Composition for immunostimulation and immunostimulation method

Abstract

Disclosed is a composition for immunostimulation, the composition containing: a microbe having immunostimulating ability; and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites having an immunostimulating-ability-enhancing action with respect to the microbe.

Description

Immunostimulating composition and immunostimulating method

[0001] The present invention relates to a composition for immunostimulation and a method for immunostimulation.

[0002] The immune system is a biological defense mechanism that prevents foreign substances from entering the body and detects and eliminates them once they have entered the body, and it plays a very important role in maintaining health. However, factors that weaken the immune system include lack of exercise, overwork, stress, lack of sleep, smoking, and alcohol consumption, and we are exposed to the risk of a weakened immune system every day. For this reason, technological means for activating the immune system are being developed.

[0003] As such technical means, for example, compositions capable of activating immune function through ingestion of pharmaceuticals, foods, etc. have been developed. For example, Patent Document 1 discloses an interferon (IFN) production inducer containing, as an active ingredient, lactic acid bacteria or a culture or processed product thereof that can activate plasmacytoid dendritic cells (pDCs) and induce interferon (IFN) production. Patent Document 2 discloses an immunopotentiating composition containing, as an active ingredient, lactic acid bacteria having immunopotentiating activity and an ester bond between a polyhydric alcohol and a saturated fatty acid. Patent Document 3 discloses a method for producing lactic acid bacteria having enhanced immunopotentiating activity that does not contain an ester bond between a polyhydric alcohol and a fatty acid, the method comprising contacting an immunopotentiating activity enhancing composition containing, as an active ingredient, an ester bond between a polyhydric alcohol and a fatty acid with lactic acid bacteria having immunopotentiating activity, and then removing the immunopotentiating activity enhancing composition.

[0004] Here, in order to use a composition capable of activating immune function as a pharmaceutical or food product that requires quality control, it is necessary to control the composition's ability to activate immune function by enhancing or suppressing it.

[0005] International Publication No. 2012 / 091081 JP 2016-005452 A JP 2017-085975 A

[0006] An object of the present invention is to provide a novel immunostimulatory composition.

[0007] The present inventors have discovered that certain compounds enhance pDC activation induced by certain bacteria having immunostimulatory activity and the accompanying IFN-α production, and have completed the present invention.

[0008] The present invention provides, for example, the following inventions: [1] An immunostimulating composition comprising a bacterium having immunostimulatory ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacterium. [2] A method for immunostimulation, comprising administering or ingesting to a subject a bacterium having immunostimulatory ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacterium. [3] A method for enhancing the immunostimulatory effect induced by a bacterium having immunostimulatory ability, comprising administering to a subject or ingesting to a subject a bacterium having immunostimulatory ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacterium. [4] An enhancer for immunostimulatory activity induced by immunostimulatory bacteria, comprising one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory activity of immunostimulatory bacteria. [5] An enhancer for immunostimulatory activity induced by immunostimulatory bacteria, comprising: a bacterium having immunostimulatory activity; and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory activity of the bacterium. [6] An immunostimulatory composition induced by immunostimulatory bacteria, comprising one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory activity of immunostimulatory bacteria.[7] Use of a bacterium having immunostimulatory ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacterium, for producing a composition for immunostimulation. [8] Use of one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacterium, for producing a composition for immunostimulation induced by the bacterium. [9] Use of one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacterium, for producing a composition for immunostimulation, to be administered or ingested in combination with the bacterium having immunostimulatory ability.

[10] Use of an immunostimulatory bacterium for producing an immunostimulatory composition, wherein the bacterium is administered or ingested in combination with one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, each having an effect of enhancing the immunostimulatory ability of the bacterium.

[11] One or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, each having an effect of enhancing the immunostimulatory ability of the bacterium, for use in immunostimulation induced by the bacterium.

[12] An immunostimulatory bacterium, wherein the bacterium is administered or ingested in combination with one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, each having an effect of enhancing the immunostimulatory ability of the bacterium, for use in a therapeutic method for immunostimulation.

[13] A compound for use in a therapeutic method of immunostimulation, which is one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, and which has an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability, and which is administered or ingested in combination with the bacteria having immunostimulatory ability.

[14] A use of a bacterium having immunostimulatory ability in a non-therapeutic method of immunostimulation, which is administered or ingested in combination with one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which has an effect of enhancing the immunostimulatory ability of the bacteria.

[15] Use of one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of immunostimulatory bacteria, in a non-therapeutic method for immunostimulation, wherein the compounds are administered or ingested in combination with the immunostimulatory bacteria.

[16] The composition, method, enhancer, use, compound, or bacterium according to any of [1] to

[15] , wherein the immunostimulatory bacteria are lactic acid bacteria and / or acetic acid bacteria.

[17] The composition, method, enhancer, use, compound, or bacterium according to

[16] , wherein the lactic acid bacteria are one or more species selected from the genus Lactococcus, the genus Bifidobacterium, and the genus Lactobacillus.

[18] The composition, method, enhancer, use, compound, or bacterium according to

[16] , wherein the lactic acid bacteria are one or more species selected from the genus Lactococcus and the genus Bifidobacterium.

[19] The composition, method, enhancer, use, compound, or bacterium described in

[17] , wherein the Lactococcus bacterium is Lactococcus lactis subsp. lactis or Lactococcus culbatus, the Bifidobacterium bacterium is Bifidobacterium animalis subsp. lactis, and the Lactobacillus bacterium is Lactobacillus paraplantarum.

[20] The composition, method, enhancer, use, compound, or bacterium according to

[18] , wherein the Lactococcus bacterium is Lactococcus lactis subsp. lactis and the Bifidobacterium bacterium is Bifidobacterium animalis subsp. lactis.

[21] The composition or use according to any one of [1], [6] to

[10] , and

[16] to

[20] , wherein the content of the bacterium having immunostimulatory ability is 0.001% by mass or more and less than 100% by mass, based on the total amount of the composition for immunostimulation.

[22] The composition or use according to any one of [1], [6] to

[10] , and

[16] to

[21] , wherein the content of the compound is 0.000001% by mass or more and 90.0% by mass or less, based on the total amount of the composition for immunostimulation.

[23] The composition, method, enhancer, use, compound, or bacterium according to any one of [1] to

[22] , wherein the ratio of the content (mass%) of the bacteria having immunostimulatory ability to the content (mass%) of the compound (compound content) / (content of the bacteria having immunostimulatory ability) is 0.001 or more and 50,000 or less.

[24] The composition, method, enhancer, use, compound, or bacterium according to any one of [1] to

[23] , wherein the immunostimulatory ability is the ability to induce interferon-α production in immune cells.

[25] The composition, method, enhancer, use, compound, or bacterium according to any one of [1] to

[24] , wherein the immune cells are pDCs.

[26] The composition, method, enhancer, use, compound, or bacterium according to any one of [1] to

[25] , wherein the immunostimulatory ability enhancing effect is the effect of enhancing the induction of interferon-α production in the immune cells by 1.10-fold or more compared to an immunostimulatory composition containing only the bacteria having immunostimulatory ability.

[27] The composition, method, enhancer, use, compound, or bacterium according to any one of [1] to

[26] , wherein the compound is one or more compounds selected from the group consisting of chlorogenic acid, catechin, lychee polyphenol, black soybean polyphenol, black soybean seed coat polyphenol, theaflavin, black currant polyphenol, hesperidin, resveratrol, methylhesperidin, curcumin, rutin, lutein, astaxanthin, paprika xanthophyll, caffeine, coenzyme Q10, pyrroloquinoline quinone, citicoline, glycerophosphocholine, phosphatidylserine, beet ceramide, pine ceramide, milk ceramide, 3-hydroxyisovaleric acid, eicosapentaenoic acid, docosahexaenoic acid, and potassium pyrosulfite.

[28] A composition for immunostimulation, comprising a bacterium having immunostimulatory ability, and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, each having an effect of enhancing the immunostimulatory ability of the bacterium.

[29] A method for producing a composition for immunostimulation, comprising a bacterium having immunostimulatory ability, and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, each having an effect of enhancing the immunostimulatory ability of the bacterium.

[0009] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0010] According to the present invention, a novel immunostimulatory composition can be provided.

[0011] While the present invention has been described with reference to specific examples and various embodiments, it will be readily apparent to those skilled in the art that many modifications and adaptations of the embodiments described herein are possible without departing from the spirit and scope of the invention.

[0012] This application claims priority based on Japanese Patent Application No. 2024-080741, filed with the Japan Patent Office on May 17, 2024, the contents of which are incorporated herein by reference in their entirety.

[0013] In the present disclosure, the phrase "one or more selected from the group consisting of" encompasses all combinations that can be formed by one element or two or more elements that constitute the group, and may be, for example, one of the elements that constitute the group, or a combination of any two, three, four, five, six, seven, eight, nine or more elements that constitute the group.

[0014] [Composition for immunostimulation] A first embodiment of the present disclosure relates to a composition for immunostimulation. The composition for immunostimulation contains bacteria having immunostimulatory ability and one or more compounds having an immunostimulatory ability enhancing effect selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites. The composition for immunostimulation according to one embodiment contains bacteria having immunostimulatory ability, and therefore has an immunostimulatory effect.

[0015] The immunopotentiating effect (immune activation effect) refers to the activation of the innate immune system in cells or living organisms, and may be an effect of increasing or maintaining (suppressing decline in) the function of the innate immune system in cells or living organisms. The immunopotentiating effect (immune activation capability) according to one embodiment may include an immune cell activation effect (immune cell activation capability), or may include or be a dendritic cell activation effect (dendritic cell activation capability). When the immunopotentiating effect includes a dendritic cell activation effect or is a dendritic cell activation effect, the bacterium having immunopotentiating capability has dendritic cell activation capability.

[0016] The dendritic cell activation effect (dendritic cell activation ability) may be an effect of increasing the amount of cytokine expression by dendritic cells when compared to when the bacteria having immunostimulatory ability is not administered, ingested, etc. The immunostimulatory effect (immunostimulatory ability) according to one embodiment may include a plasmacytoid dendritic cell activation effect (pDC activation effect) (plasmacytoid dendritic cell activation ability (pDC activation ability)), or may be a pDC activation effect (pDC activation ability). When the immunostimulatory effect includes pDC activation effect or is pDC activation effect, the bacteria have pDC activation ability. The pDC activation effect (pDC activation ability) may be an effect of increasing (ability to increase) the amount of cytokine expression by pDC when compared to when the bacteria having immunostimulatory ability is not administered, ingested, etc.

[0017] Plasmacytoid dendritic cells, also known as plasmacytoid dendritic cells, are a type of dendritic cell that constitutes the innate immune system. pDCs are the main producers of type I interferon in the body. Type I interferon exhibits growth inhibitory activity against viruses and the like. Interferon α (IFN-α) and interferon β (IFN-β) are known as representative type I interferons, and not only these but also interferon λ (IFN-λ), a type II interferon, is thought to have immunostimulatory activity. Specific examples of pDCs include CAL-1 cells. CAL-1 cells are a human plasmacytoid dendritic cell cancer cell line established from tumor cells in a patient's peripheral blood (JP 2007-044008 A), and are deposited at the National Institute of Technology and Evaluation, Biotechnology Center, Patent Microorganisms Depositary (NPMD, Japan) under deposit number FERM BP-10914.

[0018] The immunostimulatory effect (immunostimulatory ability), dendritic cell activation effect (dendritic cell activation ability), or pDC activation effect (pDC activation ability) according to one embodiment may include an effect of promoting the production of at least one or more IFNs (IFN production-promoting ability) selected from the group consisting of interferon α (IFN-α), interferon β (IFN-β), and interferon λ (IFN-λ), or may include an interferon α (IFN-α) production-promoting effect (IFN-α production-promoting ability), or may be an IFN-α production-promoting effect (IFN-α production-promoting ability).

[0019] Whether or not an immunostimulating composition according to one embodiment has an immunostimulating effect can be determined as appropriate. For example, if the function of immune cells is enhanced when cultured in the presence of an immunostimulating composition according to one embodiment, compared to when cultured in the absence of the composition, the composition is determined to have an immunostimulating effect. Furthermore, if the function of immune cells is maintained (inhibited from decline) when cultured in the presence of an immunostimulating composition according to one embodiment and a substance that reduces immune cell function, compared to when cultured in the absence of the composition and in the presence of a substance that reduces immune cell function, the composition is determined to have an immunostimulating effect. The function of immune cells may be evaluated, for example, using an activation marker molecule (protein, etc.) that indicates that the immune cells are activated, or a molecule (protein, etc.; e.g., IFN, etc.) produced when the immune cells are activated as an index.

[0020] As a more detailed example, whether or not the immunostimulating composition according to one embodiment has an immunostimulating effect can be confirmed by measuring the IFN-α concentration by the following procedures (i) to (iv): (i) Mouse-derived bone marrow cells from which red blood cells have been removed are added to RPMI medium prepared so that each component described in the <Composition of Medium> below has the respective final concentration described in the <Composition of Medium> below at a concentration of 1 x 10 ６<Culture medium composition> 10% by volume FBS 100 U / mL penicillin / streptomycin 1 mM sodium pyruvate 2.5 mM HEPES 1% by mass non-essential amino acids for MEM (NEAA) 50 μM β-mercaptoethanol 100 ng / mL Flt-3L (ii) 1 mL of the prepared cell suspension was seeded on a plate, and the plate was then heated in a CO ２ Incubated at 37°C and 5% CO ２ (iii) The bone marrow cells containing the induced pDCs are cultured at 2 × 10 ５ The bacteria are suspended at a concentration of 1 mg / mL, and 200 μL of the suspension is seeded onto a 96-well plate, to which 2 μL of a composition containing the bacteria adjusted to a concentration of 1 mg / mL with PBS is added. (iv) After 24 hours, the culture supernatant is collected, and the IFN-α concentration is measured by ELISA using an IFN-α measurement kit.

[0021] As used herein, "bacteria having immunostimulatory activity" refers to bacteria that have the ability to activate (activate) immune cells. "Immunostimulatory activity" may refer to any ability to activate immune cells, such as the ability to induce IFN production in immune cells, the ability to induce production of at least one IFN selected from the group consisting of IFN-α, IFN-β, and IFN-λ in immune cells, or the ability to induce IFN-α production in immune cells. "Immunostimulatory activity" may be either live or killed bacteria, or may be a disrupted product of live or killed bacteria, a lyophilized product of live or killed bacteria, a disrupted product of the lyophilized product, a culture medium, an extract of the culture medium, or a processed product thereof. Here, examples of the processed product include those treated with an enzyme treatment, heat treatment, or the like, or those recovered by ethanol precipitation of the treated product. The "immunostimulatory bacteria" are preferably killed bacteria, and more preferably crushed killed bacteria, freeze-dried products, or crushed freeze-dried products that have been heat-treated (heat-killed bacteria). When the "immunostimulatory bacteria" are killed bacteria, they can be produced by killing live bacteria by heat treatment, pressurization, high-pressure steam treatment, electromagnetic wave treatment, electron beam treatment, radiation treatment, ultraviolet treatment, alcohol treatment, electrolyzed water treatment, or the like, and then drying them as needed by freeze-drying, spray drying, drum drying, hot air drying, vacuum drying, or the like.

[0022] Whether or not the bacteria according to this embodiment have immunostimulatory activity is not particularly limited, and the bacteria may be determined to have immunostimulatory activity if the function of immune cells is enhanced when the immune cells are cultured in the presence of the bacteria having immunostimulatory activity compared to when the immune cells are cultured in the absence of the bacteria. As a more detailed example, whether or not the bacteria according to this embodiment have immunostimulatory activity can be confirmed by measuring the IFN-α concentration according to the above steps (i) to (iv).

[0023] Whether the bacteria according to this embodiment have immunostimulatory activity or not was determined by comparing the bacteria at a final concentration of 10 μg / mL with a final concentration of 2 × 10 cells containing pDCs obtained by culturing the bacteria collected from mouse bone marrow in a cell culture medium containing 100 ng / mL Flt3-L for 7 days.５ By co-culturing the cells with bone marrow cells at a concentration of 1000 cells / mL for 24 hours, the IFN-α produced can be expressed as an index of IFN-α production of 30 pg / mL or more, preferably 50 pg / mL or more, more preferably 60 pg / mL or more, more preferably 70 pg / mL or more, more preferably 80 pg / mL or more, more preferably 90 pg / mL or more, more preferably 100 pg / mL or more, more preferably 150 pg / mL or more, more preferably 200 pg / mL or more, more preferably 250 pg / mL or more, more preferably 300 pg / mL or more, more preferably 400 pg / mL or more, more preferably 500 pg / mL or more, more preferably 600 pg / mL or more, more preferably 700 pg / mL or more, and particularly preferably 800 pg / mL or more.

[0024] The bacteria according to this embodiment are not particularly limited, and may be bacteria that are harmless to the human body. In one embodiment, the bacteria may be gram-positive or gram-negative bacteria. The bacteria according to this embodiment may be lactic acid bacteria and / or acetic acid bacteria, and particularly lactic acid bacteria. The bacteria having immunostimulatory ability according to this embodiment may be one type of bacteria or a mixture of two or more types of bacteria, such as one or more types of lactic acid bacteria, one or more types of acetic acid bacteria, or a mixture of one or more types of lactic acid bacteria and one or more types of acetic acid bacteria.

[0025] Lactic acid bacteria are bacteria that produce lactic acid as a metabolite. Examples of lactic acid bacteria include bacteria of the genus Oenococcus, Bifidobacterium, Weissella, Tetragenococcus, Lactococcus, Leuconostoc, and Pseudomonas. Examples of such bacteria include bacteria of the genus Pediococcus, Streptococcus, Enterococcus, Lactobacillus, Bacillus, and Heyndrickxia (formerly classified as Bacillus).

[0026] In addition, the Lactobacillus bacteria in the present invention includes bacteria that were classified into the Lactobacillus genus before the reclassification of the Lactobacillus genus.For example, with the reclassification of the Lactobacillus genus, the genus Acetylactobacillus, the genus Agrilactobacillus, the genus Amylolactobacillus, the genus Apilactobacillus, the genus Bombilactobacillus, the genus Compan ... The genus Lactobacillus, the genus Dellaglioa, the genus Fructilactobacillus, the genus Furfurilactobacillus, the genus Holzapfelia, the genus Lacticaseibacillus, the genus Lactiplantibacillus, the genus Lapidilactobacillus The genus Lapidilactobacillus, the genus Latilactobacillus, the genus Lentilactobacillus, the genus Levilactobacillus, the genus Ligilactobacillus, the genus Limosilactobacillus, the genus Liquorilactobacillus, The examples include bacteria classified into the genera Lactobacillus, Loigolactobacillus, Paralactobacillus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus.

[0027] Among the above, examples of bacteria include bacteria of the genus Oenococcus, bacteria of the genus Bifidobacterium, bacteria of the genus Lentilactobacillus, bacteria of the genus Weissella, bacteria of the genus Tetragenococcus, bacteria of the genus Lactococcus, bacteria of the genus Leuconostoc, bacteria of the genus Pediococcus, and the like. Bacteria of the genus Pediococcus, Enterococcus, Lactobacillus, and Lactiplantibacillus are preferred, and bacteria of the genus Lactococcus, Bifidobacterium, and Lactobacillus are more preferred.

[0028] The above-mentioned Oenococcus bacteria are not particularly limited, but examples thereof include Oenococcus oeni, etc. Specific examples of Oenococcus bacteria include Oenococcus oeni JCM6125, etc.

[0029] The Bifidobacterium genus is not particularly limited, but examples thereof include Bifidobacterium animalis subsp. lactis and Bifidobacterium longum subsp. infantis. Specific examples of Bifidobacterium include Bifidobacterium animalis subsp. lactis JCM10602, Bifidobacterium longum subsp. infantis JCM1222, and Bifidobacterium longum subsp. longum BB536.

[0030] The above-mentioned Weissella genus bacteria is not particularly limited, but examples thereof include Weissella paramesenteroides and Weissella viridescens. Specific examples of Weissella genus bacteria include Weissella paramesenteroides JCM9890 and Weissella viridescens JCM1174.

[0031] The above-mentioned Tetragenococcus bacteria are not particularly limited, but include, for example, Tetragenococcus halophilus, etc. Specific examples of Tetragenococcus bacteria include Tetragenococcus halophilus NRIC0098, Tetragenococcus halophilus No. 1, etc.

[0032] The Lactococcus bacteria are not particularly limited, and examples thereof include Lactococcus lactis, Lactococcus lactis subsp. lactis, Lactococcus garvieae, Lactococcus lactis subsp. cremoris, Lactococcus lactis subsp. hordniae, and Lactococcus culbatus. Examples of suitable strains of Lactococcus include Lactococcus curvatus and Lactococcus plantarum.

[0033] Specific examples of the Lactococcus bacteria include Lactococcus lactis subsp. lactis JCM5805 (hereinafter sometimes referred to as JCM5805), Lactococcus lactis subsp. lactis NBRC12007, Lactococcus lactis subsp. lactis NRIC1150, Lactococcus lactis subsp. lactis JCM20101, Lactococcus lactis subsp. lactis JCM7638, Lactococcus lactis subsp. lactis ATCC 7963, Lactococcus lactis subsp. lactis ATCC 7962, Lactococcus lactis subsp. lactis ATCC 29146, and Lactococcus lactis subsp. lactis ATCC lactis ATCC 19435, Lactococcus lactis subsp. lactis ATCC 15577, Lactococcus lactis subsp. lactis ATCC 15346, Lactococcus lactis subsp. lactis ATCC 13675, Lactococcus lactis subsp. lactis ATCC 12929, Lactococcus lactis subsp. lactis ATCC 11955, Lactococcus lactis subsp. lactis ATCC 11454, Lactococcus lactis subsp. lactis ATCC 11007, Lactococcus garvieae NBRC100934, Lactococcus lactis subsp. cremoris JCM16167, Lactococcus lactis subsp. cremoris NBRC100676, Lactococcus lactis subsp. holdoniae JCM1180, Lactococcus lactis subsp. holdoniae JCM11040, Lactococcus culbatus JCM1096, and Lactococcus plantarum JCM11056.

[0034] The Leuconostoc genus bacteria is not particularly limited, but examples thereof include Leuconostoc carnosum and Leuconostoc lactis. Specific examples of Leuconostoc genus bacteria include Leuconostoc carnosum JCM9695 and Leuconostoc lactis NBRC12455.

[0035] The above-mentioned Pediococcus bacteria are not particularly limited, but examples thereof include Pediococcus acidilactici, Pediococcus pentosaceus, Pediococcus cellicola, Pediococcus claussenii, Pediococcus damnosus, and Pediococcus ethanolidurans. ethanolidurans), Pediococcus inopinatus, Pediococcus parvulus, Pediococcus stillesii, etc. Specific examples of the genus Pediococcus include Pediococcus acidilactici JCM8797, Pediococcus acidilactici K15, and Pediococcus damnosus JCM5886, etc.

[0036] The Streptococcus bacteria are not particularly limited, but include, for example, Streptococcus thermophilus, etc. Specific examples of Pediococcus bacteria include, for example, Streptococcus thermophilus SBC8781, etc.

[0037] The Enterococcus bacteria are not particularly limited, but examples thereof include Enterococcus alcedinis, Enterococcus faecalis, etc. Specific examples of Enterococcus bacteria include Enterococcus faecalis EC-12, etc.

[0038] The Lactobacillus bacteria are not particularly limited, but examples thereof include Lactobacillus paracasei, Lactobacillus paracasei subsp. paracasei, Lactobacillus paracasei subsp. paracasei, Lacticaseibacillus paracasei subsp. paracasei, Lactobacillus delbrueckii, Lactobacillus acidophilus, and the like. Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fructivorans, Lactobacillus hilgardii, Lactobacillus rhamnosus, Lacticaseibacillus rhamnosus, Lactobacillus gasseri, Lactobacillus acidophilus acidophilus), Lactobacillus bulgaricus, Lactobacillus parakefiri, Lentilactobacillus parakefiri, Lactobacillus plantarum, Lactiplantibacillus plantarum, Lactobacillus plantarum subsp. plantarum plantarum), Lactiplantibacillus plantarum subsp. plantarum,Lactobacillus pentosus, Lactiplantibacillus pentosus, Lactobacillus helveticus, Limosilactobacillus reuteri subsp. reuteri, Lactobacillus crispatus, Lactobacillus paraplantarum paraplantarum), Lactiplantibacillus paraplantarum, and Lactobacillus johnsonii.

[0039] Specific examples of Lactobacillus bacteria include Lactobacillus paracasei KW3110, Lactobacillus paracasei MCC1849, Lactobacillus paracasei K71, Lactobacillus paracasei K-2, Lactobacillus rhamnosus GG, Lactobacillus rhamnosus CRL1505, Lactobacillus gasseri SBT2055, Lactobacillus acidophilus L-92, Lactobacillus casei subsp. casei 327, Lactobacillus (newly classified as Lacticaseibacillus) casei Shirota, Lactobacillus bulgaricus OLL1073R-1, Lactobacillus parakeefili (newly classified as Lentilactobacillus parakeefili) JCM8573, Lactobacillus plantarum (newly classified as Lactipranchibacillus plantarum) L-137, Lactobacillus pentosus (newly classified as Lactipranchibacillus pentosus) ONRICb0240, Lactobacillus paraplantarum (newly classified as Lactipranchibacillus paraplantarum) JCM1149, Lactobacillus acidophilus JCM1021, Lactobacillus acidophilus JCM1132, Lactobacillus helveticus JCM1003, rimosyl Lactobacillus reuteri subsp. reuteri JCM1112, Lactobacillus crispatus JCM1185, and Lactobacillus johnsonii JCM2012.

[0040] The Bacillus bacteria are not particularly limited, but include, for example, Bacillus coagulans, etc. Specific examples of Bacillus bacteria include Bacillus coagulans SANK70258 strain, etc.

[0041] Examples of bacteria of the genus Hendricksia include, but are not limited to, Hendrickxia coagulans (also known as Bacillus coagulans). Specific examples of bacteria of the genus Hendrickxia include Hendrickxia (Bacillus) coagulans SANK 70258 and Hendrickxia (Bacillus) coagulans BC99.

[0042] Acetic acid bacteria are bacteria that produce acetic acid as a metabolite. Examples of acetic acid bacteria include, but are not limited to, bacteria of the genus Gluconacetobacter, Acetobacter, and Gluconobacter, preferably bacteria of the genus Gluconacetobacter, more preferably Gluconacetobacter hansenii, and even more preferably Gluconacetobacter hansenii GK-1.

[0043] In addition to the above, the lactic acid bacteria may be bacteria of the genus Akkermansia, Bacteroides, Blautia, Clostridium, Collinsella, Faecalibacterium, Faecalicatena, Lacrimispora, Paeniclostridium, Parabacteroides, or Roseburia.

[0044] Specific examples of Akkermansia include Akkermansia muciniphila JCM30893.

[0045] Specific examples of bacteria of the genus Bacteroides include Bacteroides caccae JCM9498T, Bacteroides fragilis JCM11019T, Bacteroides fragilis JCM11017, Bacteroides fragilis JCM17586, Bacteroides fragilis JCM17587, Bacteroides ovatus JCM5824T, Bacteroides setaiotaomicron ATCC29148T, Bacteroides setaiotaomicron ATCC29741, Bacteroides setaiotaomicron ATCC12290, Bacteroides uniformis JCM5828T, and Bacteroides uniformis JCM13286, Bacteroides uniformis JCM13287 and Bacteroides uniformis JCM13288.

[0046] Specific examples of the genus Blautia include Blautia acetiggens JCM34803T, Blautia ammoniilytica JCM34802T, Blautia algi JCM31394T, Blautia caekimuris JCM34498T, Blautia coccoides JCM1395T, Blautia faeces JCM17205T, Blautia glucellacea JCM17039T, Blautia hansenii JCM14655, Blautia hansenii JCM35484, Blautia hominis JCM32276T, Blautia hydrogenotrophica JCM31266, and Blautia liqualis. JCM34225T, Blautia luti JCM17040T, Blautia obeum JCM31340, Blautia producta JCM1471T, Blautia pseudococcoides JCM35243T, Blautia shinkii JCM14657T, Blautia wechslerae JCM31267 and Blautia wechslerae JCM35486.

[0047] Specific examples of the genus Clostridium include Clostridium butyricum JCMNT, Clostridium nexile JCM31500T, and Clostridium symbiosum JCM1297T.

[0048] Specific examples of Collinsella bacteria include Collinsella aerofaciens JCM10188T, Collinsella intestinalis JCM10643T, Collinsella stercoris JCM10641T, and Collinsella tanakaei JCM16071T.

[0049] Specific examples of the genus Faecalibacterium include Faecalibacterium hattorii JCM39210, Faecalibacterium longum JCM39208, Faecalibacterium prausnitzii JCM31915, Faecalibacterium prausnitzii JCM39207, and Faecalibacterium prausnitzii JCM39209.

[0050] Specific examples of the genus Faecalicatena include Faecalicatena oroticum JCM1429T.

[0051] Specific examples of the genus Lacrimispora include Lacrimispora celerecrescens JCM15734T, Lacrimispora sphenoides JCM1415T, and Lacrimispora xylanolytica JCM15735T.

[0052] Specific examples of the genus Paeniclostridium include Paeniclostridium sordellii JCM3814T.

[0053] Specific examples of bacteria of the genus Parabacteroides include Parabacteroides meldae JCM9497T.

[0054] Specific examples of the genus Roseburia include Roseburia hominis JCM17582, Roseburia intestinalis JCM17583, and Roseburia inulinovorans JCM17584.

[0055] In one preferred embodiment, the bacterium is Lactobacillus rhamnosus CRL1505 or a mutant thereof, Gluconacetobacter hansenii or a mutant thereof, Lactobacillus acidophilus (GK-1, Lactobacillus acidophilus) L-92 or a mutant thereof, Lactobacillus plantarum L-137 or a mutant thereof, or Lactobacillus bulgaricus. The bacterium may be at least one bacterium selected from the group consisting of Lactococcus lactis subsp. lactis JCM5805 or a mutant thereof, Lactococcus curvatus JCM1096 or a mutant thereof, Lactococcus lactis subsp. lactis ATCC7962 or a mutant thereof, and Lactobacillus paraplantarum JCM1149 or a mutant thereof. In a more preferred embodiment, the bacterium is at least one bacterium selected from the group consisting of Lactococcus lactis subsp. lactis JCM5805 or a mutant thereof, Lactococcus curvatus JCM1096 or a mutant thereof, Lactococcus lactis subsp. lactis ATCC7962 or a mutant thereof, and Lactobacillus paraplantarum JCM1149 or a mutant thereof.

[0056] Of the above-mentioned lactic acid bacteria and acetic acid bacteria, the JCM strain can be obtained from the Microbial Materials Development Laboratory, BioResource Center, RIKEN (1-1 Takanodai 3-chome, Tsukuba, Ibaraki Prefecture), the NBRC strain can be obtained from the Biological Genetic Resources Division, National Institute of Technology and Evaluation (5-8 Kazusa Kamatari 2-chome, Kisarazu, Chiba Prefecture), the NRIC strain can be obtained from the Tokyo University of Agriculture and Technology Culture Collection (1-1 Sakuragaoka 1-chome, Setagaya-ku, Tokyo), and the ATCC strain can be obtained from the American Type Culture Collection (10801 University Boulevard, Manassas, Virginia, USA). In addition to being obtained from public institutions, the above-mentioned lactic acid bacteria and acetic acid bacteria can also be obtained by isolation or purification using known methods from commercially available products containing lactic acid bacteria or acetic acid bacteria.

[0057] As mentioned above, the JCM strain can be obtained from the Microbial Materials Development Laboratory of the RIKEN BioResource Center, but the present invention can also use the same strain of the JCM strain stored in a collection institution other than the RIKEN BioResource Center Microbial Materials Development Laboratory. Specifically, the same strain of Lactococcus lactis subsp. lactis JCM 5805 can be obtained from the National Institute of Technology and Evaluation, Biological Genetic Resources Division (2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture), the Tokyo University of Agriculture, Strain Collection (1-1-1 Sakuragaoka, Setagaya-ku, Tokyo), the American Type Culture Collection (10801 University Boulevard, Manassas, Virginia, USA), etc. Lactococcus lactis subsp. lactis JCM 5805 has been deposited with the American Type Culture Collection as Lactococcus lactis subsp. lactis ATCC 9936 and Lactococcus lactis subsp. lactis ATCC 19435.

[0058] The mutant strain may be any strain having properties (e.g., immunostimulatory ability) that can achieve the object of the present technology. Furthermore, the mutant strain is preferably a bacterium that has the same bacteriological properties as the above-mentioned bacterial strain and has immunostimulatory ability equivalent to or greater than that of the above-mentioned bacterial strain. Whether a mutant strain has immunostimulatory ability equivalent to or greater than that of the above-mentioned bacterial strain can be confirmed, for example, by the evaluation method described below or the method described in the Examples below.

[0059] Such mutant strains may be constructed by non-artificially introducing mutations into the strains. Alternatively, such mutant strains may be constructed by artificially introducing mutations into the strains, for example, by introducing mutations into the bacterium by treatment with a mutagen such as ultraviolet (UV) or a DNA alkylating agent, or by introducing mutations into the strains by known genetic engineering methods such as gene recombination or gene editing typified by CRISPR-Cas9.

[0060] The bacteria according to this embodiment can be cultured by a conventional method depending on the species. For example, when the bacteria are lactic acid bacteria or acetic acid bacteria, they can be cultured by a conventional method using a conventional medium. The medium is not particularly limited as long as it is a medium that can grow the bacteria. For example, a medium prepared by appropriately adding sugar to MRS medium, GAM medium, or M17 medium can be used, and inorganic salts, vitamins, and / or amino acids, etc., can be added as appropriate. Culturing can be carried out at 25 to 40°C for several hours to several days.

[0061] The effective amount of the bacteria contained in the composition of the present embodiment is not particularly limited as long as it is an amount that can exert immunostimulatory activity, and may vary depending on the subject of application. When the subject of application is a mammal such as a human, the lower limit is, for example, 1 × 10 ８ pieces, 1×10 ９ pcs or 1 x 10 １０ The upper limit can be set to, for example, 1×10 １４ pieces, 1×10 １３ pieces, 1×10 １２ These upper and lower limits can be arbitrarily combined, and the intake range can be, for example, 1 × 10 ８ 1x10 or more １４ Less than or equal to 1 x 10８ 1x10 or more １３ Less than or equal to 1 x 10 ８ 1x10 or more １２ Less than or equal to 1 x 10 ９ 1x10 or more １４ Less than or equal to 1 x 10 ９ 1x10 or more １３ Less than or equal to 1 x 10 １０ 1x10 or more １４ Less than or equal to 1 x 10 １０ 1x10 or more １３ 10 or less, or 1 x 10 １０ 1x10 or more １２ The bacterial cell count can be measured using a known microscope, flow cytometer, or non-culture rapid microorganism testing device (e.g., ELESTA PixeeMo (AFI Technology Co., Ltd.)), but measurement using a microscope is preferred from the viewpoint of high versatility. The composition having immunopotentiating ability may be used in the form of, for example, a food composition, a pharmaceutical composition, a quasi-drug, a bacterial bulk powder (a powder of dried bacterial cells or a powder containing the same), or a feed.

[0062] The content of bacteria having immunostimulatory ability in the immunostimulatory composition of one embodiment is not particularly limited as long as it is an amount that satisfies the effective amount of immunostimulation, and therefore may vary depending on the form of the immunostimulatory composition of this embodiment. For example, the dry mass of the bacterium according to this embodiment relative to the total mass of the immunostimulating composition of this embodiment may be 0.0001% by mass or more, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.02% by mass or more, 0.05% by mass or more, 0.10% by mass or more, 0.30% by mass or more, 1.0% by mass or more, 1.5% by mass or more, 2.0% by mass or more, 2.5% by mass or more, 3.0% by mass or more, 5.0% by mass or more, 7.0% by mass or more, or 10.0% by mass or more, or may be less than 100% by mass, 95% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 30% by mass or less, 25% by mass or less, 20% by mass or less, or 15% by mass or less.

[0063] These lower and upper limits can be arbitrarily combined with each other. For example, with respect to the total mass of the immunostimulating composition of the present embodiment, the dry mass of the bacteria according to the present embodiment is 0.0001% by mass or more and less than 100% by mass, 0.0001% by mass or more and 95% by mass or less, 0.0001% by mass or more and 90% by mass or less, 0.0001% by mass or more and 80% by mass or less, 0.0001% by mass or more and 70% by mass or less, 0.0001% by mass or more and 60% by mass or less, 0.0001% by mass or more and 50% by mass or less, 0.0001% by mass or more and 30% by mass or less, 0.0001% by mass or more and 25% by mass or less, 0.0001% by mass or more and 20% by mass or less, 0.0001% by mass or more and 15% by mass or less, 0.001% by mass or more and less than 100% by mass, 0.001% by mass or more and 95% by mass or less, 0.001% by mass or more and 90% by mass or less, 0.001% by mass or more and 80% by mass or less, 0.001% by mass or more and 70% by mass or less, 0.001% by mass or more and 60% by mass or less, 0.001% by mass or more and 50% by mass or less, 0.001% by mass or more and 30% by mass or less, 0.001% by mass or more and 25% by mass or less, 0.001% by mass or more and 20% by mass or less, 0.001% by mass or more and 15% by mass or less, 0.005% by mass or more and less than 100% by mass, 0.005% by mass or more and 95% by mass or less, 0.005% by mass or more and 90% by mass or less, 0.005% by mass or more and 80% by mass or less, 0.005% by mass or more and 70% by mass or less, 0.005% by mass or more and 60% by mass or less, 0.005% by mass or more and 50% by mass or less, 0.005% by mass or more and 30% by mass or less, 0.005% by mass or more and 25% by mass or less, 0.005% by mass or more and 20% by mass or less, 0.005% by mass or more and 15% by mass or less, 0.01% by mass or more and less than 100% by mass, 0.01% by mass or more and 95% by mass or less, 0.01% by mass or more and 90% by mass or less, 0.01% by mass or more and 80% by mass or less, 0.01% by mass or more and 70% by mass or less, 0.01% by mass or more and 60% by mass or less, 0.01% by mass or more and 50% by mass or less, 0.01% by mass or more and 30% by mass or less, 0.01% by mass or more and 25% by mass or less, 0.01% by mass or more and 20% by mass or less, 0.01% by mass or more and 15% by mass or less, 0.02% by mass or more and less than 100% by mass, 0.02% by mass or more and 95% by mass or less, 0.02% by mass or more and 90% by mass or less, 0.02% by mass or more and 80% by mass or less, 0.02% by mass or more and 70% by mass or less, 0.02% by mass or more and 60% by mass or less, 0.02% by mass or more and 50% by mass or less,0.02% to 30% mass, 0.02% to 25% mass, 0.02% to 20% mass, 0.02% to 15% mass, 0.05% to 100% mass (not fully expressed), 0.05% to 95% mass, 0.05% to 90% mass, 0.05% to 80% mass, 0.05% to 70% mass, 0.05% to 60% mass, 0.05% to 50% mass, 0.05% to 30% mass, 0.05% to 25% mass, 0.05% to 20% mass, 0.05% mass The following are categories of product weight percentages: 15% or less, 0.10% or more but less than 100%, 0.10% or more but less than 95%, 0.10% or more but less than 90%, 0.10% or more but less than 80%, 0.10% or more but less than 70%, 0.10% or more but less than 60%, 0.10% or more but less than 50%, 0.10% or more but less than 30%, 0.10% or more but less than 25%, 0.10% or more but less than 20%, 0.10% or more but less than 15%, 0.30% or more but less than 100%, 0.30% or more but less than 95%, and 0.30% or more but less than 90%. Below, 0.30% mass% to 80% mass%, 0.30% mass% to 70% mass%, 0.30% mass% to 60% mass%, 0.30% mass% to 50% mass%, 0.30% mass% to 30% mass%, 0.30% mass% to 25% mass%, 0.30% mass% to 20% mass%, 0.30% mass% to 15% mass%, 1.0% mass% to 100% mass%, 1.0% mass% to 95% mass%, 1.0% mass% to 90% mass%, 1.0% mass% to 80% mass%, 1.0% mass% to 70% mass%, 1.0% mass% to 60% mass%, 1.0% mass% to 50% mass. Below 1%, 1.0% to 30%, 1.0% to 25%, 1.0% to 20%, 1.0% to 15%, 1.5% to 100%, 1.5% to 95%, 1.5% to 90%, 1.5% to 80%, 1.5% to 70%, 1.5% to 60%, 1.5% to 50%, 1.5% to 30%, 1.5% to 25%, 1.5% to 20%, 1.5% to 15%.2.0% or more of quality, less than 100% of quality; 2.0% or more of quality, less than 95% of quality; 2.0% or more of quality, less than 90% of quality; 2.0% or more of quality, less than 80% of quality; 2.0% or more of quality, less than 70% of quality; 2.0% or more of quality, less than 60% of quality; 2.0% or more of quality, less than 50% of quality; 2.0% or more of quality, less than 30% of quality; 2.0% or more of quality, less than 25% of quality; 2.0% or more of quality, less than 20% of quality; 2.0% or more of quality, less than 15% of quality; 2.5% or more of quality, less than 100% of quality; 2.5% or more of quality, less than 95% of quality; 2.5% or more of quality, less than 90% of quality; 2.5% or more of quality, less than 80% of quality; 2.5% of quality... 2.5% to 70% mass, 2.5% to 60% mass, 2.5% to 50% mass, 2.5% to 30% mass, 2.5% to 25% mass, 2.5% to 20% mass, 2.5% to 15% mass, 3.0% to 100% mass, 3.0% to 95% mass, 3.0% to 90% mass, 3.0% to 80% mass, 3.0% to 70% mass, 3.0% to 60% mass, 3.0% to 50% mass, 3.0% to 30% mass, 3.0% to 25% mass. Less than 100% of the quantity, 3.0% to 20% of the quantity, 3.0% to 15% of the quantity, 5.0% to 100% of the quantity, less than 95% of the quantity, 5.0% to 90% of the quantity, 5.0% to 80% of the quantity, 5.0% to 70% of the quantity, 5.0% to 60% of the quantity, 5.0% to 50% of the quantity, 5.0% to 30% of the quantity, 5.0% to 25% of the quantity, 5.0% to 20% of the quantity, 5.0% to 15% of the quantity, 7.0% to 100% of the quantity, less than 95% of the quantity, 5.0% to 95% of the quantity. 7.0% quality or higher, below 90% quality; 7.0% quality or higher, below 80% quality; 7.0% quality or higher, below 70% quality; 7.0% quality or higher, below 60% quality; 7.0% quality or higher, below 50% quality; 7.0% quality or higher, below 30% quality; 7.0% quality or higher, below 25% quality; 7.0% quality or higher, below 20% quality; 7.0% quality or higher, below 15% quality; 10.0% quality or higher, below 100% quality; 10.0% quality or higher, below 95% quality; 10.0% quality or higher, below 90% quality; 10.0% quality or higher, below 80% quality; 10.0% quality or higher, below 70% quality; 10.0% quality or higher, below 60% quality.The dry mass of the bacterium according to this embodiment may be 10.0% by mass or more and 50% by mass or less, 10.0% by mass or more and 30% by mass or less, 10.0% by mass or more and 25% by mass or less, 10.0% by mass or more and 20% by mass or less, or 10.0% by mass or more and 15% by mass or less. The above-mentioned dry mass of the bacterium according to this embodiment can be used as a daily dose for an adult weighing 60 kg, for example. The dose can be set depending on factors such as the health condition of the person receiving or ingesting the bacterium, the method of administration or ingestion, and the combination with other agents.

[0064] The number of bacteria having immunostimulatory ability in the immunostimulatory composition according to this embodiment is 1.0 × 10 ３ Cells / mL or more, 1.0 x 10 ４ Cells / mL or more, 1.0 x 10 ５ Cells / mL or more, 1.0 x 10 ６ Cells / mL or more, 1.0 x 10 ７ cells / mL or 4.0 x 10 ７ cells / mL or more, and may be 1.0 x 10 １１ Cells / mL or less, 1.0 x 10 １０ Cells / mL or less, 3.0 x 10 ９ cells / mL or less or 1.0 x 10 ９ These lower and upper limits can be combined in any combination. For example, the number of bacteria having immunostimulatory ability in the immunostimulatory composition according to this embodiment may be 1.0 × 10 ３ Cells / mL or more 1.0 x 10 １１ Cells / mL or less, 1.0 x 10 ３ Cells / mL or more 1.0 x 10 １０ Cells / mL or less, 1.0 x 10 ３ Cells / mL or more 3.0 x 10 ９ Cells / mL or less, 1.0 x 10 ３ Cells / mL or more 1.0 x 10 ９ Cells / mL or less, 1.0 x 10 ４ Cells / mL or more 1.0 x 10 １１ Cells / mL or less, 1.0 x 10 ４ Cells / mL or more 1.0 x 10 １０ Cells / mL or less, 1.0 x 10 ４ Cells / mL or more 3.0 x 10 ９Cells / mL or less, 1.0 x 10 ４ Cells / mL or more 1.0 x 10 ９ Cells / mL or less, 1.0 x 10 ５ Cells / mL or more 1.0 x 10 １１ Cells / mL or less, 1.0 x 10 ５ Cells / mL or more 1.0 x 10 １０ Cells / mL or less, 1.0 x 10 ５ Cells / mL or more 3.0 x 10 ９ Cells / mL or less, 1.0 x 10 ５ Cells / mL or more 1.0 x 10 ９ Cells / mL or less, 1.0 x 10 ６ Cells / mL or more 1.0 x 10 １１ Cells / mL or less, 1.0 x 10 ６ Cells / mL or more 1.0 x 10 １０ Cells / mL or less, 1.0 x 10 ６ Cells / mL or more 3.0 x 10 ９ Cells / mL or less, 1.0 x 10 ７ Cells / mL or more 1.0 x 10 １１ Cells / mL or less, 1.0 x 10 ７ Cells / mL or more 1.0 x 10 １０ Cells / mL or less, 1.0 x 10 ７ Cells / mL or more 1.0 x 10 ９ Cells / mL or less, 4.0 x 10 ７ Cells / mL or more 1.0 x 10 １１ Cells / mL or less, 4.0 x 10 ７ Cells / mL or more 1.0 x 10 １０ Cells / mL or less, 4.0 x 10 ７ Cells / mL or more 1.0 x 10 ９ In this case, the daily intake of the liquid immunostimulating composition may be 10 mL to 1,000 mL, 30 mL to 800 mL, 50 mL to 500 mL, or 100 mL to 250 mL.

[0065] In the immunostimulating composition of the present embodiment, the number of bacteria having immunostimulating ability in the immunostimulating composition according to one embodiment per unit package is 1.0 × 10 ７ pcs or more, 1.0×10 ８ pcs or more, 3.0×10 ８pcs or more, 5.0×10 ８ or more or 1.0 x 10 ９ pcs or more, 5.0×10 ９ pcs or more, 1.0×10 １０ pcs or more, 5.0×10 １０ pcs or more, 1.0×10 １１ may be 1.0 × 10 or more, １４ Less than or equal to 1.0×10 １３ or less, or 1.0 x 10 １２ These upper and lower limits can be combined in any desired manner. For example, in the immunostimulating composition of this embodiment, the number of bacteria according to this embodiment per unit package may be 1.0 × 10 or less. ７ pcs or more 1.0×10 １４ Less than or equal to 1.0×10 ７ pcs or more 1.0×10 １３ Less than or equal to 1.0×10 ７ pcs or more 1.0×10 １２ Less than or equal to 1.0×10 ８ pcs or more 1.0×10 １４ Less than or equal to 1.0×10 ８ pcs or more 1.0×10 １３ Less than or equal to 1.0×10 ８ pcs or more 1.0×10 １２ Less than or equal to 3.0×10 ８ pcs or more 1.0×10 １４ Less than or equal to 3.0×10 ８ pcs or more 1.0×10 １３ Less than or equal to 3.0×10 ８ pcs or more 1.0×10 １２ Less than or equal to 5.0×10 ８ pcs or more 1.0×10 １４ Less than or equal to 5.0×10 ８ pcs or more 1.0×10 １３ Less than or equal to 5.0×10 ８ pcs or more 1.0×10 １２ Less than or equal to 1.0×10 ９ pcs or more 1.0×10 １４ Less than or equal to 1.0×10 ９ pcs or more 1.0×10 １３ Less than or equal to 1.0×10 ９ pcs or more 1.0×10 １２ Less than or equal to 5.0×10 ９pcs or more 1.0×10 １４ Less than or equal to 5.0×10 ９ pcs or more 1.0×10 １３ Less than or equal to 5.0×10 ９ pcs or more 1.0×10 １２ Less than or equal to 1.0×10 １０ pcs or more 1.0×10 １４ Less than or equal to 1.0×10 １０ pcs or more 1.0×10 １３ Less than or equal to 1.0×10 １０ pcs or more 1.0×10 １２ Less than or equal to 5.0×10 １０ pcs or more 1.0×10 １４ Less than or equal to 5.0×10 １０ 5.0 x 10 pieces or more １３ Less than or equal to 5.0×10 １０ pcs or more 1.0×10 １２ Less than or equal to 1.0×10 １１ pcs or more 1.0×10 １４ Less than or equal to 1.0×10 １１ pcs or more 1.0×10 １３ Less than or equal to 1.0×10 １１ pcs or more 1.0×10 １２ It may be less than one.

[0066] In this specification, "polyphenol" means a compound having multiple phenolic hydroxyl groups in the molecule, "carotenoid" means a natural pigment derived from plants, algae, fungi, and bacteria, "xanthine compound" means xanthine or a derivative thereof, "quinone compound" means a compound having a quinone skeleton, "choline compound" means a compound having choline in the molecule, "sphingolipid" means a lipid having sphingosine, "phospholipid" means a lipid having a phosphate ester moiety, "fatty acid" means a monocarboxylic acid having a carboxy group in the hydrocarbon chain, and "sulfite" means a sulfite ion SO ３ ２－ or its dimer, pyrosulfite ion S ２ O ５ ２－"Dolomite" refers to a compound in which part of the calcium in calcium carbonate is replaced with magnesium. These compounds include both free and salt forms, and may be hydrates. "One or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory activity of bacteria having immunostimulatory activity" refers to the above-mentioned compounds which have an effect of enhancing the immunostimulatory activity of bacteria having immunostimulatory activity, and may be a compound which, when co-cultured with bacteria having immunostimulatory activity and immune cells, enhances the level of immunostimulatory activity compared to the level of immunostimulatory activity when only bacteria having immunostimulatory activity and immune cells are co-cultured.

[0067] Whether or not a compound according to this embodiment has an effect of enhancing the immunostimulatory ability of bacteria is not particularly limited, and if the function of immune cells in the presence of bacteria having immunostimulatory ability is enhanced in the presence of the compound compared to the absence of the compound, the compound is determined to have an effect of enhancing the immunostimulatory ability of the bacteria. As a more detailed example, whether or not a compound according to this embodiment has an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability can be confirmed by an increase in the IFN-α concentration measured by the following procedures (i') to (iv') in the presence of the compound compared to the absence of the compound. (i') Red blood cell-removed mouse-derived bone marrow cells were added to RPMI medium prepared so that each component described below in (Culture medium composition) was added to the final concentrations described below in (Culture medium composition) at a concentration of 1 x 10 ６ <Culture medium composition> 10% by volume FBS 100 U / mL penicillin / streptomycin 1 mM sodium pyruvate 2.5 mM HEPES 1% by mass non-essential amino acids for MEM (NEAA) 50 μM β-mercaptoethanol 100 ng / mL Flt-3L (ii') 1 mL of the prepared cell suspension is seeded on a plate, and the plate is then heated in a CO ２ Incubated at 37°C and 5% CO ２(iii') 2 x 10 bone marrow cells containing the induced pDCs are cultured at 4°C for 1 week to induce pDCs. ５ The bacteria are suspended at a concentration of 1 mg / mL and 200 μL of each suspension is seeded onto a 96-well plate, to which 2 μL of a bacterial suspension adjusted to a concentration of 1 mg / mL with PBS is added, followed by the addition of a compound solution adjusted to a predetermined concentration. (iv') After 24 hours, the culture supernatant is recovered and the IFN-α concentration is measured by ELISA using an IFN-α measurement kit.

[0068] Polyphenols may be derived from any part of the plant, such as leaves, stems, fruits, peels, seeds, or roots. Polyphenols may be monomeric polyphenols (e.g., flavonoids such as anthocyanins, isoflavones, and catechins (e.g., epigallocatechin, epicatechin gallate, epigallocatechin gallate, catechin, gallocatechin, catechin gallate, and gallocatechin gallate), or phenylpropanoids such as caffeic acid, chlorogenic acid, and sesamin), or polymeric polyphenols formed by polymerization of monomeric polyphenols (e.g., condensed tannins such as proanthocyanidins (particularly procyanidins formed by polymerization of catechin), hydrolyzed tannins such as gallotannins, etc.). Polyphenols may be flavonoids or non-flavonoids. Flavonoids may be, for example, anthocyanidins (e.g., cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin), flavanols (e.g., catechin, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, theaflavin, thearubigin, and proanthocyanidins), flavanones (e.g., hesperetin, naringenin, and eriodictyol), flavonols (e.g., quercetin, kaempferol, myricetin, and isorhamnetin), flavones (e.g., apigenin and luteolin), and isoflavones (e.g., daidzein, genistein, and glycitein). Non-flavonoids may be, for example, phenolic acids (e.g., chlorogenic acid), ellagic acid, lignans, curcumin, and coumarin. The polyphenol may be any of flavonoids, stilbenoids, phenolic acids and tannins.The polyphenol may be a polyphenol having an antioxidant effect (e.g., chlorogenic acid, catechin, lychee polyphenol, black soybean polyphenol, black soybean seed coat polyphenol, theaflavin, black currant polyphenol, hesperidin, resveratrol, methyl hesperidin, curcumin, rosehip polyphenol, etc.), a polyphenol having an anti-inflammatory effect (e.g., chlorogenic acid, catechin, lychee polyphenol, black soybean polyphenol, black soybean seed coat polyphenol, resveratrol, curcumin, rosehip polyphenol, etc.), a polyphenol having a vascular protective effect (e.g., catechin, hesperidin, methyl hesperidin, etc.), a polyphenol having a skin-beautifying effect (e.g., catechin, hesperidin, methyl hesperidin, rosehip polyphenol, etc.), or a polyphenol having a blood sugar level regulating effect (e.g., chlorogenic acid, catechin, etc.). Preferred polyphenols having an effect of enhancing the immunostimulatory activity of bacteria having immunostimulatory activity include chlorogenic acid, catechin, lychee polyphenol, black soybean polyphenol, black soybean seed coat polyphenol, theaflavin, black currant polyphenol, hesperidin, resveratrol, methylhesperidin, curcumin, and rutin.

[0069] The carotenoid may be either carotene (a carotenoid not containing oxygen) or xanthophyll (a carotenoid containing oxygen). Examples of carotenes include α-carotene, β-carotene, γ-carotene, δ-carotene, ε-carotene, and lycopene. Examples of xanthophyll include lutein, zeaxanthin, canthaxanthin, fucoxanthin, astaxanthin, antheraxanthin, violaxanthin, neoxanthin, α-cryptoxanthin, and β-cryptoxanthin. The carotenoid may be a carotenoid having antioxidant activity (e.g., lutein, lycopene, etc.), an immunostimulating activity, a carotenoid having a skin condition improving activity (e.g., astaxanthin, etc.), a carotenoid having a fatigue recovery activity (e.g., astaxanthin, etc.), or a carotenoid having a brain function improving activity (e.g., astaxanthin, etc.). Preferred carotenoids having an effect of enhancing the immunostimulating ability of bacteria having immunostimulating ability are lutein, astaxanthin, and paprika xanthophyll.

[0070] The xanthine compound may be, for example, xanthine, caffeine, paraxanthine, theophylline, theobromine, hypoxanthine, etc. Caffeine is preferred as a xanthine compound having an effect of enhancing the immunostimulating ability of bacteria having immunostimulating ability.

[0071] The quinone compound may be, for example, coenzyme Q10 (ubiquinone) and pyrroloquinoline quinone, etc. Preferred quinone compounds having an effect of enhancing the immunostimulating ability of bacteria having immunostimulating ability are coenzyme Q10 and pyrroloquinoline quinone.

[0072] The choline compound may be, for example, citicoline (choline cytidinediol), glycerophosphocholine, phosphocholine, phosphatidylcholine (lecithin) and sphingomyelin.The choline compound may be a choline compound having memory improving effect (for example, citicoline, etc.), a choline compound having attention improving effect (for example, citicoline, etc.), a choline compound having cognitive function improving effect (for example, citicoline, glycerophosphocholine, etc.), a choline compound having anti-aging effect (for example, glycerophosphocholine, etc.), a choline compound having sleep improving effect (for example, glycerophosphocholine, etc.), or a choline compound having skin condition improving effect.Preferably, the choline compound having the immunopotentiating effect of bacteria with immunopotentiating ability is citicoline or glycerophosphocholine.

[0073] The sphingolipid may be a ceramide in which sphingosine and a fatty acid are bonded by an amide bond, or may be sphingomyelin in which phosphocholine or phosphoethanolamine is bonded to a ceramide.The sphingolipid may be a sphingolipid having memory-improving effects, a sphingolipid having attention-improving effects, a sphingolipid having cognitive function-improving effects, a sphingolipid having anti-aging effects, a sphingolipid having sleep-improving effects, or a sphingolipid having skin condition-improving effects (e.g., beet ceramide, pine ceramide, milk ceramide, etc.).The sphingolipid having the effect of enhancing the immunopotentiation of bacteria having immunopotentiating abilities is preferably ceramide, more preferably beet semirad, pine ceramide, and milk ceramide.

[0074] The phospholipid may be a glycerophospholipid (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, etc.) or a sphingophospholipid (e.g., sphingomyelin, etc.). The phospholipid may be a phospholipid having a memory-improving effect (e.g., phosphatidylserine, etc.), a phospholipid having an attention-improving effect (e.g., phosphatidylserine, etc.), a phospholipid having a cognitive function-improving effect (e.g., phosphatidylserine, etc.), a phospholipid having an anti-aging effect, a phospholipid having a sleep-improving effect, or a phospholipid having a skin condition-improving effect. A preferred phospholipid having an effect of enhancing the immunostimulatory activity of immunostimulatory bacteria is phosphatidylserine.

[0075] The fatty acids may be medium-chain fatty acids having 6 to 12 carbon atoms (e.g., caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, and lauric acid), long-chain fatty acids having 13 to 21 carbon atoms (e.g., myristic acid, pentadecylic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, eleostearic acid, arachidic acid, mead acid, arachidonic acid, and eicosapentaenoic acid), or very long-chain fatty acids having 22 or more carbon atoms (e.g., docosahexaenoic acid). The fatty acids may be saturated or unsaturated fatty acids (e.g., monounsaturated fatty acids, polyunsaturated fatty acids, ω-3 fatty acids, ω-6 fatty acids, etc.). The fatty acids may have one or more hydroxyl groups (e.g., 3-hydroxyisovaleric acid, etc.). Fatty acids having an effect of enhancing the immunostimulating ability of bacteria having immunostimulating ability are preferably eicosapentaenoic acid, docosahexaenoic acid, a mixture thereof, and 3-hydroxyisovaleric acid.

[0076] The sulfite may be a food additive (e.g., sodium sulfite, potassium pyrosulfite, sodium pyrosulfite, etc.) that has antioxidant activity and is used to maintain the quality and appearance of food. Potassium pyrosulfite is preferred as the sulfite that has an effect of enhancing the immunostimulatory activity of bacteria having immunostimulatory activity.

[0077] Dolomite is a mineral that contains primarily calcium and magnesium, and may also contain minerals. Its chemical composition is CaMg(CO ３ ) ２ Dolomite is used not only as a building material and mineral, but also as a food ingredient. As a food ingredient, dolomite is sometimes ingested for the purposes of improving mood and lowering blood pressure.

[0078] Commercially available chlorogenic acid products can be used, for example, "Chlorogenic Acid" manufactured by Tokyo Chemical Industry Co., Ltd. Commercially available catechin products can be used, for example, "(-)-Catechin, Green Tea Derived" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Lychee polyphenols can be prepared by gently boiling lychee or its extract together with green tea or fresh tea leaves containing a large amount of low-molecular-weight catechins in an acidic aqueous solution for 2 to 3 hours, thereby fragmenting proanthocyanidins into low-molecular-weight proanthocyanidin oligomers in which catechins are bound to the terminals; for example, "Oligonol (registered trademark)" manufactured by Amino Up Co., Ltd. can be used. Black soybean polyphenols can be extracted using, for example, a method of immersing raw or dried black soybean seed coats (either in their original form, or in a coarse, shredded, crushed, or pulverized form) in an aqueous solvent; a method of extracting while stirring as needed; or a method using percolation, etc., and for example, Fujicco's "Chronocare SP60" can be used. Black soybean seed coat polyphenols can be extracted from black soybean seed coats using acid water, concentrated, neutralized, and then desalted and concentrated using an ultrafiltration membrane, and for example, "Kuromanin (registered trademark)-10" manufactured by Material Function Research Institute can be used. Theaflavins can be widely available commercially, and for example, "Theaflavin" manufactured by Tokyo Chemical Industry Co., Ltd. can be used. Black currant polyphenols can be a deep purple powder extracted and purified by water extraction (membrane concentration) from European black currant fruit, and for example, Meiji Food Materials' "Meiji Cassis Polyphenol (AC10)" can be used. The hesperidin is not necessarily limited to highly purified hesperidin, but may be a mixture of hesperidin and a flavonoid glycoside, or an extract derived from various plants containing hesperidin. Hesperidin may also be used which has been converted into α-glycosyl hesperidin using a hesperidin-transferase and which has significantly increased water solubility, and for example, "Hayashibara Hesperidin (registered trademark) S" manufactured by Hayashibara may be used.As for methyl hesperidin, for example, a mixed component obtained by treating natural hesperidin with dimethyl sulfate can be used, such as "Methyl Hesperidin" manufactured by Alps Pharmaceutical Co., Ltd. As for curcumin, a solution prepared by extracting turmeric powder prepared by crushing dried turmeric rhizomes with aqueous alcohol and removing the residue by solid-liquid separation and / or the adjusted solution can be dried and powdered, such as "Powdered Curcumin" manufactured by San-Ei Gen F.F.I. Rutin can be purified by contacting a solution containing α-glycosylglycyrrhizin and glycyrrhizin with a synthetic resin adsorbent having a macroreticular structure and intermediate polarity or non-polarity under acidic and heated conditions, allowing α-glycosylglycyrrhizin and glycyrrhizin to be adsorbed onto the synthetic resin adsorbent, and then desorbing the α-glycosylglycyrrhizin from the synthetic resin adsorbent using alkaline water, an alkaline organic solvent, an alkaline aqueous organic solvent, an aqueous organic solvent, or an organic solvent; for example, "αG Rutin" manufactured by Toyo Sugar Refining Co., Ltd. can be used. Lutein can be extracted from marigold with an organic solvent, particularly a non-polar solvent such as hexane; for example, products manufactured by Taiyo Kagaku Co., Ltd. can be used. Astaxanthin can be extracted, for example, by culturing Haematococcus algae, separating them by filtration, centrifugation, or the like, to collect the microalgae cells, followed by drying and crushing, followed by extraction using an organic solvent or edible oil or fat, or by physical extraction, such as squeezing the dried green algae. For example, Biogenic's "Astabio AW1" can be used. Paprika xanthophyll can be extracted from red peppers, purified, deodorized, and formulated, for example, Glyco Nutrition's "PapriX (registered trademark)." Caffeine can be commercially available products, such as Fujifilm Wako Pure Chemical's "Caffeine Anhydrous." Commercially available coenzyme Q10 can be used, for example, PetroEuroAsia's "ShiroQ (registered trademark)," which contains 40% or more of Kaneka's reduced coenzyme Q10.There are no particular limitations on the method of obtaining pyrroloquinoline quinone, and it may be naturally derived from animals or plants, or obtained by chemical synthesis or fermentation. A suitable method for producing pyrroloquinoline quinone and its salts can be appropriately selected based on the purity and production cost of the resulting pyrroloquinoline quinone. Furthermore, commercially available pyrroloquinoline quinone and its salts can be used. Examples of such commercially available products include "BioPQQ (registered trademark)" manufactured by Mitsubishi Gas Chemical Company. β-cryptoxanthin can be obtained by enzymatically treating the juice residue of Satsuma mandarins, removing as much water-soluble components as possible, and powdering the resulting product. For example, "β-cryptoxanthin (enzyme-treated Satsuma mandarins)" manufactured by Daicel can be used. Lycopene can be derived from natural tomato extract, such as "Lyc-O-Mato 15%" manufactured by Sunbright. Citicoline (Citidine-5'-diphosphocholine (CDP-choline)) may be obtained by any production method. Examples of methods for producing citicoline include chemical synthesis (Japanese Patent Publication Nos. 39-6541, 42-1384, and 63-6558, etc.), and enzymatic methods using microbial cells such as yeast (Japanese Patent Publication Nos. 48-2358, 48-40757, and 48-40758, Japanese Patent Laid-Open Nos. 53-109996, 54-14593, and 63-313594, etc.). Commercially available citicoline may also be used, such as "Cognitin" manufactured by Kyowa Hakko Bio. Glycerophosphocholine can be obtained, for example, by deacylation of animal or plant phosphatidylcholine. Deacylation can be performed by, but is not limited to, an enzymatic method (e.g., enzymatic reaction with phospholipase) or a chemical method (e.g., alkaline saponification decomposition). Glycerophosphocholine is an extremely safe material that has been widely used in food, and any glycerophosphocholine may be used as long as it meets the objectives of the present invention, including salts, hydrates, and solvates.Glycerophosphocholine is an extremely safe material with ample dietary experience, and may be in the form of a salt, hydrate, or solvate. The glycerophosphocholine of the present invention can preferably be "Neoliquid GPC85" manufactured by NOF Corp. or the like. Phosphatidylserine can be extracted, for example, from natural soybeans. For example, phosphatidylserine produced by base exchange of a plant-derived phospholipid fraction according to the method disclosed in Japanese Patent Laid-Open Publication No. 2002-218991 can be used, and examples thereof include "Nichiyu PS50" manufactured by NOF Corp. and the like. Beet ceramide can be obtained, for example, by concentrating and / or adding water to an ethanol extract of sugar beet pulp (e.g., beet fiber) obtained by ethanol extraction, concentrating the resulting ethanol extract, adding pectinase to the concentrate to cause an enzymatic reaction, inactivating the enzyme, emulsifying, and spray-drying the resulting emulsion into a powder. For example, "Beet Ceramide EX-1" manufactured by Meiji Food Materials can be used. The method for producing pineapple ceramide is not particularly limited and can be selected appropriately depending on the purpose, and can include, for example, a pineapple preparation step, an extraction step, a precipitation / filtration step, a redissolution step, and a purification step, and, if necessary, a product prepared through other steps such as a filtration step and a concentration step can be used, for example, "Brightening Pineapple Emulsion" manufactured by Maruzen Pharmaceuticals.Milk ceramide is a mixture of milk phospholipids (lipids), carbohydrates, and proteins, characterized by containing milk-derived sphingomyelin. Examples of methods for preparing milk ceramide include a method in which butter serum or a butter serum powder reduced solution is adjusted to a pH of 4.0 to 5.0, calcium chloride is added to promote protein aggregation, the resulting precipitate is removed, and the supernatant is subjected to ultrafiltration or microfiltration to obtain a concentrate, which is then dried (Japanese Patent Publication No. 2007-89535); and a method in which buttermilk or a buttermilk powder reduced solution is adjusted to an acidic range, protein precipitates formed by isoelectric precipitation are removed, and the supernatant is subjected to microfiltration membrane treatment to obtain a concentrate, which is then dried (Japanese Patent Publication No. 3103218).Commercially available milk ceramides can be used, and for example, "Milk Ceramide MC-5" manufactured by Megmilk Snow Brand can be used.Potassium pyrosulfite used as a food additive can be used, for example, "Food Additive Potassium Metabisulfite" manufactured by Mercian. HMBCa (calcium 3-hydroxyisovalerate) can be a commercially available product, or one produced by a known chemical synthesis method can be used, for example, one manufactured by Kyowa Hakko Bio. EPA / DHA (eicosapentaenoic acid / docosahexaenoic acid) can be, for example, "DD Oil Type 2" manufactured by Nippon Suisan (refined fish oil containing 28% by mass of eicosapentaenoic acid and 12% by mass of docosahexaenoic acid).

[0079] The compound according to this embodiment has an effect of enhancing the immunostimulatory ability of bacteria when, in the presence of the compound, the IFN-α concentration measured by the above procedures (i') to (iv') is 1.01 times or more, 1.02 times or more, 1.03 times or more, 1.05 times or more, 1.08 times or more, 1.10 times or more, 1.13 times or more, 1.15 times or more, 1.18 times or more, 1.20 times or more, 1.23 times or more, 1.24 times or more, 1.25 times or more, 1.26 times or more, 1.27 times or more, 1.28 times or more, 1.29 times or more, 1.30 times or more, 1.31 times or more, 1.32 times or more, 1.33 times or more, 1.34 times or more, 1.35 times or more, 1.36 times or more, 1.37 times or more, 1.38 times or more, 1.39 times or more, 1.40 times or more, 1.41 times or more, 1.42 times or more, 1.43 times or more, 1.44 times or more, 1.45 times or more, 1.46 times or more, 1.47 times or more, 1.48 times or more, 1.49 times or more, 1.50 times or more, 1.51 times or more, 1.52 times or more, 1.53 times or more, 1.54 times or more, 1.55 times or more, 1.56 times or more, 1.57 times or more, 1.58 times or more, 1.59 times or more, 1.60 times or more, 1.61 times or more, 1.62 times or more, 1.63 times or more, Preferably, the ratio is 2.5 or more, 1.28 or more, 1.30 or more, 1.40 or more, 1.50 or more, 1.60 or more, 1.70 or more, 1.80 or more, 1.90 or more, or 2.0 or more, and the upper limit is preferably 4.0 or less, 3.8 or less, 3.5 or less, 3.3 or less, 3.0 or less, 2.8 or less, 2.5 or less, 2.3 or less, 2.0 or less, 1.80 or less, or 1.50 or less. These upper and lower limits can be combined in any desired manner. The effect of enhancing the immunostimulatory ability of bacteria in the compound according to this embodiment is such that, in the presence of the compound, the IFN-α concentration measured by the above procedures (i') to (iv') is, for example, 1.01 to 4.0 times, 1.01 to 4.0 times, 1.01 to 3.8 times, 1.01 to 3.5 times, 1.01 to 3.3 times, 1.01 to 3.0 times, 1.01 to 2.8 times, 1.01 to 2.5 times, 1.01 to 2.3 times, 1.01 to 2.0 times, 1.01 to 1.8 times, 1.01 to 1.5 times, 1.02 to 4.0 times, 1.02 to 3.8 times, 1.02 to 4.0 times, 1.02 to 3.8 times, 1.02 to 5.0 times, 1.02 to 6.0 times, 1.02 to 7.0 times, 1.02 to 8.0 times, 1.02 to 9.0 times, 1.02 to 10.0 times, 1.02 to 11.0 times, 1.02 to 12.0 times, 1.02 to 13.0 times, 1.02 to 14.0 times, 1.02 to 15.0 times, 1.02 to 16.0 times, 1.02 to 17.0 times, 1.02 to 18.0 times, 1.02 to 20.0 times, 1.02 to 21.0 times, 1.02 to 22.0 times, 1.02 to 23.0 times, 1.02 to 24.0 times, 1.02 to 25.0 times, 1.02 to 02 times or more and 3.5 times or less, 1.02 times or more and 3.3 times or less, 1.02 times or more and 3.0 times or less, 1.02 times or more and 2.8 times or less, 1.02 times or more and 2.5 times or less, 1.02 1.02 times or more and 2.0 times or less, 1.02 times or more and 1.8 times or less, 1.02 times or more and 1.5 times or less, 1.03 times or more and 4.0 times or less, 1.03 times or more 3.8 times or less, 1.03 times or more and 3.5 times or less, 1.03 times or more and 3.3 times or less, 1.03 times or more and 3.0 times or less, 1.03 times or more and 2.8 times or less, 1.03 times or more and 2.5 times 1.03 times or more and 2.3 times or less, 1.03 times or more and 2.0 times or less, 1.03 times or more and 1.8 times or less, 1.02 times or more and 1.5 times or less, 1.05 times or more and 4.0 times or less,1.05 times to 3.8 times, 1.05 times to 3.5 times, 1.05 times to 3.3 times, 1.05 times to 3.0 times, 1.05 times to 2.8 times, 1.05 times to 2.5 times, 1.05 times to 2.3 times, 1.05 times to 2.0 times, 1.05 times to 1.8 times, 1.05 times to 1.5 times, 1.08 times to 4.0 times, 1.08 times to 3.8 times, 1.08 times to 3.5 times, 1.08 times to 3.3 times, 1.08 times to 3.0 times, 1.08 times to 2.8 times, 1.08 times to 2.5 times, 1.08 times to 2.3 times Below, 1.08 times to 2.0 times, 1.08 times to 1.8 times, 1.08 times to 1.5 times, 1.10 times to 4.0 times, 1.10 times to 3.8 times, 1.10 times to 3.5 times, 1.10 times to 3.3 times, 1.10 times to 3.0 times, 1.10 times to 2.8 times, 1.10 times to 2.5 times, 1.10 times to 2.3 times, 1.10 times to 2.0 times, 1.10 times to 1.8 times, 1.10 times to 1.5 times, 1.13 times to 4.0 times, 1.13 times to 3.8 times, 1.13 times to 3.5 times, 1.13 times and above. Below 3.3 times, 1.13 to 3.0 times, 1.13 to 2.8 times, 1.13 to 2.5 times, 1.13 to 2.3 times, 1.13 to 2.0 times, 1.13 to 1.8 times, 1.13 to 1.5 times, 1.15 to 4.0 times, 1.15 to 3.8 times, 1.15 to 3.5 times, 1.15 to 3.3 times, 1.15 to 3.0 times, 1.15 to 2.8 times, 1.15 to 2.5 times, 1.15 to 2.3 times, 1.15 to 2.0 times, 1.15 to 1.8 times, 1.15 times... The following are considered high-risk bets: 1.18 to 4.0 times, 1.18 to 3.8 times, 1.18 to 3.5 times, 1.18 to 3.3 times, 1.18 to 3.0 times, 1.18 to 2.8 times, 1.18 to 2.5 times, 1.18 to 2.3 times, 1.18 to 2.0 times, 1.18 to 1.8 times, 1.18 to 1.5 times, 1.20 to 4.0 times, 1.20 to 3.8 times, 1.20 to 3.5 times, 1.20 to 3.3 times, 1.20 to 3.0 times, and 1.20 to 2.8 times.1.20 times to less than 2.5 times, 1.20 times to less than 2.3 times, 1.20 times to less than 2.0 times, 1.20 times to less than 1.8 times, 1.20 times to less than 1.5 times, 1.23 times to less than 4.0 times, 1.23 times to less than 3.8 times, 1.23 times to less than 3.5 times, 1.23 times to less than 3.3 times, 1.23 times to less than 3.0 times, 1.23 times to less than 2.8 times, 1.23 times to less than 2.5 times, 1.23 times to less than 2.3 times, 1.23 times to less than 2.0 times, 1.23 times to less than 1.8 times, 1.23 times to less than 1.5 times, 1.25 times to less than 4.0 times, 1.25 times to more than 3.8 times. Below 1.25 times, 1.25 times to 3.5 times, 1.25 times to 3.3 times, 1.25 times to 3.0 times, 1.25 times to 2.8 times, 1.25 times to 2.5 times, 1.25 times to 2.3 times, 1.25 times to 2.0 times, 1.25 times to 1.8 times, 1.25 times to 1.5 times, 1.28 times to 4.0 times, 1.28 times to 3.8 times, 1.28 times to 3.5 times, 1.28 times to 3.3 times, 1.28 times to 3.0 times, 1.28 times to 2.8 times, 1.28 times to 2.5 times, 1.28 times to 2.3 times, 1.28 times and above. Below 2.0 times, 1.28 times to below 1.8 times, 1.28 times to below 1.5 times, 1.30 times to below 4.0 times, 1.30 times to below 3.8 times, 1.30 times to below 3.5 times, 1.30 times to below 3.3 times, 1.30 times to below 3.0 times, 1.30 times to below 2.8 times, 1.30 times to below 2.5 times, 1.30 times to below 2.3 times, 1.30 times to below 2.0 times, 1.30 times to below 1.8 times, 1.30 times to below 1.5 times, 1.40 times to below 4.0 times, 1.40 times to below 3.8 times, 1.40 times to below 3.5 times, 1.40 times to below 3.3 times, 1.4 0 to 3.0 times, 1.40 to 2.8 times, 1.40 to 2.5 times, 1.40 to 2.3 times, 1.40 to 2.0 times, 1.40 to 1.8 times, 1.40 to 1.5 times, 1.50 to 4.0 times, 1.50 to 3.8 times, 1.50 to 3.5 times, 1.50 to 3.3 times, 1.50 to 3.0 times, 1.50 to 2.8 times, 1.50 to 2.5 times, 1.50 to 2.3 times, 1.50 to 2.0 times, 1.50 to 1.8 times, 1.60 to 4.0 times.1.60 times to 3.8 times, 1.60 times to 3.5 times, 1.60 times to 3.3 times, 1.60 times to 3.0 times, 1.60 times to 2.8 times, 1.60 times to 2.5 1.60 times or more and 2.3 times or less, 1.60 times or more and 2.0 times or less, 1.60 times or more and 1.8 times or less, 1.70 times or more and 4.0 times or less, 1.70 times or more and 3.8 times or less, 1.70 times or less 3.5 times or less, 1.70 times or more and 3.3 times or less, 1.70 times or more and 3.0 times or less, 1.70 times or more and 2.8 times or less, 1.70 times or more and 2.5 times or less, 1.70 times or more and 2.3 times or less, 1. 70 times to 2.0 times, 1.70 times to 1.8 times, 1.80 times to 4.0 times, 1.80 times to 3.8 times, 1.80 times to 3.5 times, 1.80 times to 3.3 times Lower, 1.80 times to 3.0 times, 1.80 times to 2.8 times, 1.80 times to 2.5 times, 1.80 times to 2.3 times, 1.80 times to 2.0 times, 1.90 times to 4 .0 times or less, 1.90 times or more and 3.8 times or less, 1.90 times or more and 3.3 times or less, 1.90 times or more and 3.0 times or less, 1.90 times or more and 2.8 times or less, 1.90 Preferably, the ratio is 1.90 to 2.3 times, 1.90 to 2.0 times, 2.00 to 4.0 times, 2.00 to 3.8 times, 2.00 to 3.5 times, 2.00 to 3.3 times, 2.00 to 3.0 times, 2.00 to 2.8 times, 2.00 to 2.5 times, or 2.00 to 2.3 times.

[0080] The content of the compound in the composition for immunostimulation according to one embodiment can be, for example, a lower limit of 0.000001% by mass or more, 0.00001% by mass or more, 0.001% by mass or more, 0.01% by mass or more, 0.02% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1% by mass or more, or 2% by mass or more, and an upper limit of 90.0% by mass or more, based on the total amount of the composition for immunostimulation. %, 85.0% by mass or less, 80.0% by mass or less, 75.0% by mass or less, 50.0% by mass or less, 25.0% by mass or less, 10.0% by mass or less, 5.0% by mass or less, 1.0% by mass or less, 0.80% by mass or less, 0.50% by mass or less, 0.30% by mass or less, 0.25% by mass or less, 0.20% by mass or less, 0.10% by mass or less, 0.05% by mass or less, 0.02% by mass or less, or 0.01% by mass or less. These upper and lower limits can be combined in any desired manner. The content of the compound in the immunostimulating composition according to one embodiment is, for example, 0.000001% by mass to 90.0% by mass, 0.000001% by mass to 85.0% by mass, 0.000001% by mass to 80.0% by mass, 0.000001% by mass to 75.0% by mass, 0.000001% by mass to 50.0% by mass, 0.000001% by mass to 25.0% by mass, 0.000001% by mass to 10.0% by mass, 0.000001% by mass to 5.0% by mass, 0.000001% by mass to 1.0% by mass, 0.000001% by mass to 0.80% by mass, or 0.000001% by mass to 0.50% by mass, relative to the total amount of the immunostimulating composition. % or less, 0.000001 mass% or more and 0.30 mass% or less, 0.000001 mass% or more and 0.25 mass% or less, 0.000001 mass% or more and 0.20 mass% or less, 0 000001 mass% or more and 0.10 mass% or less, 0.000001 mass% or more and 0.05 mass% or less, 0.000001 mass% or more and 0.02 mass% or less, 0.0000 01 mass% or more and 0.01 mass% or less, 0.00001 mass% or more and 90.0 mass% or less, 0.00001 mass% or more and 85.0 mass% or less, 0.00001 mass% or more8 0.0 mass% or less, 0.00001 mass% or more and 75.0 mass% or less, 0.00001 mass% or more and 50.0 mass% or less, 0.00001 mass% or more and 25.0 mass% or less,0.00001% to 10.0% of mass, 0.00001% to 5.0% of mass, 0.00001% to 1.0% of mass, 0.00001% to 0.80% of mass, 0.00001% to 0.50% of mass, 0.00001% to 0.30% of mass, 0.00001% to 0.25% of mass, 0.00001% to 0.20% of mass, 0.00001% to 0.10% of mass, 0.00001% to 0.05% of mass, 0.00001% to 0.02% of mass, 0.00001% of mass... 0.01% to 0.01% of mass, 0.001% to 90.0% of mass, 0.001% to 85.0% of mass, 0.001% to 80.0% of mass, 0.001% to 75.0% of mass, 0.001% to 50.0% of mass, 0.001% to 25.0% of mass, 0.001% to 10.0% of mass, 0.001% to 5.0% of mass, 0.001% to 1.0% of mass, 0.001% to 0.80% of mass, 0.001% to 0.50% of mass, 0.001% to 0.30% of mass. 0.001% to 0.25% of mass, 0.001% to 0.20% of mass, 0.001% to 0.10% of mass, 0.001% to 0.05% of mass, 0.001% to 0.02% of mass, 0.001% to 0.01% of mass, 0.01% to 90.0% of mass, 0.01% to 85.0% of mass, 0.01% to 80.0% of mass, 0.01% to 75.0% of mass, 0.01% to 50.0% of mass, 0.01% to 25.0% of mass, 0.01% to 10.0% of mass. Less than 1% of mass, 0.01% to 5.0% of mass, 0.01% to 1.0% of mass, 0.01% to 0.80% of mass, 0.01% to 0.50% of mass, 0.01% to 0.30% of mass, 0.01% to 0.25% of mass, 0.01% to 0.20% of mass, 0.01% to 0.10% of mass, 0.01% to 0.05% of mass, 0.01% to 0.02% of mass, 0.02% to 90.0% of mass, 0.02% to 85.0% of mass, 0.02% to 80.0% of mass.0.02% to 75.0% by mass, 0.02% to 50.0% by mass, 0.02% to 25.0% by mass, 0.02% to 10.0% by mass, 0.02% to 5.0% by mass, 0.02% to 1.0% by mass, 0.02% to 0.80% by mass, 0.02% to 0.50% by mass, 0.02% to 0.30% by mass, 0.02% to 0.25% by mass, 0.02% to 0.20% by mass, 0.02% to 0.10% by mass, 0.02% to 0.05% by mass, 0.05% by mass. Quality percentage above 90.0% and below 90.0%; 0.05% and above 85.0% and below 80.0%; 0.05% and above 75.0% and below 75.0%; 0.05% and above 50.0% and below 50.0%; 0.05% and above 25.0% and below 25.0%; 0.05% and above 10.0% and below 10.0%; 0.05% and above 5.0% and below 1.0%; 0.05% and above 0.80% and below 0.05% and below 0.50%; 0.05% and above 0.30% and below 0.05% and below 0.25%; 0.05% and below 10.0% of the total mass. Above 0.20% by mass, 0.05% by mass and below 0.10% by mass, 0.10% by mass and below 90.0% by mass, 0.10% by mass and below 85.0% by mass, 0.10% by mass and below 80.0% by mass, 0.10% by mass and below 75.0% by mass, 0.10% by mass and below 50.0% by mass, 0.10% by mass and below 25.0% by mass, 0.10% by mass and below 10.0% by mass, 0.10% by mass and below 5.0% by mass, 0.10% by mass and below 1.0% by mass, 0.10% by mass and below 0.80% by mass, 0.10% by mass and below 0.50% by mass, 0.10% by mass and above 0.3% by mass. Less than 0% by mass, 0.10% to 0.25% by mass, 0.10% to 0.20% by mass, 0.50% to 90.0% by mass, 0.50% to 85.0% by mass, 0.50% to 80.0% by mass, 0.50% to 75.0% by mass, 0.50% to 50.0% by mass, 0.50% to 25.0% by mass, 0.50% to 10.0% by mass, 0.50% to 5.0% by mass, 0.50% to 1.0% by mass, 0.50% to 0.80% by mass, 1% to 90.0% by mass.1% or more of quality, less than 85.0% of quality; 1% or more of quality, less than 80.0% of quality; 1% or more of quality, less than 75.0% of quality; 1% or more of quality, less than 50.0% of quality; 1% or more of quality, less than 25.0% of quality; 1% or more of quality, less than 10.0% of quality; 1% or more of quality, less than 5.0% of quality; 2% or more of quality, less than 90.0% of quality; 2% or more of quality, less than 85.0% of quality; 2% or more of quality, less than 80.0% of quality; 2% or more of quality, less than 75.0% of quality; 2% or more of quality, less than 50.0% of quality; 2% or more of quality, less than 25.0% of quality; 2% or more of quality, less than 10.0% of quality; 2% or more of quality, less than 5.0% of quality.

[0081] The ratio of the content (% by mass) of the bacteria having immunostimulatory ability to the content (% by mass) of the compound in the immunostimulatory composition according to one embodiment ((content of the bacteria having immunostimulatory ability) / (content of the compound)) can have a lower limit of, for example, 0.001 or more, 0.003 or more, 0.005 or more, 0.01 or more, 0.015 or more, 0.02 or more, 0.025 or more, 0.03 or more, or 1.0 or more; and the upper limit can be 50,000 or less, 10,000 or less, 1,000 or less, 500 or less, 100 or less, 50 or less, 10 or less, 5 or less, 1.0 or less, 0.75 or less, 0.5 or less, or 0.3 or less. These upper and lower limits can be combined in any desired manner. The ratio of the content (mass %) of bacteria having immunostimulatory ability to the content (mass %) of the compound in the composition for immunostimulation according to one embodiment ((content of bacteria having immunostimulatory ability) / (content of compound)) is, for example, 0.001 or more and 50,000 or less, 0.001 or more and 10,000 or less, 0.001 or more and 1,000 or less, 0.001 or more and 500 or less, 0.001 or more and 100 or less, 0.001 or more and ... 50 or less, 0.001 or more and 10 or less, 0.001 or more and 5 or less, 0.001 or more and 1.0 or less, 0.001 or more and 0.75 or less, 0.001 or more and 0.5 or less, 0.001 or more and 0.3 or less, 0.003 50,000 or more, 0.003 to 10,000, 0.003 to 1,000, 0.003 to 500, 0.003 to 100, 0.003 to 50, 0.003 to 10 Lower, 0.003 to 5, 0.003 to 1.0, 0.003 to 0.75, 0.003 to 0.5, 0.003 to 0.3, 0.005 to 50000, 0.005 10000 or more, 0.005 or more and 1000 or less, 0.005 or more and 500 or less, 0.005 or more and 100 or less, 0.005 or more and 50 or less, 0.005 or more and 10 or less, 0.005 or more and 5 or less, 0. 005 to 1.0, 0.005 to 0.75, 0.005 to 0.5, 0.005 to 0.3, 0.01 to 50,000, 0.01 to 10,000, 0.01 to 1 000 or less, 0.01 or more and 500 or less, 0.01 or more and 100 or less, 0.01 or more and 50 or less, 0.01 or more and 10 or less, 0.01 or more and 5 or less, 0.01 or more and 1.0 or less, 0.01 or more and 0.75 or less,0.01 to 0.5, 0.01 to 0.3, 0.015 to 50,000, 0.015 to 10,000, 0.015 to 1,000, 0.015 to 500, 0.015 to 100 The following: 0.015 to 50, 0.015 to 10, 0.015 to 5, 0.015 to 1.0, 0.015 to 0.75, 0.015 to 0.5, 0.015 to 0.3, 0.02 to 50,000, 0.02 to 10,000, 0.02 to 1,000, 0.02 to 500, 0.02 to 100, 0.02 to 50, 0.02 to 10, 0.02 5 or more, 0.02 or more and 1.0 or less, 0.02 or more and 0.75 or less, 0.02 or more and 0.5 or less, 0.02 or more and 0.3 or less, 0.025 or more and 50,000 or less, 0.025 or more and 10,000 or less, and 0.025 or more Above 1000, 0.025 to 500, 0.025 to 100, 0.025 to 50, 0.025 to 10, 0.025 to 5, 0.025 to 1.0, 0.025 to 0. 75 or less, 0.025 or more and 0.5 or less, 0.025 or more and 0.3 or less, 0.03 or more and 50,000 or less, 0.03 or more and 10,000 or less, 0.03 or more and 1,000 or less, 0.03 or more and 500 or less, 0.03 or more and 1 00 or less, 0.03 or more and 50 or less, 0.03 or more and 10 or less, 0.03 or more and 5 or less, 0.03 or more and 1.0 or less, 0.03 or more and 0.75 or less, 0.03 or more and 0.5 or less, 0.03 or more and 0.3 or less, 1.0 or more and 50,000 or less, 1.0 or more and 10,000 or less, 1.0 or more and 500 or less, 1.0 or more and 100 or less, 1.0 or more and 50 or less, 1.0 or more and 1 ... or less.

[0082] The immunostimulatory composition according to one embodiment may be a food (including a beverage), a drug, or a quasi-drug. The food, drug, or quasi-drug can each be produced according to a conventional method. The content of the bacteria and compounds having immunostimulatory ability in the food, drug, or quasi-drug is not particularly limited and can be freely set depending on the purpose.

[0083] When the immunostimulating composition according to one embodiment is a food, drug, or quasi-drug, the food, drug, or quasi-drug may contain, in addition to the bacteria and compounds having immunostimulatory activity, ingredients typically used in foods, drugs, or quasi-drugs. The food, drug, or quasi-drug according to one embodiment may contain bases, carriers, additives, etc. typically used in foods, drugs, or quasi-drugs. Examples of additives include excipients, oils, powders, buffers, solubilizers, antioxidants, surfactants, thickeners, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, antiseptics, pigments, colorants, fragrances, gloss-imparting agents, gelling agents, alcohols, water-soluble polymers, film-forming agents, resins, etc. The bases, carriers, and various additives described above may be used singly or in combination as needed.

[0084] When the immunostimulating composition according to one embodiment is a food product, examples of the food product include health foods, functional foods, nutritional compositions, dietary supplements, supplements, health foods, foods for specified health uses, foods with nutrient functions, and foods with functional claims. Such food compositions can be labeled, for example, as supporting the maintenance of immune function in healthy individuals (immune care), or suppressing immune function decline for individuals concerned about a decline in immune function. The immunostimulating composition according to one embodiment can also be used as a food additive.

[0085] Examples of such foods include seasonings, processed meat products, processed agricultural products, beverages (lactic acid bacteria drinks, soft drinks, alcoholic drinks, carbonated drinks, dairy drinks, fruit juice drinks, tea, coffee, energy drinks, etc.), powdered drinks (powdered juice, powdered soup, powdered milk, etc.), concentrated drinks, confectioneries (candy (throat lozenges), cookies, biscuits, gum, gummy candies, chewable tablets, tablets, chocolate, etc.), bread, cereal, etc. In addition, in the case of foods for specified health uses, foods with nutrient functions, foods with functional claims, etc., the foods may be in the form of capsules, granules, powders, syrups, lozenges, etc.

[0086] When the immunostimulating composition according to one embodiment is a pharmaceutical or quasi-drug, the pharmaceutical or quasi-drug may be in the form of, for example, a liquid, suspension, capsule, granule, pill, powder, tablet, syrup, lozenge, etc. Possible indications for the pharmaceutical include allergies, obesity, heart failure, etc.

[0087] The immunostimulatory composition according to one embodiment is preferably administered or ingested into the body. The mode of administration or ingestion may be oral administration or ingestion or parenteral administration or ingestion, with oral administration or ingestion being preferred. The immunostimulatory composition according to one embodiment may be administered or ingested only once or multiple times, and, if sustained immunostimulation is desired, is preferably administered or ingested continuously or intermittently over a certain period of time. The food composition according to one embodiment may be ingested, for example, 1 to 5 times a day, once every 2 days, once every 3 days, once every 4 days, or once a week for one week or more, two weeks or more, one month or more, three months or more, six months or more, one year or more, three years or more, five years or more, or ten years or more.

[0088] An immunostimulatory composition according to one embodiment is an immunostimulatory composition induced by bacteria having immunostimulatory ability, and comprises one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacteria. "Immunostimulation induced by bacteria having immunostimulatory ability" refers to immunostimulation induced depending on the ability of bacteria having immunostimulatory ability to activate immune cells.

[0089] An immunostimulating composition according to one embodiment is an immunostimulating composition or an immunostimulating composition with enhanced immunostimulating activity, which comprises a bacterium having immunostimulating activity and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, each of which has an effect of enhancing the immunostimulating activity of the bacterium. The immunostimulating composition or the immunostimulating composition with enhanced immunostimulating activity is preferred from the viewpoint that the addition of the compound enhances the immunostimulating activity of the bacterium.

[0090] [Enhancer of Immunostimulatory Activity Induced by Immunostimulatory Bacteria] A second embodiment of the present disclosure relates to an enhancer of immunostimulatory activity induced by immunostimulatory bacteria (hereinafter simply referred to as "enhancer"). One embodiment of the enhancer comprises a bacterium having immunostimulatory activity and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory activity of the bacterium. Another embodiment of the enhancer is an enhancer of immunostimulatory activity induced by immunostimulatory bacteria, and comprises one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory activity of the bacterium. The enhancer according to this embodiment has the effect of enhancing the immunostimulatory activity induced by the bacterium having immunostimulatory activity. That is, the enhancer according to this embodiment has enhanced immunopotentiating activity compared to an immunostimulating composition containing only bacteria having immunopotentiating ability.

[0091] In one embodiment, the enhancer has an ability to induce interferon α production in immune cells that is, for example, 1.01 times or more, 1.02 times or more, 1.03 times or more, 1.05 times or more, 1.08 times or more, 1.10 times or more, 1.13 times or more, 1.15 times or more, 1.18 times or more, 1.20 times or more, 1.23 times or more, 1.25 times or more, or 1.30 times or more, as a lower limit, compared to an immunostimulating composition containing only bacteria having immunostimulating ability. Preferably, the immunopotentiation ratio is 28-fold or more, 1.30-fold or more, 1.40-fold or more, 1.50-fold or more, 1.60-fold or more, 1.70-fold or more, 1.80-fold or more, 1.90-fold or more, or 2.0-fold or more, with the upper limit being preferably 4.0-fold or less, 3.8-fold or less, 3.5-fold or less, 3.3-fold or less, 3.0-fold or less, 2.8-fold or less, 2.5-fold or less, 2.3-fold or less, 2.0-fold or less, 1.8-fold or less, or 1.50-fold or less. These upper and lower limits can be arbitrarily combined, and may be the same as the ranges described for the bacterial immunopotentiating activity enhancing effect of the compound according to this embodiment.

[0092] As other specific aspects of the enhancer according to this embodiment, aspects of the immunostimulating composition according to this embodiment can be appropriately applied.

[0093] [Immunostimulating method, method for enhancing immunostimulating activity induced by bacteria having immunostimulating ability] A third embodiment of the present disclosure relates to an immunostimulating method and a method for enhancing immunostimulating activity induced by bacteria having immunostimulating ability (hereinafter also simply referred to as an "enhancing method"). The immunostimulating method and the enhancing method include administering or ingesting to a subject bacteria having immunostimulating ability and one or more compounds having an effect of enhancing the immunostimulating ability of the bacteria, selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites. The enhancing method according to this embodiment enhances immunostimulating activity compared to administering or ingesting only bacteria having immunostimulating ability.

[0094] The subject of the above method can be a human or a non-human mammal, preferably a human. Examples of non-human mammals include a mouse, rat, guinea pig, hamster, rabbit, cat, dog, sheep, pig, cow, horse, goat, and monkey.

[0095] The subject can be a subject in need of immunostimulation, and the subject in need of immunostimulation is not particularly limited, but examples include subjects infected with a virus, subjects wishing to prevent viral infection, subjects with a cold, subjects wishing to prevent colds, and subjects aged 65 or older.

[0096] Immunostimulatory bacteria and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacteria, can be administered or ingested by a subject, for example, in the form of the composition of the first embodiment described above. Typically, pharmaceutical compositions are expressed as "administered to a subject," and food compositions are expressed as "ingested by a subject," but these expressions both mean that the composition is taken into the body of the subject and are synonymous. Therefore, the two expressions are interchangeable and there is no essential difference between them.

[0097] [Method for producing a composition] A fourth embodiment of the present disclosure relates to a method for producing a composition for immunostimulation. This method is a method for producing a composition for immunostimulation or a composition for immunostimulation with enhanced immunostimulatory activity, which comprises adding to a bacterium having immunostimulatory activity one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory activity of the bacterium. The immunostimulatory composition or the immunostimulatory composition with enhanced immunostimulatory activity is preferable from the viewpoint that the addition of the compound enhances the immunostimulatory activity of the bacterium.

[0098] [Use of bacteria and compounds for producing a composition] A fifth embodiment of the present disclosure relates to the use of bacteria and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacteria, for producing a composition. One use aspect is the use of bacteria having immunostimulatory ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacteria, for producing a composition for immunostimulation. Another use aspect is the use of one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacteria, for producing a composition for immunostimulation induced by bacteria having immunostimulatory ability. Yet another use aspect is the use of bacteria having immunostimulatory ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacteria, for producing a composition for immunostimulation induced by the bacteria having immunostimulatory ability. The present invention relates to the use of one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory ability of the bacterium, for producing a composition for immunostimulation, the compounds being administered or ingested in combination with the bacterium having the above-mentioned function. Another use embodiment relates to the use of the bacterium having immunostimulatory ability, which has an effect of enhancing the immunostimulatory ability of the bacterium, for producing a composition for immunostimulation, the compounds being administered or ingested in combination with the bacterium having the above-mentioned function. Specific aspects of the composition for immunostimulation, the bacterium, and the compound according to this embodiment are as described above.

[0099] [Compound for Use] A sixth embodiment of the present disclosure relates to one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have an effect of enhancing the immunostimulatory activity of a bacterium having immunostimulatory activity, for use in immunostimulation induced by the bacterium. Specific aspects of the bacterium and compound according to this embodiment are as described above.

[0100] [Bacteria or Compound for Use in Therapeutic Methods] A seventh embodiment of the present disclosure relates to the use of a bacterium or compound for use in an immunostimulatory therapeutic method. In one aspect, the bacterium is an immunostimulatory bacterium administered or ingested in combination with one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacterium. In another aspect, the compound is one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacterium, and which are administered or ingested in combination with the bacterium. Specific aspects of the bacterium and compound according to this embodiment are as described above. In this disclosure, use in a "therapeutic" method refers to use in treating the subject's body. Use in a therapeutic method according to the present disclosure may be, for example, use for the purpose of or in conjunction with medical practice. Use in a therapeutic method according to the present disclosure may involve, for example, a medical professional administering or ingesting a substance to a human or animal, or instructing a human or animal to administer or ingest a substance. Use in a therapeutic method according to the present disclosure may be, for example, use for therapeutic or prophylactic purposes, or may be use for therapeutic purposes, or prophylactic purposes involving the ingestion of a food composition, or may be use for therapeutic purposes. Use in a therapeutic method according to the present disclosure may be, for example, use on an unhealthy individual.

[0101] [Use of Bacteria or Compounds in Non-Therapeutic Methods] The eighth embodiment of the present disclosure relates to the use of bacteria or compounds for use in non-therapeutic immunostimulatory methods. In one aspect, the use is a use of bacteria having immunostimulatory ability in a non-therapeutic immunostimulatory method, wherein the bacteria are administered or ingested in combination with one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacteria. In another aspect, the use is a use of one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory ability of the bacteria, wherein the bacteria are administered or ingested in combination with the bacteria having immunostimulatory ability. Specific aspects of the bacteria and compounds according to this embodiment are as described above. In this disclosure, use in a "non-therapeutic" method refers to the use of a substance that does not fall under the category of use in a therapeutic method. Use in non-therapeutic methods according to the present disclosure may be, for example, use that is not intended for and / or does not involve medical practice. Use in non-therapeutic methods according to the present disclosure may not involve, for example, a medical professional administering or having a substance ingested by a human or animal and / or instructing a human or animal to administer or ingest a substance. Use in non-therapeutic methods according to the present disclosure may be, for example, use for preventive or health promotion purposes, and may be use for preventive or health promotion purposes involving the administration or ingestion of a pharmaceutical composition or quasi-drug. Use in non-therapeutic methods according to the present disclosure may be, for example, use in healthy individuals.

[0102] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0103] [Experiment 1: Examination of the effects of various compounds on JCM5805-induced pDC activation and IFN-α production] In Experiment 1, we examined whether the compounds shown in Table 1 enhance or suppress JCM5805-induced pDC activation and IFN-α production, and whether the compounds shown in Table 2 enhance or suppress them at the concentrations listed in Table 2.

[0104] <1. Preparation of Lactic Acid Bacteria Suspension> JCM5805 bacteria were inoculated into 10 mL of MRS medium (Oxoid) and cultured at 30°C for 24 hours. Then, 1 mL of the cultured lactic acid bacteria cell suspension was inoculated into 100 mL of MRS medium and cultured at 30°C for 24 hours. The lactic acid bacteria were then collected, washed three times with sterile water, heat-sterilized at 80°C for 30 minutes, and freeze-dried to obtain heat-killed bacteria. The heat-killed bacteria were then adjusted to a concentration of 1 mg / mL with PBS (Takara Bio Inc.) to prepare a lactic acid bacteria suspension.

[0105] 2. Preparation of Compound Solutions Chlorogenic acid was manufactured by Tokyo Chemical Industry Co., Ltd., catechin was manufactured by Fujifilm Wako Pure Chemical Industries Co., Ltd., lychee polyphenol was "Oligonol (registered trademark)" manufactured by Amino Up Co., Ltd., black soybean polyphenol was "Chronocare SP60" manufactured by Fujicco Co., Ltd., black soybean seed coat polyphenol was "Kuromanin (registered trademark)-10" manufactured by Material Function Research Institute Co., Ltd., theaflavin was manufactured by Tokyo Chemical Industry Co., Ltd., black currant polyphenol was "Meiji Cassis Polyphenol (AC10)" manufactured by Meiji Food Materials Co., Ltd., resveratrol was "Resveratrol Water Soluble Solution 0.2%" manufactured by Yokohama Oil & Fat Industries Co., Ltd., methylhesperidin was manufactured by Alps Pharmaceutical Industry Co., Ltd., curcumin was "Powdered Curcumin" manufactured by San-Ei Gen F.F.I., and rutin was "αG Rutin" manufactured by Toyo Sugar Refining Co., Ltd. Lutein was "Sunactive LT-L112" manufactured by Taiyo Chemical, astaxanthin was "Astabio AW1" manufactured by Biogenic, paprika xanthophyll was "PapriX (registered trademark)" manufactured by Glyco Nutrition Foods, caffeine was "Caffeine Anhydrous" manufactured by Fujifilm Wako Pure Chemical Industries, coenzyme Q10 was "ShiroQ (registered trademark)" manufactured by PetroEuroAsia, and pyrroloquinoline quinone was "BioPQQ (registered trademark)" manufactured by Mitsubishi Gas Chemical. For citicoline, Kyowa Hakko Bio's "Cognitin" was used; for glycerophosphocholine, NOF's "Neo Liquid GPC85" was used; for phosphatidylserine, NOF's "Neo Liquid PS" was used; for beet ceramide, Meiji Food Materials' "Beet Ceramide EX-1" was used; for pine ceramide, Maruzen Pharmaceutical's "Brightening Pine Emulsion" was used; and for milk ceramide, Snow Brand Megmilk's "Milk Ceramide MC-5" was used. The potassium pyrosulfite used was "Food Additive Potassium Metabisulfite" manufactured by Mercian, the HMBCa (3-hydroxyisovalerate calcium) used was "HMBCa (3-hydroxyisovalerate calcium)" manufactured by Kyowa Hakko Bio, and the EPA / DHA (eicosapentaenoic acid / docosahexaenoic acid) used was "DD Oil Type 2" manufactured by Nippon Suisan (refined fish oil containing 28% by mass of eicosapentaenoic acid and 12% by mass of docosahexaenoic acid). The rosehip polyphenol used was "Rosehip Polyphenol MJ" manufactured by Morishita Jintan.For β-cryptoxanthin, Daicel's "β-cryptoxanthin (enzyme-treated Unshu mandarin orange)" was used, and for lycopene, Sunbright's "Lyc-O-Mato (registered trademark) 15%" was used. For dolomite, Kyowa Hakko Bio's "Dolomite" was used. These compounds were adjusted to 400 μg / ml with PBS to prepare compound solutions. Note that for Table 2, compound solutions were prepared so that the compound concentrations were 400, 40, 4, 0.4, or 0.04 μg / ml.

[0106] 3. Test Procedure The test was carried out according to the following procedures (i) to (iv): (i) Bone marrow cells derived from female BALB / c mice were cultured at a concentration of 1 x 10 in RPMI medium (Sigma Corporation) prepared so that the components listed below (Culture medium composition) were added to the final concentrations listed below (Culture medium composition). ６ (ii) 1 mL of the prepared cell suspension was seeded on the cells, and the cells were suspending at a concentration of 10 cells / mL to prepare a cell suspension. (Culture medium composition) 10% by volume FBS 100 U / mL penicillin / streptomycin 1 mM sodium pyruvate 2.5 mM HEPES 1% by mass non-essential amino acids for MEM (NEAA) 50 μM β-mercaptoethanol 100 ng / mL Flt-3L ２ Incubated at 37°C and 5% CO ２ (iii) The bone marrow cells containing the induced pDCs were cultured at 2 × 10 ５ The cells were suspended at a concentration of 100 cells / mL and seeded in 200 μL aliquots onto a 96-well plate. 2 μL of the JCM5805 suspension described in 1 above was added, and simultaneously 5 μL of the compound solution described in 2 above was added. Similarly, to a 96-well plate seeded with bone marrow cells containing pDC, only the compound solution was added. Similarly, to a 96-well plate seeded with bone marrow cells containing pDC, only the JCM5805 suspension was added. (iv) After 24 hours, the culture supernatant was collected, and the IFN-α concentration was measured using an IFN-α measurement kit (PBL Assay Science Ltd.).

[0107] The amount of IFN-α produced in the presence of each substance is shown in the table below relative to the amount of IFN-α produced when JCM5805 suspension was used alone, which was set at 1. The concentration of each substance in the table means the final concentration.

[0108]

[0109]

[0110] When any of the substances was used alone, IFN-α production by pDC was not induced. Rosehip polyphenols, β-cryptoxanthin, lycopene, and dolomite suppressed JCM5805-induced pDC IFN-α production, while chlorogenic acid, catechin, lychee polyphenols, black soybean polyphenols, black soybean seed coat polyphenols, theaflavin, black currant polyphenols, hesperidin, resveratrol, methylhesperidin, curcumin, rutin, lutein, astaxanthin, paprika xanthophyll, caffeine, coenzyme Q10, pyrroloquinoline quinone, citicoline, glycerophosphocholine, phosphatidylserine, beet ceramide, pine ceramide, milk ceramide, potassium metabisulfite, HMBCa, and EPA / DHA enhanced JCM5805-induced pDC IFN-α production. Furthermore, it was confirmed that chlorogenic acid, lychee polyphenols, black soybean polyphenols, theaflavin, black currant polyphenols, lutein, caffeine, and citicoline enhanced IFN-α production by pDC induced by JCM5805, even when the concentrations were changed.

[0111] [Experiment 2: Examination of the effects of chlorogenic acid on pDC activation and IFN-α production induced by various lactic acid bacteria or bifidobacteria]

[0112] In Experiment 2, we investigated whether chlorogenic acid enhances pDC activation and IFN-α production induced by lactic acid bacteria or bifidobacteria other than JCM5805.

[0113] <1. Preparation of lactic acid bacteria suspension> Lactococcus culbatus JCM1096, Lactococcus lactis subsp. lactis ATCC7962, Lactobacillus paraplantarum JCM1149 (Lactiplantibacillus paraplantarum JCM1149) were inoculated into 10 mL of MRS medium (Becton Dickinson and Company) and cultured for 24 hours at 30 ° C. Then, 1 mL of the cultured lactic acid bacteria cell culture was inoculated into 100 mL of MRS medium and cultured for 24 hours at 30 ° C. Subsequently, the lactic acid bacteria were collected, washed three times with sterilized water, and heat-sterilized at 80 ° C. for 30 minutes, followed by lyophilization to obtain heat-killed bacteria. The heat-killed bacteria were then adjusted to a concentration of 1 mg / mL with PBS (Takara Bio Inc.) to prepare a lactic acid bacteria suspension.

[0114] 2. Preparation of Bifidobacterium Suspension Bifidobacterium animalis subspecies lactis JCM10602 was inoculated into 10 mL of MRS medium and cultured at 30°C for 24 hours. Then, 1 mL of the cultured lactic acid bacteria (bifidobacterium) cell culture solution was inoculated into 100 mL of MRS medium and cultured at 30°C for 24 hours. The lactic acid bacteria (bifidobacterium) were then collected, washed three times with sterilized water, heat-sterilized at 80°C for 30 minutes, and lyophilized to obtain heat-killed bacteria. The heat-killed bacteria were then adjusted to a concentration of 1 mg / mL with PBS (Takara Bio Inc.) to prepare a lactic acid bacteria (bifidobacterium) suspension.

[0115] <3. Preparation of Chlorogenic Acid Solution> Chlorogenic acid, a product of Tokyo Chemical Industry Co., Ltd., was used and prepared with PBS to a concentration of 1 mg / mL.

[0116] 4. Test Procedure The test was carried out according to the following procedures (i) to (iv): (i) Bone marrow cells derived from female BALB / c mice were cultured at a concentration of 1 x 10 in RPMI medium (Sigma Corporation) prepared so that the components listed below (Culture medium composition) were added to the final concentrations listed below (Culture medium composition). ６(ii) 1 mL of the prepared cell suspension was seeded on the cells, and the cells were suspending at a concentration of 10 cells / mL to prepare a cell suspension. (Culture medium composition) 10% by volume FBS 100 U / mL penicillin / streptomycin 1 mM sodium pyruvate 2.5 mM HEPES 1% by mass non-essential amino acids for MEM (NEAA) 50 μM β-mercaptoethanol 100 ng / mL Flt-3L ２ Incubated at 37°C and 5% CO ２ (iii) The bone marrow cells containing the induced pDCs were cultured at 2 × 10 ５ The cells were suspended at a concentration of 100 μg / mL and seeded in 200 μL aliquots onto a 96-well plate. 2 μL of the lactic acid bacteria suspension (1.) or the bifidobacterial suspension (2.) was added, along with 2 μL of the chlorogenic acid solution (3.) (final concentration: 10 μg / mL). Similarly, the lactic acid bacteria or bifidobacterial suspension alone was added to a 96-well plate seeded with bone marrow cells containing pDCs. (iv) After 24 hours, the culture supernatant was collected, and the IFN-α concentration was measured using an IFN-α measurement kit (PBL Assay Science Ltd.).

[0117] 5. Results The relative values ​​of the amount of IFN-α produced when various lactic acid bacteria or bifidobacteria suspensions were used alone were set to 1.0, and the relative values ​​of the amount of IFN-α produced when various lactic acid bacteria or bifidobacteria were used in combination with chlorogenic acid are summarized in the table below.

[0118]

[0119] From the above results, it was confirmed that chlorogenic acid enhances IFN-α production by pDC induced by various lactic acid bacteria and bifidobacteria.

Claims

1. An immunostimulating composition comprising a bacterium having immunostimulating ability and one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids and sulfites, which have the effect of enhancing the immunostimulating ability of the bacterium.

2. The immunostimulating composition according to claim 1, wherein the bacteria having immunostimulating ability are lactic acid bacteria and / or acetic acid bacteria.

3. The immunostimulating composition according to claim 2, wherein the lactic acid bacteria are one or more species selected from the group consisting of Lactococcus, Bifidobacterium, and Lactobacillus.

4. The immunostimulatory composition according to claim 3, wherein the Lactococcus bacterium is Lactococcus lactis subsp. lactis or Lactococcus culbatus, the Bifidobacterium bacterium is Bifidobacterium animalis subsp. lactis, and the Lactobacillus bacterium is Lactobacillus paraplantarum.

5. The immunostimulating composition according to claim 1, wherein the content of the bacteria having immunostimulating ability is 0.001% by mass or more and less than 100% by mass relative to the total amount of the immunostimulating composition.

6. The immunostimulating composition according to claim 1, wherein the content of the compound is 0.000001% by mass or more and 90.0% by mass or less relative to the total amount of the immunostimulating composition.

7. The immunostimulating composition according to claim 1, wherein the ratio of the content (mass%) of the bacteria having immunostimulating ability to the content (mass%) of the compound (content of the compound) / (content of the bacteria having immunostimulating ability) is 0.001 or more and 50,000 or less.

8. The immunostimulating composition according to any one of claims 1 to 7, wherein the immunostimulating ability is the ability to induce interferon α production in immune cells.

9. The immunostimulatory composition according to claim 8, wherein the immune cells are plasmacytoid dendritic cells.

10. The immunostimulating composition according to any one of claims 1 to 7, wherein the immunostimulating effect is an effect of enhancing the immunostimulating effect by 1.10 times or more.

11. The immunostimulating composition according to claim 8, wherein the compound is one or more compounds selected from the group consisting of chlorogenic acid, catechin, lychee polyphenol, black soybean polyphenol, black soybean seed coat polyphenol, theaflavin, black currant polyphenol, hesperidin, resveratrol, methylhesperidin, curcumin, rutin, lutein, astaxanthin, paprika xanthophyll, caffeine, coenzyme Q10, pyrroloquinoline quinone, citicoline, glycerophosphocholine, phosphatidylserine, beet ceramide, pine ceramide, milk ceramide, 3-hydroxyisovaleric acid, eicosapentaenoic acid, docosahexaenoic acid, and potassium metabisulfite.

12. A method for immunostimulation, comprising administering or having a subject ingest one or more compounds selected from the group consisting of a bacterium having immunostimulatory ability and a polyphenol, a carotenoid, a xanthine compound, a quinone compound, a choline compound, a sphingolipid, a phospholipid, a fatty acid, and a sulfite, which have the effect of enhancing the immunostimulatory ability of the bacterium.

13. A method for enhancing the immunostimulatory effect induced by bacteria having immunostimulatory ability, comprising administering or having a subject ingest one or more compounds selected from the group consisting of bacteria having immunostimulatory ability and polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids, and sulfites, which have the effect of enhancing the immunostimulatory effect of the bacteria.

14. The method according to claim 12 or 13, wherein the immunostimulatory activity is the ability to induce interferon α production in immune cells.

15. An enhancer of the immunostimulating effect induced by bacteria having immunostimulating ability, comprising one or more compounds selected from the group consisting of polyphenols, carotenoids, xanthine compounds, quinone compounds, choline compounds, sphingolipids, phospholipids, fatty acids and sulfites, which have the effect of enhancing the immunostimulating ability of bacteria having immunostimulating ability.

16. The enhancer according to claim 15, wherein the immunostimulatory activity is the ability to induce interferon α production in immune cells.

Images