CCR4 low /CCR6 high is to improve sensitivity to immune checkpoint inhibitor therapy, and the subject is a subject who has not been treated with immune checkpoint inhibitor therapy.
  • a method or non-therapeutic method for treating a disease or condition that is ameliorated by promoting the proliferation of either or both of MAIT cells and NKT cells comprising administering to a subject exopolysaccharides of lactic acid bacteria or a composition comprising exopolysaccharides of lactic acid bacteria.
  • a method for treating a disease or condition that is ameliorated by promoting the proliferation of either or both of MAIT cells and NKT cells comprising administering to a subject exopolysaccharides of lactic acid bacteria or a composition comprising exopolysaccharides of lactic acid bacteria for use in a method for treating a disease or condition that is ameliorated by promoting the proliferation of either or both of MAIT cells and NKT cells ..., comprising administering to a subject exopolysaccharides of lactic acid bacteria or a composition comprising exopolysaccharides of lactic acid bacteria for use in a method for treating a disease or condition that is [19] The method or non-therapeutic method according to [18], wherein the treatment of a disease or condition that can be improved by promoting the proliferation of either or both of MAIT cells and NKT cells is either or both of suppressing cancer metastasis and preventing cancer, and the subject is not undergoing treatment for cancer.
  • the method or non-therapeutic method according to any one of [14] to [23] comprising ingesting a food composition containing exopolysaccharides of lactic acid bacteria.
  • the proliferation of one or more of CD4 + T cells is promoted.
  • FIG. 1 shows the change in the composition ratio of MAIT/NKT cells in the PBMCs of subjects before and after the ingestion of the test product.
  • FIG. 2 shows the respective constituent ratios of clusters #44347, #44352, and #44360 in CD4 + T cells in PBMCs after ingestion of the test product.
  • Figure 3 shows the cluster lineages of CD4 + T cells in PBMCs after ingestion of the test product and the CCR6 expression intensity of each cluster.
  • the bar values indicate the relative expression levels, and the bar colors correspond to the colors of the circles.
  • composition comprising exopolysaccharides (EPS) of lactic acid bacteria.
  • EPS exopolysaccharides
  • the active ingredient in the composition of the present invention is EPS from lactic acid bacteria.
  • the EPS used in the composition of the present invention is not particularly limited as long as it has the desired effect.
  • it includes EPS produced by lactic acid bacteria and EPS produced by a microorganism (e.g., Escherichia coli) into which a lactic acid bacteria-derived EPS-producing gene has been introduced.
  • the EPS from lactic acid bacteria is EPS produced by lactic acid bacteria.
  • EPS from lactic acid bacteria are structurally classified as homopolysaccharides or heteropolysaccharides (e.g., those composed of galactose and glucose), and may be further modified by phosphorylation or sulfation.
  • EPS may be a neutral polysaccharide or an acidic polysaccharide (e.g., a neutral polysaccharide to which a phosphate group or the like has been added).
  • Such EPSs are known to be produced by Lactobacillus delbrueckii subsp. bulgaricus, Lactococcus lactis subsp. lactis, Lactococcus lactis subsp. cremoris, etc.
  • the EPS used in the present invention may be one type or a combination of two or more types.
  • the EPS may be obtained by purification from a fermentation product of lactic acid bacteria, etc.
  • Lactic acid bacteria is a general term for microorganisms that utilize glucose to produce lactic acid at a rate of 50% or more based on the sugar. Physiological properties include gram-positive cocci or bacilli, no motility, no spore formation in most cases (although some lactic acid bacteria, such as Bacillus coagulans, are capable of spore formation), and catalase-negative activity. Lactic acid bacteria have been consumed throughout the world since ancient times in the form of fermented milk and are considered to be extremely safe microorganisms. Lactic acid bacteria are classified into several genera. In the present invention, the lactic acid bacteria may be any bacteria that produce EPS, and are preferably bacteria belonging to the genus Lactobacillus or Lactococcus.
  • Lactobacillus Bacteria Belonging to the Genus Lactobacillus
  • Examples of lactic acid bacteria belonging to the genus Lactobacillus include Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus acidophilus, and Lactobacillus plantarum.
  • bacteria belonging to the genus Lactobacillus refers to bacteria described in the article "A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and The 25 genera newly established by the reorganization of lactic acid bacteria published in the "Leuconostocaceae” are: Lactobacillus, Paralactobacillus, Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, Loigolactobacilus, Lacticaseibacillus, Latilactobacillus, and
  • lactic acid bacteria refers to bacteria belonging to any of the genera Lactobacillus, Dellaglioa, Liquorilactobacillus,
  • lactic acid bacteria also referred to as bulgaricus bacteria classified into the species Lactobacillus delbrueckii subsp. bulgaricus are preferred.
  • the bacteria belonging to the genus Lactobacillus are preferably bacteria belonging to Lactobacillus delbrueckii, and more preferably bacteria belonging to Lactobacillus delbrueckii subsp. bulgaricus. That is, one particularly preferred example of EPS used in the composition of the present invention is EPS from a lactic acid bacterium classified as Lactobacillus delbrueckii subsp. bulgaricus.
  • Lactobacillus delbrueckii subsp. bulgaricus FERM BP-10741 The bacterium belonging to the genus Lactobacillus is particularly preferably Lactobacillus delbrueckii subsp. bulgaricus FERM BP-10741 or a strain taxonomically equivalent to Lactobacillus delbrueckii subsp. bulgaricus FERM BP-10741. Lactobacillus delbrueckii subsp. bulgaricus FERM BP-10741 is also sometimes referred to as Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1. Lactobacillus delbrueckii subsp.
  • the nucleotide sequence of the V1 to V3 regions of the 16S rRNA gene of Lactobacillus delbrueckii subsp. bulgaricus FERM BP-10741 (corresponding to the nucleotide sequence from bases 34 to 535 in the full-length sequence of the 16S rRNA gene) is shown in SEQ ID NO: 1 in the Sequence Listing. 16S rRNA gene. Lactobacillus delbrueckii subsp.
  • OLL1073R-1 (SEQ ID NO: 1) GCTGGCGGCGTGCCTAATACATGCAAGTCGAGCGAGCTGAATTCAAAGATYCCTTCGGGRTGATTTGTTGGACGCTAGCGGCGGATGGGTGAGTAACACGTGGGCAATCTGCCCTAAAGACTGGG ATACCACTTGGAAACAGGTGCTAATACCGGATAACAACATGAATCGCATGATTCAAGTTTGAAAGGCGGCGYAAGCTGTCACTTTAGGATGAGCCCGCGGCGCATTAGCTAGTTGGTGGGGTAAAG GCCTACCAAGGCAATGATGCGTAGCCGAGTTGAGAGACTGATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGCAAGTCTGAT GGAGCAACGCCGCGTGAGTGAAGAAGGTTTTCTGAT GGAGCAACGCCGCGTGAGTGAAGAAGGTTTTCGGATCGTAAAGGAAGGATAGAGGCAGTAACTGGTCTTTATTTG
  • a strain taxonomically equivalent to a certain strain refers to, for example, any of the following: a strain belonging to the same genus as strain S, preferably the same species as strain S, in which the sequence of the entire 16S rRNA gene or a characteristic part thereof (such as the V1 region, the V2 region, or all or part of the V1 and V2 regions, or a part including the V1 and V2 regions) has 90% or more, preferably 95% or more, more preferably 98% or more, even more preferably 98.5% or more, even more preferably more than 98.7%, even more preferably 99% or more, even more preferably 99.5% or more, and even more preferably 100% sequence identity with the sequence of strain S; A strain belonging to the same genus as strain S, preferably the same species as strain S, more preferably the same subspecies as strain S, and having the same mycological properties as strain S.
  • Lactobacillus plantarum C88 Non-patent Document 5
  • Lactobacillus johnsonii strain 151 Non-patent Document 6
  • Lactobacillus delbrueckii subsp As bacteria belonging to the genus Lactobacillus that are capable of producing EPS, the following lactic acid bacteria are known to exist. Lactiplantibacillus plantarum C88 (Non-patent Document 5); Lactobacillus johnsonii strain 151 (Non-patent Document 6); Lactobacillus delbrueckii subsp.
  • Non-patent Document 7 Lacticaseibacillus casei CG11 (Non-patent Document 8); Lacticaseibacillus rhamnosus E/N (Non-patent Document 9); Lactobacillus fermentum TDS030603 (Non-patent Document 10); and Lactobacillus gasseri FR4 (Non-patent Document 11).
  • Lactococcus lactic acid bacteria examples include species such as lactis, plantarum, and Raffinolactis.
  • lactic acid bacteria classified as lactis are preferred in the present invention.
  • those classified as Lactococcus lactis subsp. lactis or Lactococcus lactis subsp. cremoris are more preferred.
  • one particularly preferred example of the EPS used in the composition of the present invention is an EPS of a lactic acid bacterium classified as Lactococcus lactis subsp. lactis or Lactococcus lactis subsp. cremoris.
  • EPS produced by Lactococcus lactic acid bacteria is known to contain, for example, galactose and glucose.
  • the repeating units of EPS produced by Lactococcus lactis NIZO B40 consist of glucose, galactose, rhamnose, and phosphate in a ratio of 2:2:1:1 (Non-Patent Document 12, Non-Patent Document 13).
  • Lactococcus lactis subsp. cremoris FC which can be isolated from Fujicco Caspian Sea Yogurt (registered trademark)
  • produces a phosphate polysaccharide containing rhamnose, galactose, and glucose in a molar ratio of 1:1:3 Non-Patent Document 14).
  • Lactococcus lactis subsp. lactis YZ1 produces a polysaccharide composed of mannose, galactose, and glucose (Non-Patent Document 15). Based on these findings, it is believed that EPS produced by Lactococcus lactic acid bacteria also exhibit the effects of the present invention.
  • lactic acid bacteria having at least one type of DNA selected from the group consisting of DNAs encoding any of the following proteins (a) to (d) (DNAs for improving spinnability) can also be used.
  • spinnability of fermented milk refers to the property of fermented milk to form threads due to its viscosity and/or elasticity
  • the effect of improving the spinnability of fermented milk refers to the effect of imparting the spinnability to fermented milk or improving the spinnability of fermented milk (sometimes referred to as “spinnability-improving effect” in this specification). While the reason why the protein has the spinnability-improving effect is unclear, the inventors speculate that this may be because the protein of the present invention acts during the process of EPS biosynthesis by lactic acid bacteria, producing EPS with a highly spinnable structure.
  • Whether or not a lactic acid bacterium contains the spinnability-enhancing DNA of the present invention can be determined by detecting the DNA.
  • a method for detecting the spinnability-enhancing DNA known methods or methods based thereon can be appropriately adopted.
  • the EPS of a lactic acid bacterium contained in the composition of the present invention may include an acidic exopolysaccharide having a repeating structure in which repeating units represented by the following formula (I) are linked together.
  • the EPS of lactic acid bacteria contained in the composition of the present invention may include a neutral polysaccharide having a repeating structure in which repeating units represented by the following formula (II) are linked together.
  • Fermented Products EPS may be contained in the composition of the present invention as a fermented product of lactic acid bacteria (preferably, a fermented product of animal milk).
  • Fermented products of lactic acid bacteria include not only the fermented product itself but also processed products thereof. Examples of fermented products themselves include fermented milk (specifically, yogurt, etc.).
  • Processed products include, for example, crude products, precipitates obtained by removing bacteria from the fermented product by filtration, centrifugation, or membrane separation, culture concentrates with reduced liquid components, culture filtrates and culture supernatants, concentrates obtained by concentrating culture filtrates and culture supernatants, and dried concentrates.
  • the product may be a powdery or granular agglomerated product obtained by spraying a binder solution onto a culture solution, concentrated culture concentrate, culture filtrate, or culture supernatant.
  • the substrate for fermentation is not particularly limited, but may be a general medium for growing lactic acid bacteria, preferably animal milk, and preferably does not contain an extract of a legume.
  • the composition of the present invention may or may not contain bacterial cells.
  • the method for preparing lactic acid bacteria EPS may be according to conventional methods such as those described in Patent Document 4, or it may be produced by chemical synthesis. Furthermore, when preparing lactic acid bacteria EPS as a fermentation product of lactic acid bacteria, fermented milk containing EPS can be produced by adding EPS-producing lactic acid bacteria as a starter to raw milk and fermenting it to produce EPS in the fermentation product. Fermentation conditions, such as raw milk, fermentation temperature, and fermentation time, are not particularly limited as long as the lactic acid bacteria used are capable of producing EPS, and can be set appropriately by a person skilled in the art.
  • bacteria belonging to the genus Lactobacillus or bacteria belonging to the genus Lactobacillus plus bacteria belonging to Streptococcus thermophilus can be used.
  • the fermentation product of lactic acid bacteria is a fermentation product of bacteria belonging to the genus Lactobacillus and bacteria belonging to Streptococcus thermophilus.
  • the bacteria belonging to Streptococcus thermophilus is preferably Streptococcus thermophilus 1131. Streptococcus thermophilus 1131 can be isolated from Meiji Bulgaria Yogurt LB81 (Meiji Co., Ltd.) and is commercially available.
  • compositions of the present invention can be used to promote the proliferation of cells having a CXCR3 + / CCR4low / CCR6high cell surface marker expression pattern (hereinafter also referred to as Th7R cells, TH7R, or CXCR3 + / CCR4lo / CCR6hi ).
  • CD4 + T cells having a CXCR3 + / CCR4low / CCR6high cell surface marker expression pattern are sufficient as long as they have at least a CXCR3 + / CCR4low / CCR6high cell surface marker expression pattern, and examples include cluster 44352 described in the Examples.
  • the definitions of +, low (lo), high (hi), and -, which indicate the expression level of a chemokine receptor are as follows: "+" indicates that the expression of the chemokine receptor is positive, that is, the measured value in the expression analysis of the cell surface marker by flow cytometry or the like is equal to or higher than a certain measurement limit.
  • Low indicates that the expression level of the chemokine receptor is equal to or lower than the median expression intensity of the cell surface marker per cell in the PBMCs of the analyzed population. Note that “equal to or lower” may also include negative expression. High indicates that the expression level of the chemokine receptor is equal to or greater than the median expression intensity of the cell surface marker per cell in the PBMCs of the population being analyzed, or may be equal to or greater than any higher value. "-” indicates that the expression of the chemokine receptor is negative, that is, the measured value in the analysis of the cell surface marker by flow cytometry or the like is below the detection limit, that is, the expression cannot be said to be positive.
  • the expression intensity can be measured, for example, by directly analyzing cells by flow cytometry using a fluorescently labeled antibody specific to a cell surface marker, or, as in the Examples, by directly analyzing cells by mass cytometry using a metal isotope-labeled antibody specific to a cell surface marker, and quantifying the metal isotope. If the above analysis is difficult, the expression intensity can be measured based on the fluorescence intensity of the fluorescently labeled antibody. If either method is difficult, other methods well known to those skilled in the art may be used.
  • promotion of Th7R cell proliferation can be assessed by clustering CD4 + T cells, which increases the percentage of Th7R cells in CD4 + T cells contained in PBMCs (peripheral blood mononuclear cells) collected from a subject after ingestion of the component to be evaluated compared to an appropriate control.
  • Promotion of Th7R cell proliferation can include increasing the number of Th7R cells themselves, promoting differentiation into Th7R cells, preventing the death of Th7R cells to increase the percentage of the population, and promoting the influx of Th7R cells from other tissues to increase the percentage of the population.
  • promotion of Th7R cell proliferation refers to promotion of the proliferation of Th7R cells in the blood. Detection of the Th7R cell population can be achieved by clustering as well as other scientifically acceptable methods.
  • compositions of the present invention can be used to treat diseases or conditions that are improved by promoting the proliferation of Th7R cells.
  • treatment includes prevention, improvement, and inhibition of progression of the disease or condition.
  • Th7R cells can be used as a biomarker to predict the response rate of immune checkpoint inhibitors to cancer (Non-Patent Document 1). Therefore, the compositions of the present invention, which can promote the proliferation of Th7R cells, can be used to improve sensitivity to immune checkpoint inhibitor therapy. Furthermore, the compositions of the present invention can be used to improve sensitivity to immune checkpoint inhibitor therapy by promoting the proliferation of Th7R cells. Improving sensitivity to immune checkpoint inhibitor therapy means that a subject who is resistant to immune checkpoint inhibitor therapy becomes a subject who is susceptible to the therapy (improvement), or a subject who has become resistant to immune checkpoint inhibitor therapy over time becomes able to benefit again (recovery).
  • immune checkpoint inhibitor therapy include, for example, extending the survival time of cancer patients, killing cancer cells to shrink the cancer (reducing tumor volume), slowing cancer growth (inhibiting tumor volume increase), curing cancer, preventing cancer metastasis and recurrence, and killing cancer cells that may have metastasized.
  • Immune checkpoint inhibitor therapy is not particularly limited as long as it is an immune checkpoint inhibitor therapy, but may be, for example, PD-1 inhibitor therapy, PD-L1 inhibitor therapy, CTLA-4 inhibitor therapy, LAG-3 inhibitor therapy, TIGIT inhibitor therapy, CSF-1/CSF-1R inhibitor therapy, TIM-3 inhibitor therapy, or a combination of these. Immune checkpoint inhibitor therapy may also be combined with anti-cancer treatments such as chemotherapy, radiation therapy, or surgery, with PD-1 inhibitor therapy being preferred.
  • PD-1 inhibitor therapy, PD-L1 inhibitor therapy, CTLA-4 inhibitor therapy, and LAG-3 inhibitor therapy refer to therapies using PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and LAG-3 inhibitors, respectively.
  • Examples of PD-1 inhibitors include pembrolizumab and nivolumab.
  • Examples of PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab.
  • Examples of CTLA-4 inhibitors include ipilimumab and tremelimumab.
  • Examples of LAG-3 inhibitors include leratolimab.
  • Examples of multiple immune checkpoint inhibitors include combinations of the anti-PD-1 antibody nivolumab and the anti-LAG-3 antibody leratolimab (e.g., opdualag), which combine the two drugs.
  • Th7R cells are known to contribute to the suppression of cancer recurrence after surgical removal (Non-Patent Document 2). Therefore, the composition of the present invention, which can promote the proliferation of Th7R cells, can be used to suppress the recurrence of cancer (particularly lung cancer) after surgical removal. Furthermore, the composition of the present invention can be used to suppress the recurrence of cancer (particularly lung cancer) after surgical removal by promoting the proliferation of Th7R cells.
  • MAIT/NKT cells Promoting the proliferation of MAIT cells and NKT cells
  • the compositions of the present invention can be used to promote the proliferation of MAIT (Mucosal-Associated Invariant T Cells) cells and NKT (Natural Killer T Cells) cells.
  • MAIT cells and NKT cells are each a type of effector T cell that contribute to adaptive immunity while also possessing rapid effector activity and contributing to innate immunity.
  • MAIT cells and NKT cells can be detected and measured, for example, by the methods described in the Examples, as cells in PBMCs that have the expression pattern of CD3 + , CD4 - , CD28 + , and CD161 + cell surface markers.
  • promotion of MAIT cell and NKT cell proliferation can be evaluated by, for example, using mass cytometry, which comprehensively analyzes markers expressed in cells in PBMCs collected from a subject, and by determining whether the change in the percentage of MAIT/NKT cells (the sum of MAIT cells and NKT cells) in PBMCs before and after ingestion of the component to be evaluated is greater than that in an appropriate control.
  • Promotion of MAIT cell and NKT cell proliferation can include an increase in the number of MAIT cells and NKT cells themselves, promotion of differentiation into MAIT cells and NKT cells, preventing the death of MAIT cells and NKT cells and increasing the percentage of the population, and promoting influx from other tissues and increasing the percentage of the population.
  • promotion of MAIT cell and NKT cell proliferation is promotion of MAIT cells and NKT cells in the blood.
  • compositions of the present invention can be used to treat diseases or conditions that are improved by promoting MAIT cells and NKT cells.
  • the composition of the present invention which can promote the proliferation of MAIT cells and NKT cells, can be used for either or both of the suppression of cancer metastasis and the prevention of cancer. Furthermore, the composition of the present invention can be used to suppress cancer metastasis by promoting the proliferation of MAIT cells, or can be used to prevent cancer (particularly liver cancer) by promoting the proliferation of NKT cells.
  • the subject to which the composition of the present invention is administered may be, for example, a mammal, preferably a human.
  • the age and sex of the subject are not particularly limited. In the case of humans, the subject includes infants, young children, children, adults, and the elderly.
  • Non-Patent Document 1 It is known that sensitivity to immune checkpoint blockade therapy is improved when the proportion of Th7R cell clusters present in peripheral blood is equal to or greater than a predetermined level (Non-Patent Document 1). Therefore, promoting Th7R cell proliferation is considered preferable for improving sensitivity to immune checkpoint blockade therapy. Therefore, when using the compositions of the present invention to improve sensitivity to immune checkpoint blockade therapy, subjects suitable for administering the compositions of the present invention may be subjects for whom promoting Th7R cell proliferation is necessary or desirable.
  • Subjects for whom promoting Th7R cell proliferation is necessary or desirable may be, for example, subjects for whom the proportion of Th7R cells among CD4 + T cells contained in PBMCs is 6.0% or less, preferably 5.0% or less, and more preferably 4.0% or less.
  • MAIT cells are known to contribute to the suppression of cancer metastasis (Non-Patent Document 3), and NKT cells are known to contribute to the prevention of cancer (particularly liver cancer) (Non-Patent Document 4). Therefore, when the composition of the present invention is used for either or both of the suppression of cancer metastasis and the prevention of cancer, it is preferable to administer it to a subject in whom it is necessary or desirable to promote the proliferation of MAIT cells and NKT cells. Furthermore, this Example demonstrates that ingestion of the composition of the present invention increases the percentage of MAIT cells and NKT cells in PBMCs from approximately 2.56% to approximately 0.14%.
  • Subjects in whom it is necessary or desirable to promote the proliferation of MAIT cells and NKT cells may be, for example, subjects in whom the percentage of MAIT cells and NKT cells in PBMCs is 4.0% or less, preferably 3.5% or less, more preferably 3.0% or less, and even more preferably 2.5% or less.
  • subjects suitable for administering the compositions of the present invention include: Healthy subjects in whom it is necessary or desirable to promote the proliferation of one or more of Th7R cells, MAIT cells, and NKT cells; healthy subjects who have been found to have low levels of one or more of Th7R cells, MAIT cells, and NKT cells in their blood or PBMCs; healthy subjects who have been found to have low levels of Th7R cells in CD4 + T cells contained in their blood or PBMCs; healthy subjects who are not undergoing cancer treatment; healthy subjects who are not undergoing immune checkpoint inhibitor therapy; healthy subjects who have not undergone cancer removal surgery; healthy subjects in whom it is necessary or desirable to suppress cancer metastasis or recurrence (subjects after cancer treatment, etc.); healthy subjects at high risk of developing cancer (especially liver cancer) (people who consume alcohol, smokers, those with underlying diseases such as hepatitis B, hepatitis C, obesity, fatty liver, diabetes, elderly, etc.); healthy subjects who are not undergoing cancer treatment (surgery, radiation, radiation
  • the term "administer” is used not only to mean administering a pharmaceutical to a subject, but also to mean having a subject ingest (ingest by a subject) a food or the like other than a pharmaceutical.
  • a healthy subject refers to a human or a companion animal (described below) that has not been diagnosed with any disease (pre-disease). In other words, when the composition of the present invention is used on such healthy subjects, the composition of the present invention is not provided for therapeutic purposes.
  • composition of the present invention can also be used for non-therapeutic purposes in healthy subjects.
  • the composition of the present invention can be used in the form of a food or the like (e.g., as a food composition).
  • the composition is not a pharmaceutical, and is provided in the form of, for example, a food as described below.
  • Non-therapeutic purposes refer to uses for maintaining, temporarily alleviating, supporting (assisting), or taking into consideration a condition.
  • subjects suitable for receiving the compositions of the present invention include: Subjects with a disease in which it is necessary or desirable to promote the proliferation of one or more of Th7R cells, MAIT cells, and NKT cells; subjects with a disease in which it has been determined that there are few Th7R cells in the blood or PBMC; subjects with a disease in which it has been determined that there are few Th7R cells in the CD4 + T cells contained in the blood or PBMC; subjects with a disease who are not undergoing treatment for cancer; subjects with a disease who are undergoing or for whom it is desirable to undergo immune checkpoint inhibitor therapy; subjects with a disease who are not undergoing immune checkpoint inhibitor therapy; subjects with a disease who are scheduled to undergo immune checkpoint inhibitor therapy; subjects with a disease in which immune checkpoint inhibitor therapy is not sufficiently effective (for example, subjects in which cancer progression is observed even with immune checkpoint inhibitor therapy); subjects with a disease in which the effect of immune checkpoint inhibitor therapy is not progressing subjects with a disease who have undergone or are desirably undergoing cancer
  • a subject having a disease refers to a human who has been diagnosed with any disease or a companion animal as described below.
  • the composition of the present invention is not provided for therapeutic purposes, but for non-therapeutic purposes such as adjunctive treatment.
  • the composition of the present invention can be used for non-therapeutic purposes in subjects with a disease.
  • the composition of the present invention can be used as a composition to support treatment in the form of a food or the like (e.g., as a food composition).
  • support treatment refers to non-therapeutic uses in the treatment of a disease or illness. Examples of supporting treatment include use in subjects undergoing treatment for a disease or illness to enhance the therapeutic effect or provide nutritional support during treatment; use in subjects who have been treated for a disease or illness to improve the prognosis, maintain a good prognosis, or provide nutritional support after treatment; and use in subjects who are scheduled to be treated for a disease or illness to enhance the effect of subsequent treatment or provide nutritional support before treatment.
  • the composition is provided not as a pharmaceutical, but in the form of, for example, a food product as described below.
  • Non-therapeutic uses in the treatment of a disease or illness include use for nutritional management of subjects requiring special care, use as hospital food, maintenance of the condition, temporary relief, support (assistance), and uses that take the condition into consideration.
  • judgments as to whether it is desirable or necessary may include judgments as non-therapeutic procedures, such as advice other than diagnosis, by medical professionals such as doctors, nurses, pharmacists, midwives, and clinical laboratory technicians; judgments by those involved in non-therapeutic procedures, such as nutritionists (including registered dietitians and sports nutritionists), public health nurses, sports instructors, pharmaceutical manufacturers, pharmaceutical distributors, food manufacturers, and food distributors; and judgments by the subject themselves or their family.
  • the above judgments may include judgments based on lifestyle habits, eating habits, nutritional status, subjective symptom questionnaires, output results of health checkup data related to the immune system, and judgments based on subjective symptoms (concerns about obesity or lifestyle-related diseases, etc.).
  • Non-human animals include mammals, birds, reptiles, amphibians, fish, etc.
  • Non-human animals may be commercial animals, research animals, or companion animals.
  • the phrase "companion animal" refers to a domestic or domestic animal whose physical, emotional, behavioral, and social needs can be readily met as a domestic companion or through close daily association with one or more humans.
  • species included within the definition of companion animal include dogs, canines, cats, felines, cows, horses, goats, sheep, pigs, primates (such as monkeys), rabbits, ferrets, rodents (such as guinea pigs, hamsters, mice, and rats), and other small mammals.
  • species included within the definition of companion animals are dogs, cats, horses, rabbits, ferrets, guinea pigs, and other small mammals, birds, small reptiles, fish, and livestock animals.
  • the age of the subject there are no particular restrictions on the age of the subject, and if the subject is a human, it may be, for example, a newborn (within 28 days of birth); an infant (less than 1 year of age); a toddler (1-6 years of age); a child (7 years of age or older, but under 15 years of age); an adult (15 years of age or older); a person aged 40 years or older, a person aged 50 years or older, a person aged 60 years or older, or a person aged 65 years or older.
  • Some embodiments of the present invention relate to a method for promoting proliferation of Th7R cells in a subject; a method for improving sensitivity to immune checkpoint inhibitor therapy in a subject; or a method for suppressing recurrence of cancer after surgical removal in a subject, which may comprise the steps of: (a) obtaining information on Th7R cells in the blood or PBMCs of a subject; and (b) determining, based on the information, whether or not it is necessary to ingest lactic acid bacterial exopolysaccharides or a composition containing lactic acid bacterial exopolysaccharides.
  • Some embodiments of the present invention relate to a method for promoting proliferation of MAIT cells and NKT cells in a subject; a method for suppressing cancer metastasis in a subject; or a method for preventing cancer in a subject, which may comprise the steps of: (a) obtaining information on MAIT cells and NKT cells in the subject's blood or PBMCs; and (b) determining, based on the information, whether or not it is necessary to ingest lactic acid bacterial exopolysaccharides or a composition containing lactic acid bacterial exopolysaccharides.
  • the information on Th7R cells in blood or PBMCs, or information on MAIT cells and NKT cells may be, for example, the cell count, composition ratio, or concentration of Th7R cells, or MAIT cells and NKT cells in blood or PBMCs. Furthermore, this information may be obtained by any method; for example, if the information on each cell type is the composition ratio in blood or PBMCs, it can be obtained using an immunological method based on cell surface markers, as shown in this example.
  • compositions of the present invention may exclude: Treatment of rheumatoid arthritis; activation of NK cells; promotion of YAC-1 cell killing activity of NK cells; antiviral; promotion of YAC-1 cell killing activity of NK cells stimulated with IFN- ⁇ ; prevention of pneumococcal infection; suppression of decline in acquired immune function caused by anti-influenza drugs; prevention and/or treatment of influenza; increase in salivary IgA that reacts with influenza virus; regulation of cytokine (IL-1 ⁇ , TNF- ⁇ , CXCL1) production; activation of cellular immunity; activation of cellular immunity against melanoma antigens, influenza antigens, or HBV antigens; suppression of cancer cachexia; promotion of immune checkpoint inhibitor therapy promotion of immune response; prevention of or reduction of the risk of secondary infections after influenza infection; suppression of the increase in expression of cell adhesion molecules (especially tight junction molecules such as CEACAM-1) after influenza virus infection; suppression of the proliferation of human coronaviruses (
  • the composition of the present invention can be a food composition or a pharmaceutical composition.
  • Foods and pharmaceuticals include not only those for humans but also those for non-human animals, unless otherwise specified.
  • Foods include general foods, functional foods, and nutritional compositions, as well as therapeutic foods (those intended for therapeutic purposes, prepared based on a menu prepared by a nutritionist or other professional prescribed by a doctor), therapeutic diets, ingredient-modified diets, nursing care foods, therapeutic support foods, and precision nutrition (individualized nutrition, appropriate diets (nutrition) proposed according to an individual's constitution).
  • Foods include not only solid foods but also liquid foods, such as beverages, energy drinks, liquid foods, and soups, unless otherwise specified.
  • Functional foods refer to foods that can impart specific functionality to the body, and include a wide range of health foods, including foods for specified health uses (including conditional FOSHUs [foods for specified health uses]), foods with functional claims, health functional foods including foods with nutrient functions, foods for special dietary uses, dietary supplements, health supplements, dietary supplements, food supplements, medical foods (as defined by the U.S. Food and Drug Administration (FDA)), supplements (e.g., tablets, coated tablets, sugar-coated tablets, capsules, liquids, etc.), and beauty foods (e.g., diet foods).
  • “functional foods” also includes health foods to which a health claim based on the Codex Alimentarius (the Joint FAO/WHO Food Standards Commission) is applicable.
  • Food supplements are supplements to the normal diet and are concentrated with nutrients or other substances, either alone or in combination, that have nutritional or physiological effects, and are labeled as "food supplements.”
  • Dietary supplements are products (other than tobacco) intended to supplement the diet, that contain one or more of the targeted ingredients, and that are labeled as a dietary supplement.
  • composition of the present invention may be taken orally, parenterally, for example, via a tube (gastrostomy, enterostomy), or nasally, but is preferably taken orally.
  • the content of lactic acid bacteria EPS in the composition of the present invention may be any amount that achieves the desired effect.
  • the intake amount of the composition can be appropriately determined taking into account various factors such as the subject's age, weight, symptoms, metabolic and excretory functions, and concomitant medications.
  • the amount of lactic acid bacteria EPS per daily dose can be, for example, 0.1 mg or more, preferably 0.6 mg or more, more preferably 3 mg or more, and even more preferably 3.3 mg or more or 6 mg or more.
  • the upper limit of the amount of EPS per daily dose can be 4800 mg or less, preferably 3600 mg or less, more preferably 1800 mg or less, and particularly preferably 900 mg or less.
  • each component in the composition is used at an intake level that is guaranteed to be safe or below the acceptable daily intake (ADI), with priority given to the food safety laws of each country.
  • ADI acceptable daily intake
  • the amount of lactic acid bacteria EPS per intake or meal, i.e., per serving can be, for example, 0.03 mg or more, preferably 0.2 mg or more, and more preferably 1 mg or more.
  • the upper limit of the amount of EPS per serving can be 1600 mg or less, preferably 1200 mg or less, more preferably 600 mg or less, and particularly preferably 300 mg or less.
  • the daily amount of fermented milk can be, for example, 10 g or more, preferably 30 g or more, more preferably 60 g or more, even more preferably 100 g or more, and particularly preferably 112 g or more.
  • the upper limit of the daily amount of fermented milk can be, for example, 1500 g or less, preferably 1200 g or less, and more preferably 600 g or less.
  • the amount per intake or meal i.e., the amount per serving of fermented milk
  • the upper limit of the amount per serving of fermented milk can be, for example, 800 g or less, preferably 400 g or less, and more preferably 200 g or less.
  • the composition may be taken once a day, or multiple times a day, for example, three times with each meal.
  • the composition contains EPS from lactic acid bacteria that have been consumed extensively as an active ingredient. Therefore, the composition of the present invention may be taken repeatedly or over a long period of time, for example, for one week or more, preferably two weeks or more, more preferably three weeks or more, and even more preferably four weeks or more.
  • An example of a method for preparing fermented milk according to an embodiment of the present invention is a method in which, after sterilizing and cooling raw milk, a lactic acid bacteria starter containing the above-mentioned lactic acid bacteria is added to the raw milk, and the raw milk containing the lactic acid bacteria starter is fermented at a fermentation temperature and for a fermentation time that results in a predetermined lactic acid acidity.
  • the exopolysaccharides are produced by Lactobacillus lactic acid bacteria during fermentation.
  • the lactic acid acidity is, for example, 0.6 to 1.2.
  • the lactic acid acidity is 0.6 to 0.8.
  • the fermentation temperature is, for example, 40 to 45°C.
  • the fermentation time is, for example, 2 to 12 hours.
  • the fermentation time is 3 to 8 hours.
  • composition of the present invention may contain other active ingredients or nutritional components that are acceptable as foods or pharmaceuticals.
  • ingredients include amino acids (e.g., lysine, arginine, glycine, alanine, glutamic acid, leucine, isoleucine, valine), carbohydrates (glucose, sucrose, fructose, maltose, trehalose, erythritol, maltitol, palatinose, xylitol, dextrin), electrolytes (e.g., sodium, potassium, calcium, magnesium), vitamins (e.g., vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, biotin, folic acid, pantothenic acid, and nicotinic acids), minerals (e.g., copper, zinc, iron, cobalt, manganese), antibiotics, dietary fiber, protein, lipids, etc.
  • amino acids e.g., lysine,
  • compositions of the present invention may further contain additives that are acceptable for use as foods or pharmaceuticals.
  • additives include inert carriers (solid or liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, solubilizers, suspending agents, coating agents, colorants, preservatives, buffers, pH adjusters, emulsifiers, stabilizers, sweeteners, antioxidants, flavorings, acidulants, and natural products.
  • these include water, other aqueous solvents, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, sodium alginate, water-soluble dextran, water-soluble dextrin, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sodium chloride, propylene glycol, glycerin, benzalkonium chloride, methyl parahydroxybenzoate, lactose, starch, maltose, sorbitol, lactose, sucralose, stevia, aspartame, acesulfame potassium, citric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, acetic acid, fruit juice,
  • the pharmaceutical composition of the present invention can be made into any dosage form suitable for oral ingestion, such as solid preparations such as tablets, granules, powders, pills, and capsules; liquid preparations such as solutions, suspensions, and syrups; gels; and aerosols.
  • solid preparations such as tablets, granules, powders, pills, and capsules
  • liquid preparations such as solutions, suspensions, and syrups
  • gels such as gels; and aerosols.
  • the food composition of the present invention may be prepared in any form, such as a solid, liquid, mixture, suspension, powder, granules, paste, jelly, gel, or capsule.
  • the food composition of the present invention can also be in any form, such as a dairy product, supplement, confectionery, beverage, drink, seasoning, processed food, prepared dish, or soup. More specifically, the composition of the present invention can be in the form of a milk drink, soft drink, fermented milk, yogurt, ice cream, tablet, cheese, bread, biscuits, crackers, pizza crust, infant formula, liquid food, food for the sick, nutritional food, frozen food, or processed food. It can also be in the form of granules, powder, paste, or thick liquid to be mixed with beverages or food for consumption.
  • the stage of blending the EPS of lactic acid bacteria can be selected as appropriate.
  • the stage of blending is not particularly limited as long as the properties of the EPS of lactic acid bacteria are not significantly impaired.
  • it can be blended by mixing with raw materials at an early stage of production.
  • the composition of the present invention contains EPS as a fermented product of lactic acid bacteria
  • EPS-producing lactic acid bacteria can be added as a starter to raw milk, fermented, and used to produce EPS, thereby producing fermented milk containing EPS.
  • lactic acid bacteria can be cultured in a medium suitable for culturing lactic acid bacteria, a medium suitable for increasing or producing EPS, or in milk (including animal milk, soy milk, etc., with animal milk being preferred), and the culture solution itself can be concentrated by methods known in the food industry, such as centrifugation, removal of denatured proteins, or filtration, to produce a concentrated culture solution, a dried product of the culture solution, or a granulated product of the culture solution or concentrated culture solution (such as spray drying using a binder), which can be used as a composition of the present invention containing EPS as is, or can be incorporated into compositions of various dosage forms to produce a composition of the present invention containing EPS.
  • a medium suitable for culturing lactic acid bacteria a medium suitable for increasing or producing EPS
  • milk including animal milk, soy milk, etc., with animal milk being preferred
  • the culture solution itself can be concentrated by methods known in the food industry, such as centrifugation, removal of denatured proteins, or
  • lactic acid bacteria can be cultured in a medium suitable for culturing lactic acid bacteria, a medium suitable for increasing and producing EPS, or in milk (including animal milk, soy milk, etc., with animal milk being preferred), and the culture is then filtered, centrifuged, or membrane-separated to obtain a culture filtrate, culture supernatant, or culture isolate, a concentrated culture filtrate, or a concentrate obtained by concentrating the culture filtrate, culture supernatant, or culture isolate, or a dried concentrate.
  • milk including animal milk, soy milk, etc., with animal milk being preferred
  • purification means that the purified product has an increased EPS concentration compared to before purification, and does not necessarily have to be 99-100% pure. Furthermore, the purified product may contain bacterial cells, bacterial components, and medium components within the range of miscalculation (such as carryover from the culture).
  • composition of the present invention can be labeled with its intended use (application), and can also be labeled to recommend its intake to a specific target.
  • the intended use and target can be selected as described in the "Application" and "Target” sections above, respectively.
  • Labeling can be direct or indirect. Examples of direct labeling include inscription on tangible objects such as the product itself, packaging, containers, labels, and tags. Examples of indirect labeling include advertising and promotional activities by place or means such as package inserts, pharmaceutical interview forms (IFs), websites, in-store locations, pamphlets, exhibitions, media seminars, books, newspapers, magazines, television, radio, mail, email, sales talks, video streaming sites, social media, influencer marketing, and audio.
  • IFs pharmaceutical interview forms
  • compositions of the present invention may exclude: A composition produced by culturing Lactobacillus and yeast, or Lactobacillus, yeast and Lactococcus, in a medium containing an aqueous soybean extract, filtering to remove solids, sterilizing and concentrating the prepared liquid solution; a fermentate produced by fermenting a mixture containing lactic acid bacteria and yeast in a medium containing an aqueous soybean extract under conditions that allow the soybean extract to be fermented by the microorganisms.
  • a randomized, placebo-controlled, double-blind, parallel-group comparative study was conducted on healthy Japanese men and women aged 35 to under 60 years (specifically, excluding the following: those suffering from, undergoing treatment for, or with a history of serious diseases such as diabetes, kidney/liver disease, or heart disease, thyroid disease, adrenal gland disease, or other metabolic diseases; those with chronic diseases and regular medication use; and those with a history of gastrointestinal diseases or gastrointestinal surgery that affect digestion and absorption).
  • This study used PBMC (peripheral blood mononuclear cells) samples isolated from blood drawn before and after the study period.
  • fermented milk (yogurt described in Production Example 1) (112 g, EPS content 3.3 mg or more) made with Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 strain as the test product, and acidic milk (112 g, EPS-free) as a placebo every day for four weeks.
  • PBMCs Manual gating analysis> PBMCs were gated according to Standard Biotools' technical note, "Approach to Bivariate Analysis of Data Acquired Using the Maxpar Direct Immune Profiling Assay," and the changes in the percentage of each immune cell population determined before and after test product ingestion were compared with those in placebo.
  • ⁇ Analysis 2 Machine learning analysis> We used various cytometry analysis software capable of machine learning analysis to cluster PBMCs and compare them between sample populations.
  • CITRUS cluster identification, characterization, and regression: a statistical intergroup comparison using correlation or prediction algorithms
  • Three clusters (#44347, #44352, #44360) were identified with significantly different composition rates (FDR ⁇ 0.01, p ⁇ 0.05). Of these, cluster #44352 was found to have a higher composition rate after ingestion of the test product ( Figure 2). It was found to strongly express CCR6 and to be systematically distinct from the other strongly CCR6-expressing clusters ( Figure 3).
  • the composition of the present invention may have a proliferation-promoting effect on the cell population classified into cluster #44352 (the cell surface marker expression pattern is CXCR3 + /CCR4 low /CCR6 high ).
  • Non-patent document 5 Zhang, L., Liu, C., Li, D., Zhao, Y., Zhang, X., Zeng, X., Yang, Z., Li, S., 2013. Antioxidant activity on exopolysaccharide isolated from Lactobacillus plantarum C88. Int. J. Biol. Macromol. 54, 270-275.
  • Non-patent document 6 Gorska-Froczek, S., Sandstrom, C., Kenne, L., Paociak, M., Brzozowska, E., Strus, M., Heczko, P., Gamian, A., 2013.
  • Non-Patent Document 7 Harding, LP, Marshall, VM, Hernandez, Y., Gu, Y., Maqsood, M., Mclay, N., Laws, AP, 2005. Structural characterization of a highly branched exopolysaccharide produced by Lactobacillus delbrueckii ssp. bulgaricus NCFB2074. Carbohydr. Res. 340, 1107-1111.
  • Non-patent document 8 J. C. M. C. Cerning, C. M. G. C.
  • Non-patent document 9 M. Polak-Berecka, A. Wasko, D. Szwajgier & A. Choma: Bifidogenic and antioxidant activity of exopolysaccharides produced by Lactobacillus rhamnosus E/N cultivated on different carbon sources. Pol. J. Microbiol., 62, 181 (2013).
  • Non-Patent Document 10 K. Fukuda, T. Shi, K. Nagami, F. Leo, T. Nakamura, K. Yasuda, A. Senda, H. Motoshima & T. Urashima: Effects of carbohydrate source on physicochemical properties of the exopolysaccharide produced by Lactobacillus fermentum TDS030603 in a chemically defined medium. Carbohydr. Polym., 79, 1040 (2010).
  • Non-Patent Document 11 Rizwana Parveen RaniMarimuthu AnandharajAbraham David Ravindran: Characterization of a novel exopolysaccharide produced by Lactobacillus gasseri FR4 and demonstration of its in vitro biological properties. International Journal of Biological Macromolecules Volume 109, 1 April 2018, Pages 772-783.
  • Non-patent document 12 Van Casteren W H M, Dijkema C, Schols H A, Beldman G, Voragen A G J. Characterization and modification of the exopolysaccharide produced by Lactococcus lactis subsp. cremoris B40. Carbohydr Polym. 1998;37:123-130.
  • Non-patent document 13 Van Kranenburg R, Marugg J D, Van Swam I I, Willem J, De Vos W M. Molecular characterization of the plasmid-encoded eps gene cluster essential for exopolysaccharide biosynthesis in Lactococcus lactis. Mol Microbiol. 1997;24:387-397.
  • Non-patent document 14 Goto, Yayoi: Research on exopolysaccharide-producing lactic acid bacterium Lactococcus lactis subsp. cremoris FC 2021.11.19 https://doi.org/10.24729/00017528

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Abstract

Le problème décrit par la présente invention est de fournir un moyen pour favoriser la prolifération d'au moins un type de cellules qui sont incluses dans des lymphocytes T effecteurs et qui sont sélectionnées parmi des lymphocytes T CD4+ ayant un motif d'expression de marqueurs de surface cellulaire de CXCR3+/CCR4low/CCR6high, des cellules MAIT et des cellules NKT. La solution selon l'invention porte sur : une composition permettant de favoriser la prolifération de (i) lymphocytes T CD4+ ayant un motif d'expression de marqueurs de surface cellulaire de CXCR3+/CCR4low/CCR6high et (ii) cellules MAIT et/ou cellules NKT ; ou une composition permettant de traiter une maladie ou une pathologie qui est améliorée par la prolifération d'au moins un type de cellules choisies parmi des lymphocytes T CD4+ ayant un motif d'expression d'un marqueur de surface cellulaire de CXCR3+/CCR4low/CCR6high, des cellules MAIT et des cellules NKT. Chacune des compositions contient un exopolysaccharide issu de bactéries d'acide lactique.
PCT/JP2025/010645 2024-03-21 2025-03-19 Composition permettant de favoriser la prolifération de cellules immunitaires Pending WO2025197951A1 (fr)

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