Immunostimulatory composition, and immunostimulation method

Abstract

Disclosed is an immunostimulatory composition comprising: a bacterium having an immunostimulating ability; and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having the effect of enhancing the immunostimulating ability of said bacterium.

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 one or more sugars selected from the group consisting of specific monosaccharides, disaccharides, oligosaccharides, and polysaccharides enhance pDC activation induced by specific bacteria having immunostimulatory activity and the associated IFN-α production, and have completed the present invention.

[0008] The present invention provides, for example, the following inventions: [1] A composition for immunostimulation, comprising a bacterium having immunostimulatory ability and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of the bacterium. [2] A method for immunostimulation, comprising administering to or having a subject ingest, a bacterium having immunostimulatory ability and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an 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 or having a subject ingest, a bacterium having immunostimulatory ability and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of the bacterium. [4] An enhancer for the immunostimulatory effect induced by a bacterium having immunostimulatory ability, comprising one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of the bacterium. [5] An enhancer of immunostimulatory activity induced by bacteria having immunostimulatory activity, comprising a bacterium having immunostimulatory activity and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory activity of the bacterium. [6] A composition for immunostimulation induced by bacteria having immunostimulatory activity, comprising one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory activity of the bacterium. [7] Use of a bacterium having immunostimulatory activity and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory activity of the bacterium, for producing a composition for immunostimulation. [8] Use of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory activity of the bacterium, for producing a composition for immunostimulation induced by bacteria having immunostimulatory activity. [9] Use of one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of a bacterium having immunostimulatory ability, for producing an immunostimulatory composition to be administered or ingested in combination with the bacterium.

[10] Use of an immunostimulatory bacterium for producing a composition for immunostimulation, wherein the bacterium is administered or ingested in combination with one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of an immunostimulatory bacterium.

[11] One or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of the bacterium, for use in immunostimulation induced by the bacterium.

[12] An immunostimulatory bacterium for use in a therapeutic method for immunostimulation, wherein the bacterium is administered or ingested in combination with one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of the bacterium.

[13] The sugar for use in a therapeutic method for immunostimulation, wherein the sugar is one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having an effect of enhancing the immunostimulatory ability of an immunostimulatory bacterium, wherein the sugar is administered or ingested in combination with the bacterium.

[14] Use of a bacterium having immunostimulatory ability in a non-therapeutic method for immunostimulation, wherein the bacterium is administered or ingested in combination with one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have an effect of enhancing the immunostimulatory ability of the bacterium.

[15] Use of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have an effect of enhancing the immunostimulatory ability of a bacterium having immunostimulatory ability in a non-therapeutic method for immunostimulation, wherein the bacterium is administered or ingested in combination with the bacterium having immunostimulatory ability.

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

[15] , wherein the bacterium having immunostimulatory ability is a lactic acid bacterium and / or an acetic acid bacterium.

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

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

[18] The composition, method, enhancer, use, sugar or bacterium described in

[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, sugar, or bacterium according to

[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, sugar, 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 immunostimulatory bacteria is 0.001% by mass or more and less than 100% by mass, relative to 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 sugar is 0.000001% by mass or more and 90.0% by mass or less, relative to the total amount of the composition for immunostimulation.

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

[22] , wherein the ratio of the content (mass%) of the immunostimulatory bacteria to the content (mass%) of the sugar (the content of one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides) / (the content of the immunostimulatory bacteria) is 0.001 or more and 50,000 or less.

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

[24] , wherein the immune cells are pDCs.

[26] The composition, method, enhancer, use, sugar 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 bacteria having immunostimulatory ability.

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

[26] , wherein the sugar is one or more sugars selected from the group consisting of mannose, glucose, sucrose, lactose, galactose, isomaltulose, allulose, fructooligosaccharide, dextrin, resistant dextrin, hyaluronic acid, pullulan, tamarind gum, soybean polysaccharide, alginic acid, resistant starch, β-glucan, sialic acid, sugar derived from cockscomb extract, and acacia gum.

[28] A composition for immunostimulation, comprising a bacterium having immunostimulatory ability and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have 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 sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have 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. 2024-072658, filed with the Japan Patent Office on April 26, 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 saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, which have an effect of enhancing the immunostimulatory ability. 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 ５The 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 Lapidilactob ... The genus Lapidilactobacillus, the genus Latilactobacillus, the genus Lentilactobacillus, the genus Levilactobacillus, the genus Ligilactobacillus, the genus Limosilactobacillus, the genus Liquorilactobacillus, The present invention includes 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, bacteria of the genus Enter ... Bacteria of the genus Lactococcus, Lactobacillus, Lactiplantibacillus, Lacticaseibacillus, and Limosilactobacillus 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 capable of growing 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., may 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 limit values and upper limit values 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] As used herein, "sugar" refers to a polyhydric alcohol having a formyl group or a carbonyl group. As used herein, a sugar refers to one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides. As used herein, a "monosaccharide" refers to a sugar building block that is not further hydrolyzed. As used herein, a "disaccharide" refers to a sugar in which two monosaccharide molecules are linked by a glycosidic bond, an "oligosaccharide" refers to a sugar in which 3 to 10 monosaccharide molecules are linked by a glycosidic bond, and a "polysaccharide" refers to a sugar in which more than 10 monosaccharide molecules are linked by a glycosidic bond. The sugar may be either an L-sugar or a D-sugar. "One or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory activity of immunostimulatory bacteria" means the above sugars that have the effect of enhancing the immunostimulatory activity of immunostimulatory bacteria, and may be sugars that, when co-cultured with the immunostimulatory bacteria and immune cells, have a higher level of immunostimulatory activity than the level of immunostimulatory activity when only the immunostimulatory bacteria and immune cells are co-cultured. Note that sugars include sugar alcohols and sugars chemically modified with chlorine, etc.

[0067] Whether or not the saccharide 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 saccharide compared to the absence of the saccharide, it is determined that the saccharide has an effect of enhancing the immunostimulatory ability of the bacteria. As a more detailed example, whether or not the saccharide 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 steps (i') to (iv') in the presence of the saccharide compared to the absence of the saccharide. (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 concentration 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 sugar 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] Examples of monosaccharides include triose, tetrose, pentose, and hexose (e.g., mannose, glucose, galactose, allulose, and fructose), amino sugars (e.g., sialic acid), and derivatives of these monosaccharides. Examples of monosaccharides include reducing sugars (e.g., mannose, glucose, fructose, galactose, and allulose), sugars with insulin secretion activity (e.g., glucose, maltose, and allulose), sugars with arteriosclerosis prevention activity (e.g., allulose), and sugars with blood glucose elevation suppression activity (e.g., allulose). Matsutani Chemical's "ASTRAEA" can be used as allulose.

[0069] Preferred monosaccharides having an effect of enhancing the immunostimulatory activity of bacteria having immunostimulatory activity include reducing sugars (e.g., mannose, glucose, galactose, and allulose), sugars having an insulin secreting activity (e.g., glucose and allulose), sugars having an arteriosclerosis preventing activity (e.g., allulose), and sugars having an effect of suppressing blood glucose elevation (e.g., allulose).

[0070] Specific examples of the monosaccharide include mannose, glucose, galactose, allulose, sialic acid, fructose, etc. The monosaccharide having an effect of enhancing the immunostimulatory activity of the immunostimulatory bacteria is preferably one or more monosaccharides selected from the group consisting of mannose, glucose, galactose, allulose, and sialic acid.

[0071] Examples of disaccharides include sugars containing one or two of the above-mentioned monosaccharides or derivatives thereof. Disaccharides may be, for example, sugars containing glucose (e.g., maltose, sucrose, lactose, isomaltulose (palatinose)), sugars containing fructose (e.g., sucrose, isomaltulose), or sugars containing galactose (e.g., lactose). Disaccharides may also include sugars having an insulin secretion effect (e.g., trehalose, lactose), sugars having an arteriosclerosis prevention effect (e.g., trehalose), sugars having a blood glucose elevation suppression effect (e.g., isomaltulose), etc.

[0072] Disaccharides having an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability are preferably sugars containing glucose (e.g., sucrose, lactose, isomaltulose (palatinose), etc.). Disaccharides having an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability are preferably sugars containing fructose (e.g., sucrose, isomaltulose, etc.) and sugars containing galactose (e.g., lactose, etc.). Disaccharides having an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability are preferably sugars having an insulin secreting effect (e.g., trehalose, lactose, etc.), sugars having an arteriosclerosis preventing effect (e.g., trehalose, etc.), and sugars having an effect of suppressing blood glucose elevation (e.g., isomaltulose, etc.).

[0073] Specific examples of the disaccharide include maltose, sucrose, lactose, isomaltulose, etc. The disaccharide having an effect of enhancing the immunostimulatory activity of the immunostimulatory bacteria is preferably one or more disaccharides selected from the group consisting of sucrose, lactose, and isomaltulose.

[0074] Examples of oligosaccharides include sugars containing one or more of the above-mentioned monosaccharides or derivatives thereof. Examples of oligosaccharides include reducing sugars (e.g., fructooligosaccharides), sugars with insulin secretion activity (e.g., fructooligosaccharides and galactooligosaccharides), sugars with arteriosclerosis prevention activity (e.g., indigestible α-oligosaccharides), and sugars with blood glucose elevation suppression activity (e.g., indigestible α-oligosaccharides). Examples of oligosaccharides include sugars containing glucose (e.g., fructooligosaccharides, galactooligosaccharides, and glucooligosaccharides), sugars containing fructose (e.g., fructooligosaccharides), and sugars containing galactose (e.g., galactooligosaccharides).

[0075] Oligosaccharides having the effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability are preferably reducing sugars (e.g., fructooligosaccharides, etc.). Oligosaccharides having the effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability are preferably sugars having an insulin secreting effect (e.g., fructooligosaccharides, galactooligosaccharides, etc.), sugars having an arteriosclerosis preventing effect (e.g., indigestible α-oligosaccharides, etc.), sugars having an effect of suppressing blood glucose elevation (e.g., indigestible α-oligosaccharides, etc.). Oligosaccharides having the effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability are preferably sugars containing glucose (e.g., fructooligosaccharides, galactooligosaccharides, glucooligosaccharides, etc.), sugars containing fructose (e.g., fructooligosaccharides, etc.), or sugars containing galactose (e.g., galactooligosaccharides, etc.).

[0076] Specific examples of oligosaccharides include fructooligosaccharides, galactooligosaccharides, and fructooligosaccharides, etc. Fructooligosaccharides are preferred as oligosaccharides having an effect of enhancing the immunostimulating activity of bacteria having immunostimulating activity.

[0077] Examples of polysaccharides include sugars containing one or more of the above-mentioned monosaccharides or derivatives thereof. Examples of polysaccharides include polysaccharides containing N-acetylglucosamine (e.g., hyaluronic acid, etc.), polysaccharides containing D-glucuronic acid (e.g., hyaluronic acid, etc.), mucopolysaccharides (e.g., hyaluronic acid, etc.), water-soluble polysaccharides (e.g., hyaluronic acid, pullulan, tamarind gum, soybean polysaccharides, alginic acid, β-glucan (e.g., derived from bacteria, mushrooms, barley, etc.), and acacia gum), and polysaccharides (e.g., hyaluronic acid, pullulan, tamarind gum, soybean polysaccharides, sodium alginate, alginate esters, and β-glucan (e.g., derived from bacteria, mushrooms, barley, etc.)). The polysaccharide may be a polysaccharide used as a thickening stabilizer (for example, pullulan, tamarind gum, sodium alginate, alginate ester, and β-glucan (e.g., derived from bacteria, mushrooms, barley, etc.)), a non-digestible polysaccharide (for example, hyaluronic acid, pullulan, tamarind gum, soybean polysaccharide, sodium alginate, alginate ester, and β-glucan), a polysaccharide having an intestinal regulating effect (for example, tamarind gum, soybean polysaccharide, sodium alginate, alginate ester, and β-glucan), or a polysaccharide that functions as a dietary fiber (for example, non-digestible dextrin, acacia gum, etc.).

[0078] The polysaccharide having an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability is preferably a polysaccharide containing N-acetylglucosamine (e.g., hyaluronic acid, etc.), a polysaccharide containing D-glucuronic acid (e.g., hyaluronic acid, etc.), or a mucopolysaccharide (e.g., hyaluronic acid, etc.). The polysaccharide having an effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability is preferably a water-soluble polysaccharide (e.g., hyaluronic acid, pullulan, tamarind gum, soybean polysaccharide, alginic acid, β-glucan (e.g., derived from bacteria, mushrooms, barley, etc.), and acacia gum, etc.), a polysaccharide (e.g., hyaluronic acid, pullulan, tamarind gum, soybean polysaccharide, sodium alginate, alginate ester, and β-glucan (e.g., derived from bacteria, mushrooms, barley, etc.), etc.), or a polysaccharide used as a thickening stabilizer (e.g., pullulan, tamarind gum, soybean polysaccharide, sodium alginate, alginate ester, and β-glucan (e.g., derived from bacteria, mushrooms, barley, etc.) ...). Examples of suitable polysaccharides include lind gum, sodium alginate, alginate esters, and β-glucans (e.g., derived from bacteria, mushrooms, barley, etc.), indigestible polysaccharides (e.g., hyaluronic acid, pullulan, tamarind gum, soybean polysaccharides, sodium alginate, alginate esters, and β-glucans), polysaccharides that regulate the intestines (e.g., tamarind gum, soybean polysaccharides, sodium alginate, alginate esters, and β-glucans), and polysaccharides that function as dietary fiber (e.g., indigestible dextrin, acacia gum, etc.).

[0079] The polysaccharide having an effect of enhancing the immunostimulatory activity of bacteria having immunostimulatory activity has a lower limit of dynamic viscosity of 1.0 mm ２ / s or more, 2.0mm ２ / s or more, 10mm ２ / s or more, 30mm ２ / s or more, 100mm ２ / s or more, 300mm ２ / s or more, and the upper limit is preferably 1000 mm ２ / s or less, 500mm ２ / s or less, 300mm ２ / s or less, 100mm ２ / s or less, 30mm ２ / s or less, 10mm ２ / s or less, 2.0mm ２The kinematic viscosity of the polysaccharide having the effect of enhancing the immunostimulatory activity of the bacteria having immunostimulatory activity is preferably 1.0 mm / s or less. These upper and lower limits can be combined in any desired manner. ２ / s or more 1000mm ２ / s or less, 1.0mm ２ / s or more 500mm ２ / s or less, 1.0mm ２ / s or more 300mm ２ / s or less, 1.0mm ２ / s or more 100mm ２ / s or less, 1.0mm ２ / s or more 30mm ２ / s or less, 1.0mm ２ / s or more 10mm ２ / s or less, 1.0mm ２ / s or more 2.0mm ２ / s or less, 2.0mm ２ / s or more 1000mm ２ / s or less, 2.0mm ２ / s or more 500mm ２ / s or less, 2.0mm ２ / s or more 300mm ２ / s or less, 2.0mm ２ / s or more 100mm ２ / s or less, 2.0mm ２ / s or more 30mm ２ / s or less, 2.0mm ２ / s or more 10mm ２ / s or less, 10mm ２ / s or more 1000mm ２ / s or less, 10mm ２ / s or more 500mm ２ / s or less, 10mm ２ / s or more 300mm ２ / s or less, 10mm ２ / s or more 100mm ２ / s or less, 10mm ２ / s or more 30mm ２ / s or less, 30mm ２ / s or more 1000mm ２ / s or less, 30mm ２ / s or more 500mm ２ / s or less, 30mm ２ / s or more 300mm ２ / s or less, 30mm ２ / s or more 100mm ２ / s or less, 100mm ２ / s or more 1000mm ２ / s or less, 100mm ２ / s or more 500mm ２ / s or less, 100mm ２ / s or more 300mm ２ / s or less, 300mm ２ / s or more 1000mm ２ / s or less, 300mm ２ / s or more 500mm ２ The kinematic viscosity can be determined based on a 1% by mass aqueous solution at 30° C. The kinematic viscosity can be measured by a conventional method, and the measurement method is not particularly limited.

[0080] Specific examples of polysaccharides include dextrin, indigestible dextrin, hyaluronic acid, pullulan, tamarind gum, soybean polysaccharides, alginic acid or a derivative thereof, indigestible starch (resistant starch), β-glucan, sugar derived from cockscomb extract, acacia gum, etc. The polysaccharide having an effect of enhancing the immunostimulatory activity of immunostimulatory bacteria is preferably one or more polysaccharides selected from the group consisting of dextrin, indigestible dextrin, hyaluronic acid, pullulan, tamarind gum, soybean polysaccharides, alginic acid or a derivative thereof, indigestible starch (resistant starch), β-glucan, sugar derived from cockscomb extract, and acacia gum.

[0081] The resistant dextrin can be prepared by roasting corn starch, hydrolyzing it with amylase, and then extracting the resistant components, and can be, for example, "Kenja no Shokutaku" (Wise Man's Table) manufactured by Otsuka Pharmaceutical Co., Ltd. The resistant dextrin is preferably one that is low in viscosity, low in sweetness, and easily soluble, is preferably nearly transparent when dissolved in water, and has excellent heat resistance and acid resistance.

[0082] The hyaluronic acid used can be hyaluronic acid obtained by fermentation and highly purified, such as Kewpie's "HyaBest (registered trademark) (J)," "Hyaronano (registered trademark)," "HyaBest (registered trademark) (S) LF-P," "Hyaluronic San HA-LF5-A," "HAbooster (registered trademark)," "Hyalocatch (registered trademark)," "Hyaroberu (registered trademark)," "Hyarorepair (registered trademark)," and "Hyalooligo (registered trademark)." The number-average molecular weight of hyaluronic acid can be 300 or more and 100,000 or less, and preferably 1,000 or more and 50,000 or less.

[0083] The cockscomb extract is a component extracted from cockscomb, and can be one that is rich in hyaluronic acid and collagen. The sugar derived from cockscomb extract refers to at least one or more sugars contained in cockscomb extract, and may be all of the sugars contained in cockscomb extract. In addition to hyaluronic acid, examples of sugars contained in cockscomb extract include glycosaminoglycans, chondroitin sulfate, and peptides. Furthermore, the immunostimulating composition according to one embodiment may contain cockscomb extract. As the cockscomb extract, for example, "Hyalocollagen (registered trademark)" manufactured by LS Corporation can be used.

[0084] The mixture of fructooligosaccharides and acacia gum preferably contains 45% or more by weight of fructooligosaccharides, 45% or more by weight of acacia gum, 5% or less by weight of monosaccharides and sucrose, and 7% or less by weight of water; for example, "Oligo and Acacia FG" manufactured by Meiji Food Materials can be used. The fructooligosaccharide can be a reaction product of sucrose treated with an enzyme mixture of fructosidase and glucose oxidase. The acacia gum is a thickening polysaccharide obtained by drying a resin derived from the Acacia acacia tree, whose main component is arabic acid, and can be composed of galactose, arabinose, rhamnose, glucuronic acid, or protein.

[0085] The dextrin may be a branched dextrin obtained by treating starch extracted from tapioca with maltose-forming amylase and transglucosidase, such as "TK-16" manufactured by Matsutani Chemical Industry Co., Ltd. It is preferable to use a dextrin that becomes transparent when dissolved in cold water and has low viscosity, and that has a degree of decomposition (DE) of 1 to 50, preferably 10 to 30.

[0086] Pullulan is a water-soluble polysaccharide produced by a mutant strain of Aureobasidium pullulans, a type of filamentous fungus, using corn-derived starch syrup as a carbon source, and pullulan having a contaminating carbohydrate content of 3% by mass or less in the contaminating carbohydrate fraction contained in the entire powder and having properties such as lubricity, adhesiveness, caking, adhesion, stickiness, film-forming properties, and moldability can be used. For example, pullulan manufactured by Hayashibara can be used, and it is preferable to use pullulan having a loss on drying of 6.0% by mass or less and a pH of 5.0 to 7.0 in a 10% by mass aqueous solution.

[0087] The tamarind gum can be one obtained by crushing tamarind seeds and separating and purifying the polysaccharides, such as "Glyloid (registered trademark) 5S" manufactured by MP Gokyo Food & Chemical Co., Ltd. Preferably, the tamarind gum exhibits a substantially constant viscosity in an aqueous solution regardless of the strength of shear force, and thickens or gels due to a synergistic effect when used in combination with sugars or alcohols.

[0088] The soybean polysaccharide is preferably a water-soluble polysaccharide extracted and purified from soybean lees, containing galactose, arabinose, or galacturonic acid as its main constituent sugars as well as rhamnose, fucose, xylose, glucose, etc., and having the effect of inhibiting protein aggregation in an acidic range. For example, "SM-1200(K)" manufactured by San-Ei Gen F.F.I. can be used as the soybean polysaccharide.

[0089] Alginic acid or a derivative thereof includes alginic acid or a salt thereof, an ester derivative of alginic acid or a salt thereof, an ether derivative of alginic acid or a salt thereof, etc. Specific examples include alginic acid, alginates such as sodium alginate, potassium alginate, calcium alginate, ammonium alginate, and sodium alginate sulfate, and alginate esters such as propylene glycol alginate, with alginate and / or alginate esters being preferred.

[0090] Sodium alginate can be a bonded salt of alginic acid and sodium ions obtained by swelling dried and crushed macroalgae (Laminariales, genus Lessonia) with water and then subjecting it to ion exchange with sodium, and examples of such salts include "Kimica Arginine I-3" manufactured by Kimica. Sodium alginate preferably has a viscosity (1% by mass aqueous solution, 20°C) of 300 mPa·s to 400 mPa·s.

[0091] The alginate ester may be a propylene glycol alginate ester obtained by esterifying propylene glycol to alginic acid derived from seaweed, which is preferred because it exhibits stable viscosity even in an acidic pH range of 3 to 5, and has excellent foam stability and emulsifying power. Examples of the alginate ester that can be used include "Kimiloid" manufactured by Kimica.

[0092] The origin of the resistant starch is not particularly limited, but examples include bananas, potatoes, rice, whole grains, and beans, and banana-derived resistant starch (e.g., green banana resistant starch, etc.) is preferred. Green banana resistant starch can be resistant starch extracted from yellow, immature green bananas, and products such as Nippon Kimi Food can be used. Products containing 30% by mass or more and 50% by mass or less of resistant starch are preferred, and products containing serotonin, tryptophan, potassium, magnesium, etc. in addition to resistant starch are preferred.

[0093] β-glucan is glucose linked by β-glucosidic bonds and is found in yeast, barley, mushrooms, etc. Among β-glucans, glucopolysaccharide extracted and powdered from the cell wall of baker's yeast can be used, for example, Ryusendo's "Wellmune (registered trademark) WGP F3020" can be used. β-glucans derived from baker's yeast are preferably those containing many β-1,3-branched glucose molecules extending from β-1,6-branched chains, and preferably those that form a three-dimensional triple helix structure.

[0094] The sugar in the immunostimulating composition according to one embodiment is preferably an oligosaccharide and / or a polysaccharide, and more preferably one or more sugars selected from the group consisting of mannose, glucose, sucrose, lactose, galactose, palatinose, allulose, fructooligosaccharide, dextrin, resistant dextrin, hyaluronic acid, pullulan, tamarind gum, soybean polysaccharides, alginic acid, resistant starch, β-glucan, sialic acid, sugars derived from cockscomb extract, and acacia gum.

[0095] The sweetness of the sugar having the effect of enhancing the immunostimulatory activity of immunostimulatory bacteria is not particularly limited, but the lower limit is preferably 0.1 or more, 0.2 or more, 0.3 or more, 0.5 or more, 0.7 or more, or 0.9 or more, and the upper limit is preferably 1000 or less, 100 or less, 70 or less, 10 or less, 1.8 or less, 1.1 or less, 0.8 or less, 0.6 or less, 0.4 or less, or 0.3 or less. These upper and lower limits can be arbitrarily combined. The sweetness is not particularly limited, and can be measured by known methods, for example, by reference to publications such as Hackh's Chemical Dictionary, p. 85 (1944). Examples of sugars with a sweetness of 0.1 or more include xylose (sweetness 0.40), glucose (sweetness 0.74), fructose (sweetness 1.75), galactose (sweetness 0.32), rhamnose (sweetness 0.32), sucrose (sweetness 1.00), maltose (sweetness 0.32), lactose (sweetness 0.16), raffinose (sweetness 0.23), invert sugar (sweetness 1.23), mannose (sweetness 0.59), allulose (sweetness 0.70), dextrin, isomaltulose (palatinose) (sweetness 0.5), indigestible dextrin, and trehalose (sweetness 0.50). 0.5), lactulose (sweetness level 0.6 to 0.7), trehalulose (sweetness level 0.5), coupling sugar (sweetness level 0.5 to 0.6), fructooligosaccharides (sweetness level 0.3 to 0.6), sorbitol (sweetness level 0.54), mannitol (sweetness level 0.57), maltitol (sweetness level 0.8 to 0.95), lactitol (sweetness level 0.35), xylitol (sweetness level 1.08), erythritol (sweetness level 0.7 to 0.8), reduced starch syrup (sweetness level 0.2 to 0.7), reduced palatinose (isomaltitol) (sweetness level 0.5), and sucralose (sweetness level 600) are examples of such sweetness levels. Sweetness levels can be measured according to conventional methods, and the measurement method is not particularly limited.

[0096] The saccharide according to this embodiment has an effect of enhancing the immunostimulatory ability of bacteria when the IFN-α concentration measured by the above steps (i') to (iv') in the presence of the saccharide 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, 1.25 times or more, as the lower limit, compared to the case in the absence of the saccharide. Preferably, the ratio is 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 the saccharide according to this embodiment on enhancing the immunostimulatory ability of bacteria is, for example, when the IFN-α concentration measured by the above steps (i') to (iv') in the presence of the saccharide is increased by 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, or 1.02 to 3.5 times Lower, 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 times or more and 2.3 times or less, 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 and 3.8 times or less, 1.03 times 3.5 times or more, 1.03 times or more and 3.3 times or less, 1.03 times or more and 3.0 times or less, 1.03 or more and 2.8 times or less, 1.03 times or more and 2.5 times or less, 1.03 times or more and 2.3 times or more 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 or more and 3.8 times or less,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, 1.08 times to 2.0 times. Below, 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 to 3.3 times, 1.13 times and above. Below 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 to 1.5 times, 1.18 times The following are considered high-risk betting rates: 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, 1.20 to 2.8 times, and 1.20 to 2.5 times.1.20 times or more but less than 2.3 times, 1.20 times or more but less than 2.0 times, 1.20 times or more but less than 1.8 times, 1.20 times or more but less than 1.5 times, 1.23 times or more but less than 4.0 times, 1.23 times or more but less than 3.8 times, 1.23 times or more but less than 3.5 times, 1.23 times or more but less than 3.3 times, 1.23 times or more but less than 3.0 times, 1.23 times or more but less than 2.8 times, 1.23 times or more but less than 2.5 times, 1.23 times or more but less than 2.3 times, 1.23 times or more but less than 2.0 times, 1.23 times or more but less than 1.8 times, 1.23 times or more but less than 1.5 times, 1.25 times or more but less than 4.0 times, 1.25 times or more but less than 3.8 times, 1.25 times or more but less than 3.5 times. Below 1.25 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 to 2.0 times, 1.28 times and above. 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, 1.40 times to below 3.0 times, 1.4 0 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 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 times, 1.60 times to 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 3.5 times or less, 1. 70 times to 3.3 times, 1.70 times to 3.0 times, 1.70 times to 2.8 times, 1.70 times to 2.5 times, 1.70 times to 2.3 times, 1.70 times to 2.0 1.70 times or more and 1.8 times or less, 1.80 times or more and 4.0 times or less, 1.80 times or more and 3.8 times or less, 1.80 times or more and 3.5 times or less, 1.80 times or more and 3.3 times or less, 1.80 times 3.0 times or more, 1.80 times or more and 2.8 times or less, 1.80 times or more and 2.5 times or less, 1.80 times or more and 2.3 times or less, 1.80 times or more and 2.0 times or less, 1.90 times or more and 4.0 times or less , 1.90 times or more and 3.8 times or less, 1.90 times or more and 3.5 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 times or more Preferably, the ratio is 2.5 times or less, 1.90 times or more and 2.3 times or less, 1.90 times or more and 2.0 times or less, 2.00 times or more and 4.0 times or less, 2.00 times or more and 3.8 times or less, 2.00 times or more and 3.5 times or less, 2.00 times or more and 3.3 times or less, 2.00 times or more and 3.0 times or less, 2.00 times or more and 2.8 times or less, 2.00 times or more and 2.5 times or less, or 2.00 times or more and 2.3 times or less.

[0097] The content of one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides in the composition for immunostimulation according to one embodiment can have a lower limit of, for example, 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, relative to the total amount of the composition for immunostimulation. The upper limit can be set to 90.0% by mass or less, 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 one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides 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, or 0.000001% by mass to 1.0% by mass, based on the total amount of the immunostimulating composition. % or less, 0.000001 mass% or more and 0.80 mass% or less, 0.000001 mass% or more and 0.50 mass% 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, 0.000001 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 more and 80.0 mass% or less,0.00001% of mass or more but less than 75.0% of mass, 0.00001% of mass or more but less than 50.0% of mass, 0.00001% of mass or more but less than 25.0% of mass, 0.00001% of mass or more but less than 10.0% of mass, 0.00001% of mass or more but less than 5.0% of mass, 0.00001% of mass or more but less than 1.0% of mass, 0.00001% of mass or more but less than 0.80% of mass, 0.00001% of mass or more but less than 0.50% of mass, 0.00001% of mass or more but less than 0.30% of mass, 0.00001% of mass or more but less than 0.25% of mass, 0.00001% of mass or more but less than 0.20% of mass, 0.00001% of mass or more... The following percentages are considered as high as 0.10% of mass, 0.00001% of mass, 0.05% of mass, 0.00001% of mass, 0.02% of mass, 0.00001% of mass, 0.01% of mass, 0.001% of mass, 90.0% of mass, 0.001% of mass, 85.0% of mass, 0.001% of mass, 75.0% of mass, 50.0% of mass, 25.0% of mass, 10.0% of mass, 5.0% of mass, and 0.001% of mass. % or more but less than 1.0% of mass, 0.001% or more but less than 0.80% of mass, 0.001% or more but less than 0.50% of mass, 0.001% or more but less than 0.30% of mass, 0.001% or more but less than 0.25% of mass, 0.001% or more but less than 0.20% of mass, 0.001% or more but less than 0.10% of mass, 0.001% or more but less than 0.05% of mass, 0.001% or more but less than 0.02% of mass, 0.001% or more but less than 0.01% of mass, 0.01% or more but less than 90.0% of mass, 0.01% or more but less than 85.0% of mass, 0.01% or more but less than 80.0% of mass Below, 0.01% by mass and below 75.0% by mass, 0.01% by mass and below 50.0% by mass, 0.01% by mass and below 25.0% by mass, 0.01% by mass and below 10.0% by mass, 0.01% by mass and below 5.0% by mass, 0.01% by mass and below 1.0% by mass, 0.01% by mass and below 0.80% by mass, 0.01% by mass and below 0.50% by mass, 0.01% by mass and below 0.30% by mass, 0.01% by mass and below 0.25% by mass, 0.01% by mass and below 0.20% by mass, 0.01% by mass and below 0.10% by mass, 0.01% by mass and below 0.05% by 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% of mass, 0.02% to 50.0% of mass, 0.02% to 25.0% of mass, 0.02% to 10.0% of mass, 0.02% to 5.0% of mass, 0.02% to 1.0% of mass, 0.02% to 0.80% of mass, 0.02% to 0.50% of mass, 0.02% to 0.30% of mass, 0.02% of mass... Quantity % or more but less than 0.25% of mass, 0.02% or more but less than 0.20% of mass, 0.02% or more but less than 0.10% of mass, 0.02% or more but less than 0.05% of mass, 0.05% or more but less than 90.0% of mass, 0.05% or more but less than 85.0% of mass, 0.05% or more but less than 80.0% of mass, 0.05% or more but less than 75.0% of mass, 0.05% or more but less than 50.0% of mass, 0.05% or more but less than 25.0% of mass, 0.05% or more but less than 10.0% of mass, 0.05% or more but less than 5.0% of mass, 0.05% or more but less than 1.0% of mass, 0.05% or more but less than 0.0% of mass. <80% mass percentage; <0.05% mass percentage; <0.50% mass percentage; <0.05% mass percentage; <0.30% mass percentage; <0.05% mass percentage; <0.25% mass percentage; <0.05% mass percentage; <0.20% mass percentage; <0.05% mass percentage; <0.10% mass percentage; <0.10% mass percentage; <90.0% mass percentage; <0.10% mass percentage; <85.0% mass percentage; <0.10% mass percentage; <80.0% mass percentage; <0.10% mass percentage; <75.0% mass percentage; <0.10% mass percentage; <50.0% mass percentage; <25.0% mass percentage; <10.0% mass percentage; <0.10% mass percentage; <5.0% mass percentage. Less than 10% of mass, 0.10% to 1.0% of mass, 0.10% to 0.80% of mass, 0.10% to 0.50% of mass, 0.10% to 0.30% of mass, 0.10% to 0.25% of mass, 0.10% to 0.20% of mass, 0.50% to 90.0% of mass, 0.50% to 85.0% of mass, 0.50% to 80.0% of mass, 0.50% to 75.0% of mass, 0.50% to 50.0% of mass, 0.50% to 25.0% of mass, 0.50% to 10.0% of 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% to 85.0% by mass, 1% to 80.0% by mass, 1% to 75.0% by mass, 1% to 50.0% by mass, 1% to 25.0% by mass, 1% to 1% by mass. 0.0% or less, 1% or more but less than 5.0% of mass, 2% or more but less than 90.0% of mass, 2% or more but less than 85.0% of mass, 2% or more but less than 80.0% of mass, 2% or more but less than 75.0% of mass, 2% or more but less than 50.0% of mass, 2% or more but less than 25.0% of mass, 2% or more but less than 10.0% of mass, 2% or more but less than 5.0% of mass.

[0098] The ratio of the content (% by mass) of immunostimulatory bacteria to the content (% by mass) of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides in an immunostimulatory composition according to one embodiment ((content of immunostimulatory bacteria) / (content of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides)) 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, or 0.03 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 one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides in the immunostimulatory composition according to one embodiment ((content of bacteria having immunostimulatory ability) / (content of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides)) is, for example, 0.001 to 50,000, 0.001 to 10,000, 0.001 to 1,000, 0.001 to 500, 0.001 to 100, 0.001 to 50, 0.001 to 10, 0.001 to 5, 0.001 to 1.0, 0.001 to 0.75, 0.001 to 0.5, 0.001 to 0.3, or 0.003 to 50 000 or less, 0.003 or more and 10,000 or less, 0.003 or more and 1000 or less, 0.003 or more and 500 or less, 0.003 or more and 100 or less, 0.003 or more and 50 or less, 0.003 or more 10 or less, 0.003 or more and 5 or less, 0.003 or more and 1.0 or less, 0.003 or more and 0.75 or less, 0.003 or more and 0.5 or less, 0.003 or more and 0.3 or less, 0.005 or more and 5000 0 or less, 0.005 to 10,000, 0.005 to 1,000, 0.005 to 500, 0.005 to 100, 0.005 to 50, 0.005 to 10 Below, 0.005 to 5, 0.005 to 1.0, 0.005 to 0.75, 0.005 to 0.5, 0.005 to 0.3, 0.01 to 50000,0.01 to 10,000, 0.01 to 1,000, 0.01 to 500, 0.01 to 100, 0.01 to 50, 0.01 to 10, 0.01 to 5, 0.01 to 1.0 Lower, 0.01 to 0.75, 0.01 to 0.5, 0.01 to 0.3, 0.015 to 50,000, 0.015 to 10,000, 0.015 to 1000, 0.015 to 500 Below, 0.015 to 100, 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 1 0 or less, 0.02 or more and 5 or less, 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, 0.025 to 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 It may be 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 100 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, or 0.03 or more and 0.3 or less.

[0099] 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 contents of the immunostimulatory bacteria and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides in the food, drug, or quasi-drug are not particularly limited and can be freely set depending on the purpose.

[0100] When the immunostimulating composition according to one embodiment is a food, drug, or quasi-drug, the food, drug, or quasi-drug may contain components typically used in foods, drugs, or quasi-drugs, in addition to the immunostimulatory bacteria and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides. 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, flavorings, 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] An immunostimulatory composition according to one embodiment is an immunostimulatory composition induced by bacteria having immunostimulatory ability, and comprises one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, 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.

[0106] An immunostimulating composition according to one embodiment is a composition for immunostimulation or a composition for immunostimulation with enhanced immunostimulating activity, which comprises a bacterium having immunostimulating activity and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, 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 preferable from the viewpoint that the addition of the saccharide enhances the immunostimulating activity of the bacterium.

[0107] [Enhancer of immunostimulatory activity induced by bacteria having immunostimulatory activity] A second embodiment of the present disclosure relates to an enhancer of immunostimulatory activity induced by bacteria having immunostimulatory activity (hereinafter also simply referred to as "enhancer"). One embodiment of the enhancer comprises a bacterium having immunostimulatory activity and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory activity of the bacterium. Another embodiment of the enhancer is an enhancer of immunostimulatory activity induced by bacteria having immunostimulatory activity, and comprises one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that 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. In other words, the enhancer according to this embodiment has an enhanced immunostimulatory activity compared to an immunostimulatory composition containing only bacteria having immunostimulatory activity.

[0108] 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 ratio is 28 times or more, 1.30 times or more, 1.40 times or more, 1.50 times or more, 1.60 times or more, 1.70 times or more, 1.80 times or more, 1.90 times or more, or 2.0 times or more, with the upper limit being preferably 4.0 times or less, 3.8 times or less, 3.5 times or less, 3.3 times or less, 3.0 times or less, 2.8 times or less, 2.5 times or less, 2.3 times or less, 2.0 times or less, 1.8 times or less, or 1.50 times or less. These upper and lower limits can be arbitrarily combined and may be the same as the ranges described for the bacterial immunostimulatory activity enhancing effect of the saccharide according to this embodiment.

[0109] As other specific aspects of the enhancer according to this embodiment, aspects of the immunostimulating composition according to this embodiment can be appropriately applied.

[0110] [Immunostimulating method, method for enhancing immunostimulating effect induced by bacteria having immunostimulating ability] A third embodiment of the present disclosure relates to an immunostimulating method and a method for enhancing immunostimulating effect induced by bacteria having immunostimulating ability (hereinafter also simply referred to as an "enhancing method"). The immunostimulating method and the enhancing method include administering to or having a subject ingest one or more sugars selected from the group consisting of bacteria having immunostimulating ability and monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have an effect of enhancing the immunostimulating ability of the bacteria. The enhancing method according to this embodiment enhances the immunostimulating effect compared to when only bacteria having immunostimulating ability are administered or ingested.

[0111] 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.

[0112] 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.

[0113] The bacteria having immunostimulatory activity and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having the effect of enhancing the immunostimulatory activity 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.

[0114] [Method for producing a composition] A fourth embodiment of the present disclosure relates to a method for producing a composition for immunostimulation. This production method is a method for producing a composition for immunostimulation or a composition for immunostimulation with enhanced immunostimulating activity, which comprises adding, to a bacterium having immunostimulatory activity, one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, 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 sugar enhances the immunostimulatory activity of the bacterium.

[0115] [Use of bacteria and sugars for producing a composition] A fifth embodiment of the present disclosure relates to the use of bacteria and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have an effect of enhancing the immunostimulatory ability of the bacteria for producing a composition. One embodiment of the use is the use of an immunostimulatory bacterium and one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having the effect of enhancing the immunostimulatory ability of the bacterium, to produce a composition for immunostimulation; another embodiment of the use is the use of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having the effect of enhancing the immunostimulatory ability of the bacterium, to produce a composition for immunostimulation that is induced by the immunostimulatory bacterium; yet another embodiment of the use is the use of one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having the effect of enhancing the immunostimulatory ability of the bacterium, to produce a composition for immunostimulation that is administered or ingested in combination with the immunostimulatory bacterium; and another embodiment of the use is the use of an immunostimulatory bacterium to produce a composition for immunostimulation that is administered or ingested in combination with one or more saccharides selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides having the effect of enhancing the immunostimulatory ability of the immunostimulatory bacterium. Specific aspects of the immunostimulatory composition, bacterium, and saccharide according to this embodiment are as described above.

[0116] [Sugars for Use] A sixth embodiment of the present disclosure relates to one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that 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 sugar according to this embodiment are as described above.

[0117] [Bacteria or Sugar for Use in a Therapeutic Method] A seventh embodiment of the present disclosure relates to the use of a bacterium or a sugar for use in a therapeutic method of immunostimulation. In one aspect, the bacterium has immunostimulatory activity for use in a therapeutic method of immunostimulation, and is administered or ingested in combination with one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory activity of the bacterium. In another aspect, the sugar is one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory activity of the bacterium, and is administered or ingested in combination with the bacterium. Specific aspects of the bacterium and sugar according to this embodiment are as described above. In the present disclosure, use in a "therapeutic" method refers to use in treating the body of a subject. Use in a therapeutic method according to the present disclosure may, for example, be use for the purpose of or accompanying a medical procedure. 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, for therapeutic or prophylactic purposes, for therapeutic purposes, or for prophylactic purposes involving the ingestion of a food composition, or for therapeutic purposes. Use in a therapeutic method according to the present disclosure may be, for example, for use in an unhealthy individual.

[0118] [Use of Bacteria or Sugars in Non-Therapeutic Methods] The eighth embodiment of the present disclosure relates to the use of bacteria or sugars for use in non-therapeutic methods of immunostimulation. In one aspect, the use is a use of bacteria having immunostimulatory ability in a non-therapeutic method of immunostimulation, wherein the bacteria are administered or ingested in combination with one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory ability of the bacteria. In another aspect, the use is a use of one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory ability of the bacteria in a non-therapeutic method of immunostimulation, wherein the bacteria are administered or ingested in combination with the bacteria having immunostimulatory ability. Specific aspects of the bacteria and sugars according to this embodiment are as described above. In the present disclosure, use in a "non-therapeutic" method refers to use of a substance that does not fall under the category of use in a therapeutic method. Use in a non-therapeutic method according to the present disclosure may, for example, be use that is not intended for and / or does not involve medical treatment. Use in non-therapeutic methods according to the present disclosure may not involve, for example, a medical professional administering or having a substance be taken by a human or animal, and / or instructing a human or animal to administer or take 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 intake 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.

[0119] 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.

[0120] [Experiment 1: Examination of the effects of sugars on JCM5805-induced pDC activation and IFN-α production] In Experiment 1, we examined whether the sugars shown in Table 1 enhance or suppress JCM5805-induced pDC activation and IFN-α production. We also examined whether the sugars shown in Table 2 enhance or suppress them at the concentrations listed in Table 2.

[0121] <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.

[0122] 2. Preparation of sugar solution Fujifilm products were used for mannose, glucose, maltose, sucrose, lactose, fructose, and galactose. Dextrin is "TK-16" manufactured by Matsutani Chemical Industry Co., Ltd. Palatinose is "Crystalline Palatinose IC" manufactured by Mitsui Sugar Co., Ltd. Indigestible dextrin is "Kenja no Shokutaku" manufactured by Otsuka Pharmaceutical Co., Ltd. Hyaluronic acid is "Hyabestos (registered trademark) (J)" manufactured by Kewpie Co., Ltd. Pullulan is a product manufactured by Hayashibara Co., Ltd. Tamarind gum is "Glyloid (registered trademark) 5S" manufactured by MP Gokyo Food & Chemical Co., Ltd. Soybean polysaccharides are "SM-1200 (K)" manufactured by San-ei Gen F.F.I. Sodium alginate is "Kimica Arginine 1-3K" manufactured by Kimica Co., Ltd. Alginate ester is "Kimiloid" manufactured by Kimica Co., Ltd. Green banana resistant starch is a product manufactured by Nippon Kimi Food Co., Ltd. Beta-glucan is "Wellmune (registered trademark) WGP" manufactured by Ryusendo Co., Ltd. The sugar solutions used were "F3020" manufactured by Fujifilm Wako Co., Ltd., "N-acetylneuraminic acid" manufactured by Fujifilm Wako Co., Ltd., "Hyalocollagen (registered trademark)" manufactured by LS Corporation, and "Oligo and Acacia FG" manufactured by Meiji Food Materials Co., Ltd., for the mixture of fructooligosaccharides and acacia gum. These sugars were adjusted to 400 μg / ml with PBS to prepare sugar solutions. Sugar solutions were also prepared for galactose and pullulan, adjusted to 40 μg / ml, 4 μg / ml, 0.4 μg / ml, or 0.04 μg / ml with PBS. Sugar solutions were also prepared for hyaluronic acid, adjusted to 40 μg / ml or 4 μg / ml with PBS.

[0123] 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 1000 μL / mL and seeded in 96-well plates. 2 μL of the JCM5805 suspension described in 1 above was added to each well, and 5 μL of the sugar solution described in 2 above was simultaneously added. Similarly, the sugar solution alone was added to a 96-well plate seeded with bone marrow cells containing pDCs. Similarly, the JCM5805 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.).

[0124] 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.

[0125]

[0126]

[0127] When any of these substances were used alone, IFN-α production by pDC was not induced. It was confirmed that fructose and maltose suppressed IFN-α production by pDC induced by JCM5805, while substances other than fructose and maltose enhanced IFN-α production by pDC induced by JCM5805. It was also confirmed that galactose, hyaluronic acid, and pullulan enhanced IFN-α production by pDC induced by JCM5805, even when the concentrations were changed.

[0128] [Experiment 2: Examination of the effect of sugars on JCM5805-induced pDC activation and IFN-α production] In the following experiments, CAL-1 cells (deposit number FERM BP-10914) were used as pDCs to examine whether sugars enhance or suppress JCM5805-induced pDC activation and IFN-α production. The above-mentioned CAL-1 cells (deposit number FERM BP-10914) are a sample (hereinafter referred to as the "Sample") provided by Nagasaki University, a national university corporation (all rights to the Sample belong to Nagasaki University, and permission to use the Sample has been obtained from Nagasaki University). The cells were cultured at 37°C and 5% CO ２ The basal medium used for culturing CAL-1 cells and for tests using CAL-1 cells was RPMI-1640 medium (Sigma, R8758) supplemented with penicillin / streptomycin (Gibco, 15140-12) at a final concentration of 1.0% by volume (hereinafter also referred to as "serum-free medium").

[0129] <1. Preparation of Lactic Acid Bacteria Suspension> The lactic acid bacteria suspension was prepared in the same manner as described in Experiment 1, 1.

[0130] <2. Preparation of sugar solution> The sugars used were those described in <2. Preparation of sugar solution> in Experiment 1, and were diluted with PBS to 200 mg / mL for glucose and 1 mg / mL for sugars other than glucose.

[0131] 3. Test Procedure: CAL-1 cells were cultured at 5.0 x 10 in a serum-free medium. ５A cell suspension containing 2.0 × 10 cells / mL was prepared, and the cell suspension was seeded at 10 mL / well in a 10 cm diameter culture dish and cultured for 16 hours (pretreatment step). CAL-1 cells were recovered by pipetting. The recovered CAL-1 cells were transferred to serum-free medium at a concentration of 2.0 × 10 cells / mL. ５ The cells were resuspended at a concentration of 1000 cells / mL and seeded at 200 μL / well into each well of a 96-well microplate. Then, 2 μL of the JCM5805 suspension described in 1 above was added, and simultaneously, 2 μL of the sugar solution described in 2 above was added. Similarly, the sugar solution alone was added to a 96-well plate seeded with CAL-1 cells. Similarly, the JCM5805 suspension alone was added to a 96-well plate seeded with CAL-1 cells. After 24 hours, the culture supernatant was collected, and the IFN-α concentration in the culture supernatant was measured by ELISA using the Human IFN-Alpha Multi-Subtype ELISA Kit (PBL Assay Science).

[0132] 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.

[0133]

[0134] When either substance was used alone, IFN-α production by pDC was not induced. Maltose and fructose suppressed JCM5805-induced IFN-α production by pDC, whereas galactose and glucose enhanced JCM5805-induced IFN-α production by pDC.

[0135] [Experiment 3: Investigation into the effects of sugars on pDC activation and IFN-α production induced by various lactic acid bacteria or bifidobacteria] In Experiment 3, we investigated whether the sugars shown in Table 4 enhance pDC activation and IFN-α production induced by lactic acid bacteria or bifidobacteria other than JCM5805.

[0136] <1. Preparation of lactic acid bacteria suspension> Lactococcus culbatus JCM1096, Lactococcus lactis subsp. lactis ATCC7962, and 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.

[0137] 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.

[0138] 3. Preparation of sugar solution: Mannose, sucrose, and lactose were all products of Fujifilm Wako Pure Chemical Industries, Ltd. Palatinose (isomaltulose) was "Crystalline Palatinose IC" from Mitsui Sugar Co., Ltd., and indigestible dextrin was "Wise Man's Table" from Otsuka Pharmaceutical Co., Ltd. These sugars were each adjusted to 1 mg / mL with PBS to prepare a sugar solution.

[0139] 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 1000 μL / mL and seeded in a 96-well plate. 2 μL of the lactic acid bacteria suspension described in 1. above or the bifidobacterial suspension described in 2. above was added, and 2 μL of the sugar solution described in 3. above was simultaneously added (final concentration: 0.5 mg / mL). Similarly, the lactic acid bacteria suspension or the 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.).

[0140] 5. Results The amount of IFN-α produced when various lactic acid bacteria or bifidobacteria suspensions were used alone was set to 1, and the relative values ​​of the amount of IFN-α produced when various lactic acid bacteria or bifidobacteria were used in combination with sugar are summarized in the table below.

[0141]

[0142] From the above results, it was confirmed that mannose, sucrose, lactose, palatinose and indigestible dextrin enhance the IFN-α production of pDC induced by various lactic acid bacteria and bifidobacteria.

Claims

1. A composition for immunostimulation comprising a bacterium having immunostimulatory activity and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, which have the effect of enhancing the immunostimulatory activity 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 sugar 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 sugars (content of one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides) / (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 ability enhancing effect is an effect of enhancing the immunostimulating ability by 1.10 times or more.

11. The immunostimulating composition according to claim 8, wherein the sugar is one or more sugars selected from the group consisting of mannose, glucose, sucrose, lactose, galactose, isomaltulose, allulose, fructooligosaccharide, dextrin, resistant dextrin, hyaluronic acid, pullulan, tamarind gum, soybean polysaccharide, alginic acid or a derivative thereof, resistant starch, β-glucan, sialic acid, sugar derived from cockscomb extract, and acacia gum.

12. A method for immunostimulation, comprising administering or having a subject ingest a bacterium having immunostimulatory ability and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that 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 to said subject bacteria having immunostimulatory ability and one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory effect of said 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 immunostimulatory effect induced by bacteria having immunostimulatory ability, comprising one or more sugars selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides that have the effect of enhancing the immunostimulatory ability of bacteria having immunostimulatory ability.

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

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