Composition for controlling proliferation of butyric acid bacteria

Abstract

Provided is a means for controlling butyric acid production in the intestine. The present invention addresses the problem of providing a means for controlling the proliferation of butyric acid bacteria, of which Faecalibacterium bacteria are a representative example. Provided is a composition for controlling the proliferation of butyric acid bacteria, preferably Faecalibacterium bacteria, said composition including a saccharide selected from among kojibiose and an oligosaccharide having kojibiose as a constituent saccharide. In one embodiment, the composition includes galactosyl kojibiose as the saccharide selected from among kojibiose and an oligosaccharide having kojibiose as a constituent saccharide.

Description

Composition for controlling the growth of butyric acid bacteria

[0001] The present invention relates to a composition for controlling the growth of butyric acid bacteria, such as bacteria of the genus Faecalibacterium.

[0002] Faecalibacterium bacteria are among the most common bacteria present in the intestines of healthy adults and possess physiological functions favorable to human health, such as butyrate production and anti-inflammatory activity. It has been reported that Faecalibacterium bacteria are reduced in the intestines of patients with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis (Non-Patent Document 1). Similar findings have also been reported in patients with asthma, food allergies, non-alcoholic fatty liver disease, and chronic kidney disease (Non-Patent Documents 2-6). Furthermore, it has been shown that Faecalibacterium bacteria are reduced in the intestines of patients with irritable bowel syndrome (IBS) (Non-Patent Document 7), inflammatory bowel disease (IBD) (Non-Patent Document 8), Parkinson's disease (Non-Patent Document 9), and cancer (Non-Patent Document 10) compared with healthy individuals. It has also been reported that administration of this genus of bacteria to IBD model mice improves symptoms such as weight loss and diarrhea (Non-Patent Document 11), and that administration of this genus of bacteria to Alzheimer's disease model mice improves cognitive impairment (Non-Patent Document 12). Furthermore, it has been reported that Faecalibacterium prausnitzii exhibited anti-inflammatory effects in cultured cell lines and in TNBS colitis model mice (Non-Patent Document 13).

[0003] 1-Kestose is known as an active ingredient in an agent for promoting the growth of bacteria of the genus Faecalibacterium (Patent Document 1).

[0004] On the other hand, kojibiose is known to have a growth-promoting effect on bifidobacteria (e.g., Non-Patent Document 14). Patent Document 2 describes an in vivo lipid regulator containing one or more active ingredients selected from kojibiose, kojitriose, kojibiosyl glucoside, kojitetraose, and kojitriosyl glucoside.

[0005] On the other hand, it has been reported that kojibiose and 4'-galactosyl lactose do not promote the growth of Faecalibacterium prausnitzii in a fecal culture test system (Non-Patent Documents 15 and 16).

[0006] In addition, a study of various isomeric glucose disaccharides using a human colonic batch fermentation model reported that fermentation of diglucose α(1-1) (trehalose) resulted in significantly higher butyrate production compared to other α-linked diglucoses, including kojibiose (Non-Patent Document 20). Furthermore, co-cultures of Bifidobacterium adolescentis L2-32 with Faecalibacterium prausnitzii S3 / L3 using fructooligosaccharides as a carbon source and with F. prausnitzii A2-165 using starch as a carbon source reported higher butyrate concentrations in the co-cultures compared to the respective F. prausnitzii monocultures (Non-Patent Document 21).

[0007] WO2017 / 159647 (Patent No. 6301024) JP2005-281188A (Patent No. 4746281A)

[0008] Gastroenterol Res Pract. 2014; 2014:872725.Allergol Immunopathol (Madr). 2019:47(4):365-371.Int Arch Allergy Immunol. 2018;175(1-2):77-84Nat Rev Gastroenterol Hepatol. 2020;17(5):279-297.Genome Med. 2016:29;8(1):8.Circ Res. 2022 Oct 14;131(9):e120-e134.Gastroenterology. 2019;157(1):97-108.Gut. 2014;63(8):1275-1283.Microb Pathog. 2021;160:105187.Bioengineered. 2021;12(1):7046-7060.Mol Med Rep. 2019;20(1):25-32.Cell Rep Med. 2021;2(9):100398.Proc Natl Acad Sci US A. 2008;105(43):16731-16736.Journal of agricultural and food chemistry. 2005, 53, 5192-5199Journal of functional foods, 2016, 20, 532-544Appl Microbiol Biotechnol. 2013 Jul;97(13):5743-52World J Gastroenterol. 2017:23(1): 60-75.Front Nutr. 2022:9:1067647.Nature 2013:504:446-450Nutrients 2017:9(1):26FEMS Microbiology Letters, 2015:362(21), fnv176

[0009] Since there are many reports that intestinal bacteria are closely related to health, it may be possible to reduce the risk of various diseases by controlling the growth of important bacteria.

[0010] On the other hand, butyric acid is expected to have anti-fatty liver and anti-obesity effects (Non-Patent Documents 17, 18), and it has been reported that an increase in butyric acid in the intestine acts on immune control, such as inflammation suppression via an increase in regulatory T cells (Non-Patent Document 19). However, because butyric acid has a characteristic unpleasant odor, it would be preferable to have a means to control butyric acid production in the intestine rather than directly ingesting it. By using prebiotics to control the growth of butyric acid bacteria, such as Faecalibacterium bacteria, in the intestine, it is expected that various diseases can be prevented and improved.

[0011] The present invention provides the following: [1] A composition for controlling the growth of butyric acid bacteria, comprising any one selected from kojibiose and oligosaccharides containing kojibiose as a constituent sugar. [2] The composition according to 1, wherein the butyric acid bacteria are bacteria of the genus Faecalibacterium. [3] The composition according to 1 or 2, for use as a prebiotic or synbiotic. [4] A composition for treating any one selected from inflammation, asthma, food allergy, non-alcoholic fatty liver disease, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis, comprising any one selected from kojibiose and oligosaccharides containing kojibiose as a constituent sugar. [5] The composition according to 4, wherein the treatment is mediated by controlling the growth of bacteria of the genus Faecalibacterium. [6] A composition for controlling butyric acid production in the intestine, comprising any one selected from kojibiose and oligosaccharides containing kojibiose as a constituent sugar. [7] The composition according to 6, wherein the control of butyric acid production is mediated by growth control of intestinal Faecalibacterium bacteria. [8] A composition for treating a disease or condition that is ameliorated by growth control of intestinal Faecalibacterium bacteria, comprising kojibiose and oligosaccharides having kojibiose as a constituent sugar. [9] The composition according to any one of 1 to 8, wherein the composition is obtained by allowing glucansucrase to act on a raw material composition containing lactose and sucrose.

[10] The composition according to any one of 1 to 3, 5, 7, and 8, wherein the growth control is growth promotion.

[11] The composition according to any one of 1 to 3, 5, 7, 8, and 10, wherein the butyric acid bacteria or Faecalibacterium bacteria is Faecalibacterium prausnitzii.

[12] The composition according to 6 or 7, wherein the control of butyric acid production is growth promotion.

[13] The composition according to any one of 1 to 12, wherein the composition contains one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, which has the ability to promote the growth of Parabacteroides.

[14] The composition according to any one of 1 to 13, wherein the composition contains galactosyl kojibiose as any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar.

[15] A food information providing method comprising the steps of: acquiring information on the intestinal flora of a subject; deriving information on foods to be provided to the subject based on the information on the intestinal flora; and providing the derived food information to the subject, wherein in the information acquiring step, information on the presence or absence or amount of bacteria of the genus Faecalibacterium is acquired from the information on the intestinal flora, and in the food information deriving step, information on foods that are compositions containing any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar, based on the information on the presence or absence or amount of bacteria of the genus Faecalibacterium.

[16] A food information providing method comprising the steps of: acquiring information on the amount of intestinal butyric acid in a subject; deriving information on a food to be provided to the subject based on the information on the amount of intestinal butyric acid; and providing the derived food information to the subject, wherein the step of deriving food information derives information on a food that is a composition containing any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar, based on the information on the amount of intestinal butyric acid.

[17] A method for controlling Faecalibacterium bacteria in the intestines of a subject, or a method for supporting the dietary habits or health of a subject, comprising the steps of carrying out the method described in 15 or 16 and providing the food to the subject based on the derived food information.

[18] The method described in 15 or 16, wherein the food is for use as a prebiotic or synbiotic.

[19] The method described in any one of 16 to 18, further comprising the step of displaying the provided food information on a terminal of the subject.

[20] Use of any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, for controlling the growth of bacteria of the genus Faecalibacterium in intestinal bacterial flora.

[0012]

[21] A composition comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, for use in a method for controlling the growth of butyric acid bacteria. Use of any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar in the production of a composition for controlling the growth of butyric acid bacteria. A method or non-therapeutic method for controlling the growth of butyric acid bacteria, comprising the step of administering to a subject a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar. Use or non-therapeutic use of a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar, for controlling the growth of butyric acid bacteria.

[22] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to 21, wherein the butyric acid bacteria are bacteria of the genus Faecalibacterium.

[23] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to 21 or 22, wherein the composition is for use as a prebiotic or synbiotic.

[24] A composition comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent saccharide, for use in a method for treating any one selected from inflammation, asthma, food allergy, non-alcoholic fatty liver, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis. Use of any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent saccharide in the production of a composition for treating any one selected from inflammation, asthma, food allergy, non-alcoholic fatty liver, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis. A method or non-therapeutic method for treating any condition selected from inflammation, asthma, food allergy, non-alcoholic fatty liver disease, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis, comprising the step of administering to a subject a composition containing any condition selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar.

[25] Use or non-therapeutic use of a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar for treating any one selected from inflammation, asthma, food allergy, non-alcoholic fatty liver disease, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis.

[26] A composition comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar for use in a method for controlling butyric acid production in the intestine. Use of any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar in the production of a composition for controlling butyric acid production in the intestine. A method or non-therapeutic method for controlling intestinal butyric acid production, comprising the step of administering to a subject a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar. Use or non-therapeutic use of a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar, for controlling intestinal butyric acid production.

[27] The composition, use in manufacturing, method or non-therapeutic method, or use or non-therapeutic use according to 26, wherein the control of butyric acid production is mediated by control of the growth of Faecalibacterium bacteria in the intestine.

[28] A composition comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, for use in a method for treating a disease or condition that is ameliorated by control of the growth of Faecalibacterium bacteria in the intestine. Use of any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar in the manufacture of a composition for treating a disease or condition that is improved by controlling the growth of Faecalibacterium bacteria in the intestine.A method or non-therapeutic method for treating a disease or condition that is ameliorated by growth control of intestinal Faecalibacterium bacteria, comprising the step of administering to a subject a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar. Use or non-therapeutic use of a composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar, for treating a disease or condition that is ameliorated by growth control of intestinal Faecalibacterium bacteria.

[29] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to any one of items 21 to 28, wherein the composition is obtained by treating a raw material composition containing lactose and sucrose with glucansucrase.

[30] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to any one of items 21 to 23, 25, 27, and 28, wherein the growth control is growth promotion.

[31] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to any one of items 21 to 23, 25, 27, and 28, wherein the butyric acid bacterium or Faecalibacterium bacterium is Faecalibacterium prausnitzii.

[32] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to any one of items 21 to 31, wherein the composition comprises kojibiose and oligosaccharides having kojibiose as a constituent sugar, which have the ability to promote the growth of Parabacteroides.

[33] The composition, use in production, method or non-therapeutic method, or use or non-therapeutic use according to any one of items 21 to 31, wherein the composition comprises galactosyl kojibiose as the selected one of kojibiose and oligosaccharides having kojibiose as a constituent sugar.

[34] A method for controlling the growth of bacteria of the genus Faecalibacterium in intestinal bacterial flora, the method comprising a step of causing intestinal bacterial flora containing bacteria of the genus Faecalibacterium to contain any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar.

[0013] By using kojibiose or any of the oligosaccharides containing kojibiose as a prebiotic, it is possible to increase butyric acid bacteria, such as bacteria of the genus Faecalibacterium, in the intestines. Furthermore, increasing butyric acid bacteria in the intestines is expected to prevent and improve various diseases.

[0014] Changes in the occupancy rate of Faecalibacterium bacteria in the V3-V4 region amplicon sequence by MiSeq (Illumina) using galactosyl kojibiose (trisaccharide fraction) in a human fecal culture system. Black circles indicate the progress of each subject, and horizontal bars indicate the average. Chromatograms of the enzyme reaction solution and the trisaccharide and tetrasaccharide fractions after fractionation and purification. Growth inhibition effect of Parabacteroides distasoins or Parabacteroides merdae culture supernatant on Faecalibacterium prausnitzii. Growth inhibition effect of Parabacteroides distasoins or Parabacteroides merdae culture supernatant on F. hattorii, F. longum, F. gallinarum, and F. butyricigenerans.

[0015] The present embodiment relates to a composition for controlling the growth of butyric acid bacteria, typified by Faecalibacterium, which contains kojibiose and oligosaccharides having kojibiose as a constituent sugar as active ingredients.

[0016] [Active Ingredient] The composition of this embodiment contains, as an active ingredient, any one selected from the group consisting of kojibiose and oligosaccharides containing kojibiose as a constituent saccharide. When referring to oligosaccharides containing kojibiose, kojibiose itself is not included. In the present invention, the term "any one" is used to mean "at least one" unless otherwise specified. For example, "any one selected from the group consisting of kojibiose and oligosaccharides containing kojibiose" includes kojibiose alone, only one type of oligosaccharide containing kojibiose as a constituent saccharide, kojibiose and one type of oligosaccharide containing kojibiose as a constituent saccharide, and two types of oligosaccharides containing kojibiose as a constituent saccharide. "Containing as an active ingredient" means that the active ingredient is used in the composition in an effective amount to exert the intended function, or is specifically labeled as a component contributing to the intended purpose. In functional food products, active ingredients are sometimes referred to as functional ingredients (ingredients that contribute to specific health purposes (excluding those related to reducing disease risk)).

[0017] The kojibiose and oligosaccharides containing kojibiose as constituent saccharides used in the composition are not particularly limited as long as they have the desired effect. Furthermore, the kojibiose and oligosaccharides containing kojibiose as constituent saccharides used in the composition may be one type or a combination of two or more types.

[0018] Examples of oligosaccharides containing kojibiose as a constituent sugar include the trisaccharides galactosyl kojibiose, kojitriose, selaginose (kojibiosylglucoside), centose, and kojibiosylfructoside, as well as tetrasaccharides in which one molecule of a monosaccharide such as glucose is bound to one of these trisaccharides, such as kojitetraose and kojitriosylglucoside.

[0019] In a preferred embodiment, the composition contains either kojibiose or galactosyl kojibiose. Examples of such a composition include a composition containing kojibiose, a composition containing galactosyl kojibiose, a composition containing kojibiose and galactosyl kojibiose, and a composition containing kojibiose, galactosyl kojibiose, and a tetrasaccharide in which one glucose molecule is bound to galactosyl kojibiose.

[0020] In the present invention, unless otherwise specified, galactosyl kojibiose refers to kojibiose in which galactose is α- or β-linked to any of positions 1 to 8. Theoretically, galactose can be linked to the OH at position 8 in four ways (α-α, α-β, β-α, and β-β), and to the OH at positions 2 to 7 in two ways, so 18 types of galactosyl kojibiose are expected. They are called 8α-α kojibiose, 8α-β kojibiose, 8β-α kojibiose, 8β-β kojibiose, 1α kojibiose, 2β kojibiose, 2α kojibiose, 2β kojibiose, 3α kojibiose, 3β kojibiose, 4α kojibiose, 4β kojibiose, 5α kojibiose, 5β kojibiose, 6α kojibiose, 6β kojibiose, 7α kojibiose, and 7β kojibiose, respectively.

[0021]

[0022] In one embodiment, the composition comprises any one of 18 types of galactosyl kojibiose, namely, 8α-α kojibiose, 8α-β kojibiose, 8β-α kojibiose, 8β-β kojibiose, 1α kojibiose, 2β kojibiose, 2α kojibiose, 2β kojibiose, 3α kojibiose, 3β kojibiose, 4α kojibiose, 4β kojibiose, 5α kojibiose, 5β kojibiose, 6α kojibiose, 6β kojibiose, 7α kojibiose, and 7β kojibiose, and may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of these.

[0023] In a preferred embodiment, the galactosyl kojibiose contained in the composition is α-D-glucopyranosyl-(1→2)-[β-D-galactopyranosyl-(1→4)-]D-glucopyranoside. This sugar can also be described as a type of glucosyllactose.

[0024] According to the studies of the present inventors, galactosyl kojibiose has been confirmed to have an excellent growth inhibitory effect on Faecalibacterium bacteria, a type of butyric acid bacteria. Here, galactosyl kojibiose is a type of oligosaccharide containing kojibiose as a constituent sugar, and after being administered to a subject, it can be decomposed by lactase in the subject's digestive tract to produce kojibiose. Therefore, any sugar containing kojibiose as a constituent sugar can similarly produce kojibiose in the intestine and exhibit the same effect as galactosyl kojibiose.

[0025] In another preferred embodiment, the composition contains either kojibiose or an oligosaccharide having kojibiose as a constituent sugar, which has the ability to promote the growth of bacteria of the genus Parabacteroides.

[0026] Parabacteroides bacteria are one of the most common bacteria present in the intestines of healthy adults. According to the inventors' studies, when Faecalibacterium bacteria, a type of butyric acid bacteria, were cultured in the culture supernatant of Parabacteroides bacteria, their growth was promoted compared to when they were cultured in fresh medium. Therefore, it can be said that the growth of butyric acid bacteria such as Faecalibacterium bacteria may be controlled through the growth of Parabacteroides bacteria. The inventors have separately confirmed that kojibiose and oligosaccharides containing kojibiose promote the growth of Parabacteroides bacteria (PCT / JP2023 / 030455). Furthermore, other experiments have suggested that promoting the growth of Parabacteroides bacteria can control the growth of Faecalibacterium bacteria (application in preparation).

[0027] According to studies by the present inventors, among kojibiose and oligosaccharides containing kojibiose as their constituent sugars, kojibiose and galactosyl kojibiose promote the growth of Parabacteroides bacteria. Other oligosaccharides containing kojibiose as their constituent sugars that promote the growth of Parabacteroides bacteria can be identified according to the procedure for evaluating whether a certain component inhibits the growth of Faecalibacterium bacteria in the intestine, as described below.

[0028] In one aspect, the composition contains either kojibiose or an oligosaccharide having kojibiose as a constituent sugar, which promotes the growth of Parabacteroides bacteria selected from P. distasonis and P. merdae, preferably P. distasonis.

[0029] The origin and production method of the kojibiose and oligosaccharides containing kojibiose used in the present invention are not particularly limited, and they may be produced by any method, such as fermentation, enzymatic methods, or organic synthesis. One preferred production method includes a step of treating a raw material composition containing lactose and sucrose with glucansucrase, or lactic acid bacteria expressing glucansucrase, or a processed product thereof, to obtain a composition containing galactosyl kojibiose. In the present invention, glucansucrase refers to an enzyme belonging to glycoside hydrolase (also known as glycosyl hydrolases) family 70 (GH70), unless otherwise specified (see (CAZy) databases and Cantarel et al., Nucleic Acids Res. 37:D233-238, 2009).

[0030] When lactic acid bacteria are used, it is preferable that they are lactic acid bacteria that express glucansucrase. Preferred examples of lactic acid bacteria are lactic acid bacteria belonging to the family Leuconostoc, more preferably lactic acid bacteria belonging to the genus Leuconostoc, and even more preferably Leuconostoc mesenteroides. When lactic acid bacteria are used, it is preferable that they are lactic acid bacteria that constantly express glucansucrase. Preferred examples of lactic acid bacteria include lactic acid bacteria belonging to the Lactobacillaceae family, more preferably lactic acid bacteria belonging to the genus Liquorilactobacillus or Limosilactobacillus, and even more preferably Limosilactobacillus reuteri and Liquorilactobacillus satsumensis. When using lactic acid bacteria, it is preferable that the lactic acid bacteria constantly express glucansucrase, and more preferably that the glucansucrase is of the cell-bound type. Preferred examples of lactic acid bacteria include lactic acid bacteria belonging to the Lactobacillaceae family, more preferably lactic acid bacteria belonging to the genus Liquorilactobacillus, and even more preferably Liquorilactobacillus satsumensis. A particularly preferred example of Liquorilactobacillus satsumensis strain is JCM12392. Note that JCM12392 is referred to as Lactobacillus satsumensis in RIKEN BioResource Center, GENERAL CATALOG No.9, 2012, JAPAN COLLECTION OF MICROORGANISMS, M51.

[0031] In addition, when describing lactic acid bacteria in relation to the present invention, unless otherwise specified, the classification follows the reclassification by Zheng J, Wittouck S, Salvetti E, Franz CMAP, Harris HMB, Mattarelli P, O'Toole PW, Pot B, Vandamme P, Walter J, Watanabe K, Wuyts S, Felis GE, Ganzle MG, Lebeer S.: A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae. Int J Syst Evol Microbiol. 2020 Apr; 70(4): 2782-2858. According to the classification before the reorganization, Liquorilactobacillus satsumensis is classified as Lactobacillus satsumensis.

[0032] The lactic acid bacteria that express glucansucrase or a processed product thereof is preferably any one selected from the group consisting of live bacteria, killed bacteria, a culture containing bacteria, crushed bacteria, and a purified product of glucansucrase.

[0033] Glucansucrase, or lactic acid bacteria expressing glucansucrase, or processed products thereof, used for producing kojibiose and oligosaccharides containing kojibiose as a constituent sugar can be produced using transformation, chemical synthesis, or genome editing techniques.

[0034] The composition containing galactosyl kojibiose obtained by such a production method can be used as is as a solution containing kojibiose and oligosaccharides composed of kojibiose as a constituent sugar, or can be used after purification with an ion exchange resin, etc. That is, the composition of the present invention may be a composition containing galactosyl kojibiose obtained by treating a composition containing sucrose and lactose with glucansucrase, or a lactic acid bacterium expressing glucansucrase, or a processed product thereof.

[0035] [Uses] (Function, Action, and Effect) The composition of this embodiment can be used to control the growth of butyric acid bacteria. In the present invention, butyric acid bacteria are beneficial bacteria (bacteria beneficial to health) that can produce butyric acid in the intestine. Butyric acid bacteria are also sometimes called butyrate-producing bacteria. In a preferred embodiment, the composition can be used to control the growth of butyric acid bacteria in the human intestine. Controlling the growth of butyric acid bacteria in the human intestine refers to controlling the growth of butyric acid bacteria in a state where various bacteria living in the human intestine are present (sometimes referred to as "intestinal flora"). In the present invention, "intestinal flora" refers to the flora in which various bacteria living in the intestine are present, including, for example, the flora contained in feces, but is not limited to the flora present in the intestine. In the present invention, "control" includes upward control (also referred to as "promotion" or "increase") and downward control (also referred to as "inhibition" or "decrease"), preferably upward control. Control of growth can be control of the number of bacteria or control of the occupancy rate, as described below.

[0036] In the present invention, the intestine refers to the digestive organ in humans and animals where bacteria normally reside and which digests and absorbs ingested food. The intestine includes the small intestine and the large intestine, and is preferably the large intestine.

[0037] In one embodiment, the composition is used to control the growth of any butyric acid bacteria selected from the group consisting of bacteria belonging to the genus Faecalibacterium, bacteria belonging to the genus Coprococcus, bacteria belonging to the genus Clostridium, bacteria belonging to the genus Eubacterium, bacteria belonging to the genus Roseburia, bacteria belonging to the genus Butyrivibrio, bacteria belonging to the genus Anaerostipes, bacteria belonging to the genus Subdoligranulum, bacteria belonging to the genus Anaerotruncus, bacteria belonging to the genus Ruminococcus, bacteria belonging to the genus Shuttleworthia, bacteria belonging to the genus Lachnospira, bacteria belonging to the genus Megasphaera, and bacteria belonging to the genus Butyricicoccus.

[0038] In another aspect, the composition is used to control the growth of any selected from the following bacteria: The following are the main butyric acid bacteria isolated from the human large intestine: Faecalibacterium prausnitzii, Faecalibacterium longum, Faecalibacterium butyricigenerans, Faecalibacterium hattorii, Faecalibacterium ducaniae, Eubacterium lomosum, Eubacterium rectale, Roseburia intestinalis, Roseburia faecis, Roseburia hominis, Roseburia inulinivorans, Roseburia ceccicola, Butyrivibrio fibrisolvens, Butyrivibrio crossotus, Butyrivibrio proteoclasticus, Eubacterium ramulus, Eubacterium hallii, Anaerostipes caccae, Anaerostipes butyraticus, Anaerostipes handrus, Anaerostipes rhamnosivorans, SSC / 2, SS2 / 1, SS3 / 4,GM2 / 1, Coprococcus catus, Coprococcus eutactus, Coprococcus comes, Eubacterium cylindroides, Subdoligranulum variabile, Anaerotruncus colihominis, Clostridium acetobutylicum, Clostridium butyricum, Clostridium saccharobutylicum, Clostridium tyrobutyricum, Clostridium hathewayi, Clostridium indolis, Clostridium nexile, Clostridium symbiosum, Clostridium orbiscidens, Ruminococcus gnavus, Ruminococcus obeum, Shuttleworthia satelles, Lachonpira multipara, Lachnospira eligens, Lachonpira multiparis, Lachnospira pectinoschiza, Megasphaera elsdenii, Butyricicoccus pullicaecorum,

[0039] In a preferred embodiment, the composition is used to control the growth of bacteria belonging to the genus Faecalibacterium (sometimes simply referred to as Faecalibacterium bacteria) in the intestine. Note that, in the following, the present invention, embodiments, and examples will be explained using Faecalibacterium bacteria as an example of butyric acid bacteria, but those skilled in the art will be able to apply and understand the explanation to other butyric acid bacteria.

[0040] Examples of the bacterium of the genus Faecalibacterium include: Faecalibacterium prausnitzii; Faecalibacterium duncaniae Faecalibacterium longum Faecalibacterium butyricigenerans Faecalibacterium hattorii The bacterium of the genus Faecalibacterium is preferably Faecalibacterium prausnitzii.

[0041] In the present invention, the term "Faecalibacterium bacteria" refers to bacteria identified as belonging to the genus Faecalibacterium by molecular phylogenetic analysis based on the 16S rRNA gene. Criteria for determining genera based on molecular phylogenetic analysis based on the 16S rRNA gene are well known to those skilled in the art (Stackebrandt E, Ebers J. Taxonomic parameters revisited: tarnished gold standards. Microbiol Today 2006;33:152-155).

[0042] In the present invention, controlling the growth of a specific bacterium in a bacterial flora means controlling the proportion (occupancy rate) of the specific bacterium in the bacterial flora.

[0043] Whether a certain component inhibits the growth of Faecalibacterium bacteria in the intestine can be evaluated as follows: Feces containing Faecalibacterium bacteria provided by a healthy subject is added to an appropriate medium and, if necessary, incubated for a certain period of time. After that, the component to be evaluated is added and incubated under appropriate conditions (e.g., 37°C, anaerobic conditions, 48 ​​hours, similar to intestinal conditions). The number of Faecalibacterium bacteria in the bacterial flora in the culture is then measured. The measurement results can then be compared with those of a culture incubated under identical conditions except for the addition of a control (e.g., sterilized water) instead of the component to be evaluated.

[0044] The number of Faecalibacterium bacteria contained in the bacterial flora can be determined by known methods. One preferred method is to perform 16S metagenomic analysis (sequencing analysis of 16S rRNA gene amplicons) on DNA extracted from the culture. When performing 16S metagenomic analysis, DNA extraction can be performed using a commercially available kit. The genomic region to be analyzed is not particularly limited as long as it allows identification of the bacteria, but the V3-V4 region of the 16S rRNA gene can be used. Primers, amplification conditions, amplicon purification, and other methods for bacterial analysis are also well known to those skilled in the art. Sequence analysis is preferably performed using a next-generation sequencer with higher performance. QIIME 2 is used to analyze the obtained data. TM For 16S metagenomic analysis, those skilled in the art can refer to information such as Sanschagrin S, Yergeau E. Next-generation sequencing of 16S ribosomal RNA gene amplicons. J Vis Exp. 2014;(90):51709. Published 2014 Aug 29. doi:10.3791 / 51709.

[0045] In one embodiment, the composition can be used to treat any condition selected from inflammation, asthma, food allergy, non-alcoholic fatty liver disease, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis. Unless otherwise specified, the treatment is not limited to treatments mediated by growth control of Faecalibacterium bacteria in the intestine.

[0046] Faecalibacterium bacteria are among the most common bacteria present in the intestines of healthy adults and possess physiological functions favorable to human health, such as butyrate production and anti-inflammatory activity. It has also been reported that Faecalibacterium bacteria are reduced in the intestines of patients with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis (Non-Patent Document 1). Similar findings have also been reported in patients with asthma, food allergies, non-alcoholic fatty liver disease, and chronic kidney disease (Non-Patent Documents 2-6). Furthermore, it has been shown that Faecalibacterium bacteria are reduced in the intestines of patients with irritable bowel syndrome (IBS) (Non-Patent Document 7), inflammatory bowel disease (IBD) (Non-Patent Document 8), Parkinson's disease (Non-Patent Document 9), and cancer (Non-Patent Document 10) compared with healthy individuals. It has also been reported that administration of this genus of bacteria to IBD model mice improves symptoms such as weight loss and diarrhea (Non-Patent Document 11), and that administration of this genus of bacteria to Alzheimer's disease model mice improves cognitive impairment (Non-Patent Document 12). Furthermore, it has been reported that Faecalibacterium prausnitzii exhibited anti-inflammatory effects in cultured cell lines and TNBS colitis model mice (Non-Patent Document 13). Therefore, in one embodiment, the composition can be used for treating intestinal inflammation through the control of intestinal Faecalibacterium bacteria proliferation. Also, in another embodiment, the composition can be used for treating Crohn's disease and inflammatory bowel disease through the control of intestinal Faecalibacterium bacteria proliferation. Inflammatory bowel diseases include ulcerative colitis and Crohn's disease. In another embodiment, the composition can be used for treating any disease or condition selected from asthma, food allergy, non-alcoholic fatty liver disease, chronic kidney disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Parkinson's disease, cancer, symptoms associated with IBD such as weight loss and diarrhea, cognitive impairment in Alzheimer's disease, and inflammation through the control of intestinal Faecalibacterium bacteria proliferation.

[0047] When used as an anti-inflammatory agent or for the treatment of inflammatory bowel disease, the composition may be configured to be free of any of the following: oligosaccharides (e.g., raffinose, stachyose, galactooligosaccharides, isomaltooligosaccharides, lactulose, xylooligosaccharides, agarooligosaccharides, mannooligosaccharides, or fructooligosaccharides), inulin, pectin, modified pectin, guar gum, hydrolyzed guar gum, psyllium seed gum, karaya gum, tragacanth gum, gum arabic, resistant starch, resistant dextrin, polydextrose, cellulose, hemicellulose, soybean polysaccharides, β-glucan, glucomannan, galactomannan, chondroitin sulfate, hyaluronic acid, levan, lignin, alginic acid and salts thereof, agarose, and chitosan.

[0048] When used for anti-inflammatory purposes or for treating inflammatory bowel disease, the composition contains any one selected from sugar acid-containing oligosaccharides and salts thereof as an active ingredient, and may not contain any other oligosaccharides.

[0049] Furthermore, the composition can be used for treating a variety of diseases or conditions that can be improved by controlling the growth of Faecalibacterium bacteria in the intestines.

[0050] The composition of this embodiment can also be used to regulate butyric acid production in the intestine, preferably to promote butyric acid production. In a preferred embodiment, the composition regulates butyric acid production through the regulation of the growth of Faecalibacterium bacteria in the intestine.

[0051] Whether a certain component can regulate butyrate production in the intestine can be determined by measuring the butyrate concentration in feces provided by healthy individuals who have ingested the component and comparing it with an appropriate control, if necessary. Alternatively, feces provided by healthy individuals can be added to an appropriate medium and, if necessary, incubated for a certain period of time. The component to be evaluated is then added and incubated under appropriate conditions (e.g., 37°C under anaerobic conditions for 48 hours, similar to intestinal conditions). The butyrate concentration in the culture is then measured. The measurement results can then be compared with those of a culture cultured under identical conditions except for the addition of a control (e.g., sterile water, which is known not to regulate butyrate production) instead of the component to be evaluated. The method for measuring butyrate in a sample can be determined appropriately depending on the sample and butyrate concentration, and can be measured by, for example, HPLC, gas chromatography, etc.

[0052] Butyric acid is a short-chain fatty acid present in the intestine. Butyric acid is expected to have anti-fatty liver and anti-obesity effects (Non-Patent Documents 17 and 18). It has also been reported that an increase in butyric acid in the intestinal tract acts on immune control, such as inflammation suppression, via an increase in regulatory T cells (Non-Patent Document 19). Therefore, the composition of the present invention can be used to treat diseases or conditions that can be prevented or improved by increasing intestinal butyric acid, or diseases or conditions caused by a decrease in intestinal butyric acid, and can also be used for inhibiting fatty liver, obesity, and immune control.

[0053] In the present invention, the term "treatment" for a disease or condition includes reducing the risk of onset, delaying onset, prevention, cure, and halting or delaying progression. Treatment also includes maintaining a normal or desirable state, maintaining ability, and alleviating symptoms (preferably temporary symptom relief). Treatment also includes helping to improve from a disease or condition, alleviating a disease or condition, and reducing the risk of developing a disease or condition. Treatment includes radical treatment (treatment that eliminates the cause) and symptomatic treatment (treatment that improves symptoms). Actions for improvement or treatment include medical procedures performed by physicians and nurses and midwives under the direction of a physician, as well as non-therapeutic procedures performed by persons other than physicians, such as pharmacists, nutritionists (including registered dietitians and sports nutritionists), public health nurses, midwives, nurses, clinical laboratory technicians, sports instructors, pharmaceutical manufacturers, pharmaceutical distributors, food manufacturers, and food distributors. It also includes subjects who, based on the judgment of a computer program, are recommended to consume foods, beverages, or medicines capable of controlling Fusobacterium spp. Furthermore, prevention or reduction of the risk of onset includes recommending the intake of specific foods and nutritional guidance (including nutritional guidance necessary for the medical treatment of injured or sick people, and nutritional guidance for maintaining and promoting health).

[0054] (Subjects) The composition of this embodiment is suitable for administration to subjects for whom it is desirable or necessary to control the growth of butyric acid bacteria, preferably Faecalibacterium bacteria, in the intestine; subjects for whom it is desirable or necessary to control intestinal butyric acid production; subjects with a disease or condition that can be prevented or improved by increasing intestinal butyric acid; subjects with a disease or condition caused by a decrease in intestinal butyric acid; subjects with or at risk of fatty liver; subjects with or at risk of obesity; subjects for whom it is desirable or necessary to control immunity; subjects for whom it is desirable or necessary to treat intestinal anti-inflammatory diseases; subjects with or at risk of inflammatory bowel disease; and subjects with a disease or condition that can be improved by controlling the growth of Faecalibacterium bacteria in the intestine. Examples of subjects for whom it is desirable or necessary to control the growth of Faecalibacterium bacteria include those with inflammatory bowel disease, allergies (asthma), food allergies, non-alcoholic fatty liver disease, chronic kidney disease, and dementia.

[0055] Subjects for whom it is desirable or necessary to control the growth of butyric acid bacteria, preferably Faecalibacterium bacteria, in the intestine include subjects for whom relatively low amounts of intestinal butyric acid bacteria, preferably Faecalibacterium bacteria, are detected in at least one of the intestine and feces, or in whom relatively low amounts of butyric acid are detected in the intestine. Furthermore, subjects for whom it is desirable or necessary to control the growth of butyric acid bacteria, preferably bacteria of the genus Faecalibacterium, in the intestine include subjects who have been found to have a relatively low number or occupancy of butyric acid bacteria, preferably bacteria of the genus Faecalibacterium, in the intestine, or subjects who have been found to have a relatively low amount of butyric acid in the intestine, through any test or analysis such as an intestinal flora test, a test for substances in the feces, or a fecal metabolome analysis; subjects who have been found to be at high risk of any of inflammation, asthma, food allergies, non-alcoholic fatty liver disease, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis; and subjects who have been recommended, based on the test or analysis results, by a doctor, nurse, pharmacist, nutritionist, etc., or by a computer program, to take a food, drink, or medicine that controls the growth of butyric acid bacteria, preferably bacteria of the genus Faecalibacterium, in the intestine.

[0056] A subject in which a relatively low number or occupancy rate of Faecalibacterium bacteria has been detected in at least one of the intestines and feces includes, for example, a subject in which, when a culture solution containing stool collected from the subject is cultured at 37°C under anaerobic conditions for 24 hours, the occupancy rate of Faecalibacterium bacteria in the culture solution is 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.3% or less.

[0057] In one embodiment, the subject is healthy (not having a medically diagnosed illness). The subject may be a human or a non-human animal.

[0058] The age of the subject is not particularly limited, and the subject may be, for example, a newborn (within 28 days of birth); an infant (less than 1 year of age); a toddler (1 to 6 years of age); a child (7 years of age or older, but less than 15 years of age); an adult (15 years of age or older); or a person 65 years of age or older.

[0059] [Composition] (Food composition, etc.) The composition of the present invention can be a food composition or a pharmaceutical composition. Foods and pharmaceuticals include not only those for humans but also those for non-human animals, unless otherwise specified. Foods include general foods, functional foods, nutritional compositions, and also therapeutic foods (those that serve the purpose of treatment; prepared based on a menu prepared by a nutritionist or the like in accordance with a doctor's dietary prescription), dietary therapy foods, ingredient-modified foods, nursing care foods, and foods for medical support, unless otherwise specified. Foods include not only solid foods but also liquid foods, such as beverages, energy drinks, liquid foods, and soups, unless otherwise specified. Functional foods refer to foods that can impart a specific functionality to the body, and include a wide range of health foods, including foods for specified health uses (including conditional FOSHUs [foods for specified health uses]), foods with functional claims, health functional foods including foods with nutrient functions, foods for special dietary uses, dietary supplements, health supplements, supplements (e.g., tablets, coated tablets, sugar-coated tablets, enteric-coated preparations, capsules (e.g., enteric-coated soft capsules, enteric-coated hard capsules, colon delivery capsules, etc.), liquids, etc.), dietary supplements, food supplements, medical foods (as defined by the U.S. Food and Drug Administration (FDA)), and beauty foods (e.g., diet foods). In the present invention, "functional foods" also includes health foods that make health claims based on the Codex Alimentarius (the Joint FAO / WHO Food Standards Commission). Food supplements are supplements to the normal diet and are concentrated with nutrients or other substances that have nutritional or physiological effects, either alone or in combination, and are labeled as "food supplements." Dietary supplements are products (excluding tobacco) intended to supplement the diet, contain one or more of the targeted ingredients, and are labeled as dietary supplements. The ingredients may also be refined products of specific sugars. Refined products include fractionated, partially refined, and crudely refined products. Actual labeling of the product on food products follows the labeling laws of each country.

[0060] (Route of Administration, etc.) The composition of the present invention may be administered orally, parenterally, for example, via a tube (gastrostomy, enterostomy), or nasally, but is preferably administered orally. In the present invention, "administer" is used not only to refer to administering a pharmaceutical to a subject, but also to refer to ingesting food or other non-pharmaceutical substances into a subject. "Administer" can be read as "intake," and "administer" can be read as "administer."

[0061] The composition can be administered to a subject repeatedly or continuously for a long period of time. The period is not particularly limited, but to ensure sufficient efficacy, it is preferable to administer the composition continuously for a relatively long period of time, for example, 3 days or more, 1 week or more, 2 weeks or more, 1 month or more, 3 months or more, 6 months or more, or 1 year or more.

[0062] The compositions may be administered routinely, proactively, such as when at high risk, or when the need arises. The compositions may be administered with a meal, before a meal, after a meal, between meals, or at the onset of the disease or condition that the composition is intended to ameliorate.

[0063] (Dose, Content) In this embodiment, the active ingredient kojibiose or any one selected from oligosaccharides having kojibiose as a constituent sugar can be used in an amount acceptable for food or pharmaceutical use. The dosage of the composition of this embodiment may be any amount that achieves the desired effect. The dosage can be set appropriately taking into consideration various factors such as the age, weight, and symptoms of the subject.

[0064] The daily dosage of the composition can be an amount acceptable for food or pharmaceutical use, and the amount of active ingredient can be 0.5 g or more, 1 g or more, preferably 2 g or more, preferably 3 g or more, more preferably 5 g or more, and even more preferably 10 g or more. Regardless of the lower limit, the upper limit of the active ingredient per day can be 80 g or less, 70 g or less, 60 g or less, 50 g or less, 40 g or less, 30 g or less, 20 g or less, or 15 g or less. When multiple active ingredients are contained in a composition, the amount of active ingredient refers to the total amount of the active ingredients contained.

[0065] Administration may be once a day or multiple times a day, for example, 2 to 10 times. The amount of active ingredient administered per dose can be, for example, 0.5 g or more, 1 g or more, preferably 2 g or more, more preferably 3 g or more, and even more preferably 5 g or more. The upper limit of the amount of active ingredient per dose, regardless of the lower limit, can be 70 g or less, 60 g or less, 50 g or less, 40 g or less, 30 g or less, 25 g or less, or 10 g or less.

[0066] The content of the active ingredient in the composition can be an amount acceptable for food or pharmaceutical use, and can be adjusted appropriately depending on the form of the composition. For example, when the composition is in a form to be eaten or consumed as is, such as fermented milk or a beverage, the content of the active ingredient per 100 g of the composition can be 0.01% or more, preferably 0.1% or more, more preferably 0.3% or more, and even more preferably 0.5% or more. The upper limit of the active ingredient per 100 g of the composition, regardless of the lower limit, can be 8% or less, 5% or less, 4% or less, or even 3% or less. Alternatively, the content of the active ingredient per solid content of the composition can be 0.1% or more, preferably 1% or more, more preferably 3% or more, and even more preferably 5% or more. The upper limit of the active ingredient per solid content, whatever the lower limit, may be 80% or less, 50% or less, 40% or less, or even 30% or less. In the present invention, % means % by mass unless otherwise specified.

[0067] (Other Ingredients, Additives) The composition of the present invention may contain other active ingredients or nutritional ingredients that are acceptable as foods or pharmaceuticals. Examples of such ingredients include lipids (e.g., milk fat, vegetable oil, medium-chain fatty acid-containing oil), proteins (e.g., milk protein, milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin (α-La), β-lactoglobulin (β-Lg), heat-denatured whey protein, and enzyme-treated whey protein), amino acids (e.g., lysine, arginine, glycine, alanine, glutamic acid, leucine, isoleucine, valine), kojibiose, and sugars containing kojibiose as a constituent sugar. carbohydrates other than oligosaccharides (glucose, sucrose, fructose, maltose, trehalose, erythritol, maltitol, palatinose, xylitol, dextrin), electrolytes (e.g., sodium, potassium, calcium, magnesium), vitamins (e.g., vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, biotin, folic acid, pantothenic acid, and nicotinic acids), minerals (e.g., copper, zinc, iron, cobalt, manganese), antibiotics, dietary fiber, etc.

[0068] In the present invention, the composition may contain a prebiotic other than the active ingredient. Prebiotics can be defined as indigestible food ingredients that have a beneficial effect on the host and improve the host's health by selectively altering the growth and activity of specific bacteria in the large intestine. The composition may contain one or more prebiotics other than the active ingredient.

[0069] The prebiotics other than the active ingredient are not particularly limited as long as they do not interfere with the effects of the active ingredient contained in the composition. Examples of prebiotics other than the active ingredient include galactooligosaccharides, fructooligosaccharides (GF2, GF3, GF4), xylooligosaccharides, isomaltooligosaccharides, raffinose, lactulose, lactosucrose, soybean oligosaccharides, coffee oligosaccharides, dietary fiber, and gluconic acid.

[0070] The composition can also be used as a synbiotic, and may contain probiotics in addition to the active ingredient. Synbiotics are a combination of probiotics and prebiotics. Probiotics can be defined as microorganisms that have beneficial effects on the host when introduced into the intestines of the host in a live state.

[0071] The probiotics are not particularly limited as long as they do not interfere with the effects of the active ingredients contained in the composition. Known examples of probiotics include certain lactic acid bacteria.

[0072] The composition may further contain additives acceptable for use as food or pharmaceuticals, such as inert carriers (solid or liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, solubilizers, suspending agents, coating agents, colorants, preservatives, buffers, pH adjusters, emulsifiers, stabilizers, sweeteners, antioxidants, flavors, acidulants, and natural products. More specifically, examples of the additives include water, other aqueous solvents, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, sodium alginate, dextrin, water-soluble dextran, water-soluble dextrin, corn starch, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, magnesium stearate, precipitated calcium carbonate, talc, human serum albumin, mannitol, sorbitol, lactose, sucralose, lactose hydrate, candy powder, white sugar, stevia, aspartame, acesulfame potassium, citric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, acetic acid, fruit juice, and vegetable juice.

[0073] (Dosage Form / Form) In one embodiment, the food composition may be prepared in any form, such as a solid, liquid, mixture, suspension, powder, granules, paste, jelly, gel, or capsule. The food composition of the present invention may also be in any form, such as dairy products, supplements (e.g., tablets, coated tablets, sugar-coated tablets, enteric-coated preparations such as enteric coatings, capsules (enteric-coated soft capsules, enteric-coated hard capsules, colon-delivery capsules, etc.), confectioneries, beverages, health drinks, seasonings, processed foods, prepared foods, or soups. More specifically, the composition of the present invention may be in the form of liquid food, semi-liquid food, jelly, gel, powder, infant formula, infant formula, powdered or liquid milk for pregnant or lactating women, fermented milk, bar, mousse, chocolate, biscuits, ice cream, fermented milk, lactic acid bacteria drink, dairy drink, dairy drink, soft drink, fruit juice drink, tablet, cheese, bread, biscuit, cracker, pizza crust, food for the sick, nutritional food, frozen food, or processed food. The formulation may be in the form of granules, powder, paste, concentrated liquid, etc., for mixing with beverages or foods. The granules and powder may be in the form of cubes or sticks (single-serving packets). For the purposes of this invention, modified milk powder refers to a powdered form of raw milk, cow's milk, special cow's milk, or raw buffalo milk, or a food made from these ingredients, processed or used as the main ingredient, to which nutrients necessary for infants have been added, as defined in the Ministerial Ordinance on Milk and Dairy Products (hereinafter referred to as the "Milk and Dairy Products Ordinance"). For the purposes of this invention, modified liquid milk refers to a liquid form of raw milk, cow's milk, special cow's milk, or raw buffalo milk, or a food made from these ingredients, processed or used as the main ingredient, to which nutrients necessary for infants have been added, as defined in the Milk and Dairy Products Ordinance.

[0074] In one aspect, the pharmaceutical composition can be in any dosage form suitable for oral administration, such as a solid formulation such as a tablet, granules, powder, pill, or capsule; a liquid formulation such as a solution, suspension, or syrup; a gel; or an aerosol.

[0075] (Production method, etc.) In one embodiment, in the production of a composition, the stage of blending the active ingredient can be selected as appropriate. The stage of blending is not particularly limited as long as it does not significantly impair the properties of the active ingredient. For example, the active ingredient can be blended by mixing it with raw materials. Alternatively, the active ingredient can be added at the final stage of production to produce a composition containing the active ingredient.

[0076] (Labeling) In one embodiment, the composition can be labeled with its intended use (application), and in another embodiment, the function of the composition or active ingredient or the usage based on that function is labeled. Examples of usage based on the displayed function are as described above for functions, actions, and effects. In addition, the composition of the present invention can be labeled with the fact that it can be used as a prebiotic or as a synbiotic (a combination of probiotics and prebiotics). Note that a period such as "temporary" or "long-term" may be displayed at the beginning of each statement as appropriate.

[0077] In one embodiment, the composition is labeled to recommend administration to a specific subject. Examples of subjects for which the labeling is provided are as described above for subjects.

[0078] Representation can be explicit or implicit. Examples of explicit representations are direct descriptions on tangible objects such as the product itself, packaging, containers, labels, tags, etc., while examples of implicit representations (which can also be called implied) include advertising and promotional activities by place or means such as websites, stores, pamphlets, exhibitions, seminars such as media seminars, books, newspapers, magazines, television, radio, mail, email, and audio.

[0079] In one embodiment, the recommendation to consume the composition is displayed personally. Such a display can be provided via a document (whether written or electronic) addressed to the subject, the subject's tablet, smartphone, personal computer, or social networking site. Furthermore, such a display can be provided together with the results of any test or analysis, such as an intestinal flora test, a fecal substance test, or a fecal metabolome analysis, for the subject. This can also be utilized in precision nutrition (individualized nutrition, which refers to proposing an appropriate diet (nutrition) tailored to an individual's constitution).

[0080] [Device, provision method, etc.] In this embodiment, a food information provision device is provided, comprising: an information acquisition unit that acquires information on the intestinal flora of a subject; a derivation unit that derives information on food to be provided to the subject based on the information on the intestinal flora; and a provision unit that provides the derived food information to the subject.

[0081] In a preferred embodiment, the information acquisition unit of the device acquires information on the presence or amount of butyric acid bacteria from information on the intestinal bacterial flora, and the derivation unit derives information on a food that is a composition containing either kojibiose or an oligosaccharide having kojibiose as a constituent sugar, based on the information on the presence or amount of butyric acid bacteria.

[0082] In one embodiment, along with obtaining information on the subject's intestinal microbiota, any of the following information about the subject may be obtained: attribute information including any selected from the group consisting of the subject's sex and age; test result information on the subject's physical and health condition including any selected from the group consisting of the subject's height, weight, body mass index (BMI), obesity level, body fat, abdominal circumference, blood pressure, lipids, liver and pancreas function, metabolic system, blood, urine, kidney function, and large intestine; survey results information on the subject's preferences and lifestyle including any selected from the group consisting of the subject's eating habits (preferences), drinking habits, smoking habits, smoking history, exercise habits, and sleep time; and the subject's subjective symptoms, stress, illnesses currently being treated or monitored, medications and health foods being taken, medical history, and experience of pregnancy and childbirth; and other information about the subject's work history and general lifestyle.

[0083] The information may be obtained based on responses obtained from the subject to predetermined questions (eg, responses to a questionnaire).

[0084] In one aspect, the food information providing device can display the provided food information on a target terminal. In another aspect, the device further includes a display unit that displays the provided food information. The display unit can be a target terminal, such as a tablet terminal, a smartphone, or a personal computer.

[0085] In one aspect, the food information providing device may be equipped with an analysis unit that analyzes samples obtained from a subject for bacterial flora and fecal substance testing, butyric acid content, and fecal metabolome analysis, and may also be equipped with an order receiving unit that receives food orders from a subject based on the provided food information.

[0086] This embodiment also provides a food information providing method, which includes the following steps: acquiring information on the intestinal microbiota of a subject; deriving information on foods to be provided to the subject based on the information on the intestinal microbiota; and providing the derived food information to the subject.

[0087] In a preferred embodiment, in the step of acquiring information, information on the presence or amount of butyric acid bacteria is acquired from information on the intestinal bacterial flora, and in the step of deriving food information, information on the food is a composition containing any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, based on the information on the presence or amount of butyric acid bacteria.

[0088] Such a method may further include displaying the provided food information on a target terminal, which may be, for example, a tablet terminal, a smartphone, or a personal computer.

[0089] This embodiment also provides a method for controlling Faecalibacterium bacteria in the intestines of a subject or a method for supporting the dietary habits or health of a subject, which method comprises carrying out the above-mentioned method for providing food information and further carrying out the following steps: A method for controlling Faecalibacterium bacteria in the intestines of a subject or a method for supporting the dietary habits or health of a subject, which method comprises a step of providing food to the subject based on the derived food information.

[0090] The food in this embodiment is preferably for use as a prebiotic or synbiotic. The food here can also be referred to as a food composition, and the explanation in the section on compositions above applies as is.

[0091] [Culturing Method, etc.] In another embodiment, there is provided a method for culturing butyric acid bacteria, preferably bacteria of the genus Faecalibacterium, using any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, or the use of any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar in culturing butyric acid bacteria, preferably bacteria of the genus Faecalibacterium. The culturing or use may be carried out in intestinal bacterial flora. In another embodiment, there is provided a method for controlling the growth of bacteria of the genus Faecalibacterium in intestinal bacterial flora, the method comprising a step of incorporating any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar into intestinal bacterial flora containing bacteria of the genus Faecalibacterium. The incorporating step can be achieved by adding, providing, strengthening, supplementing, or the like, the desired component.

[0092] The present invention will be described in more detail below using examples, although the technical scope of the present invention is not limited to these examples.

[0093] [Culture Example 1] (Fecal culture) Feces from healthy adults were suspended in a semi-solid medium for GAM glycolysis "Nissui" (Nissui Pharmaceutical Co., Ltd.) from which the agar had been removed by filtration, and a diluted fecal solution was prepared. Galactosyl kojibiose was added to the diluted solution to a concentration of 0.25% (n=60).

[0094] Feces from 60 individuals were promptly aliquoted under refrigerated conditions after excretion and stored frozen at -80°C until use. Each fecal sample was used for testing without mixing. The culture medium used for the test was left to stand overnight in an anaerobic glove box before use. A 96-well deepwell plate was used for culture, and the culture was carried out in an anaerobic environment at 37°C for one day. The prebiotic potential of the added test substance was evaluated by comparing the cultured bacterial flora with that in a control condition in which distilled water was added instead of galactosyl kojibiose.

[0095] (Sample) Galactosyl kojibiose (α-D-Glcp-(1→2)-[β-D-Galp-(1→4)-]D-Glcp) was prepared from the trisaccharide fraction containing galactosyl kojibiose as the main component prepared in Production Example 1.

[0096] (Analysis of intestinal bacterial occupancy using next-generation sequencing) After incubation, DNA was extracted and purified from the diluted fecal samples using the Maxwell RSC PureFood GMO & Authentication Kit (Promega), and amplicon sequencing of the V3-V4 region was performed using MiSeq (Illumina). The resulting .fastq files were analyzed using QIIME2 (https: / / qiime2.org / ) to calculate the occupancy of each intestinal bacterial species.

[0097] When galactosyl kojibiose was added, a significant increase in the occupancy rate of bacteria of the genus Faecalis was observed (Fig. 1, Wilcoxon signed-rank test, p = 4.51x10 -7 ).

[0098] [Production Example 1] (Preparation of enzyme solution) Lactobacillus satsumensis JCM12392 was cultured overnight at 30°C using commercially available MRS liquid medium, and then the culture was terminated by cooling to below 10°C. JCM12392 is available from the Microbial Materials Development Division, RIKEN BioResource Center (RIKEN BRC JCM; Tsukuba, Ibaraki Prefecture, Japan).

[0099] The resulting culture medium was centrifuged, the supernatant was discarded, and the cells were collected. The cells were then washed by adding an equal volume of citrate phosphate buffer (pH 5.0) and collecting them again. The resulting cells were suspended in the buffer in an amount half the volume of the original culture medium, and the resulting suspension was used as the enzyme solution.

[0100] (Enzyme reaction) 32 w / w% sucrose, 16 w / w% lactose, and 10 w / w% enzyme solution were mixed and allowed to react at 48°C for 18 hours under static conditions. The composition contained 25-30% galactosyl kojibiose, 15-20% lactose, and 30-35% fructose based on the solid content.

[0101] (Purification of galactosyl kojibiose) After the enzyme reaction mixture was passed through a carbon celite column, non-adsorbed substances were removed by passing distilled water through the column. Stepwise elution with aqueous ethanol solutions of varying concentrations yielded a trisaccharide fraction containing galactosyl kojibiose as the main component (Figure 2).

[0102] Supplementary Example 1 The present inventors have previously confirmed that kojibiose and oligosaccharides containing kojibiose promote the growth of Parabacteroides bacteria (PCT / JP2023 / 030455, WO 2024 / 043298). Furthermore, it has been suggested that promoting the growth of Parabacteroides bacteria can control the growth of Faecalibacterium (JP Application No. 2024-042874).

[0103] Parabacteroides distasoins JCM5825T and Parabacteroides merdae JCM9497T were cultured in a filtered semi-solid medium for GAM saccharolysis. The culture was then centrifuged, and the supernatant was filter-sterilized to remove the bacterial cells. F. prausnitzii NCIMB13872T, F. hattorii, F. longum, F. gallinarum, and F. butyricigenerans, stimulated and cultured in MRC medium, were added at 1% to the filter-sterilized culture medium and cultured under anaerobic conditions for 24 hours. The growth of these Faecalibacterium bacteria was evaluated by measuring the turbidity during the culture. Strains designated NCIMB in the strain name are available from the National Collection of Industrial and Marine Bacteria (NCIMB) in the UK. Strains with JCM in their strain name can be obtained from the RIKEN BioResource Center Microbial Materials Division (RIKEN BRC JCM; Tsukuba, Ibaraki Prefecture, Japan).

[0104] The results showed that the growth of Faecalibacterium bacteria was promoted in the culture supernatants of P. distasonis and P. merdae compared to the control (Figs. 3 and 4).

[0105] Therefore, it can be said that the growth control of bacteria of the genus Faecalibacterium by kojibiose and oligosaccharides containing kojibiose may be mediated by the growth of bacteria of the genus Parabacteroides. From the above, oligosaccharides that have the ability to grow bacteria of the genus Parabacteroides may also have the ability to promote the growth of bacteria of the genus Faecalibacterium.

[0106] [Summary] From the above, it can be said that galactosyl kojibiose can be used to control the growth of Faecalibacterium bacteria in the intestine. Faecalibacterium bacteria are a type of butyric acid bacteria known to produce butyric acid in the intestine. Therefore, it can be said that kojibiose and oligosaccharides containing kojibiose can be used to control the growth of butyric acid bacteria, or to control butyric acid production in the intestine, and further to treat diseases or conditions that are improved by controlling the growth of butyric acid bacteria.

[0107] In addition, it has been reported that Faecalibacterium bacteria are reduced in the intestines of patients with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis (Non-Patent Document 1, etc.), and similar reports have been published in patients with asthma, food allergies, non-alcoholic fatty liver disease, and chronic kidney disease (Non-Patent Documents 2-6, respectively). Furthermore, it has been reported that Faecalibacterium bacteria are reduced in the intestines of patients with irritable bowel syndrome (IBS) (Non-Patent Document 7), inflammatory bowel disease (IBD) (Non-Patent Document 8), Parkinson's disease (Non-Patent Document 9), and cancer (Non-Patent Document 10) compared to healthy individuals. It has also been reported that administration of this genus of bacteria to IBD model mice improves symptoms such as weight loss and diarrhea (Non-Patent Document 11), and that administration of this genus of bacteria to Alzheimer's disease model mice improves cognitive impairment (Non-Patent Document 12). Furthermore, it has been reported that Faecalibacterium prausnitzii exhibits anti-inflammatory effects in cultured cell lines and TNBS colitis model mice (Non-Patent Document 13). Therefore, kojibiose and oligosaccharides containing kojibiose as a constituent sugar can be used to treat these diseases or conditions. Furthermore, ingestion of a composition containing kojibiose and oligosaccharides containing kojibiose as a constituent sugar can be useful for supporting the dietary habits and promoting the health of a subject.

[0108] [Food Production Example 1: 100% Orange Juice Beverage] 168 g of 1 / 6 concentrated orange juice, 20 g of the oligosaccharide composition (60% solids) obtained in Production Example 1, and an appropriate amount of flavoring were dissolved in ion-exchanged water to make a total volume of 1000 ml. This mixture was filled into a container and sterilized by heating at 65°C for 10 minutes to obtain a 100% orange juice beverage containing a trisaccharide fraction containing galactosyl kojibiose as the main component. This juice beverage contained approximately 0.36-0.42 g / 100 g of galactosyl kojibiose. This juice beverage can be used to control the growth of bacteria of the genus Faecalibacterium.

[0109] Food Production Example 2: Drinkable Yogurt: Raw material cream, concentrated skim milk, and raw material water were mixed and dissolved, heat-sterilized at 110°C for 30 seconds, and cooled to 43°C. A lactic acid bacteria starter consisting of Lactobacillus bulgaricus and Streptococcus thermophilus was added, and the mixture was fermented until the acidity reached 0.75. The homogenized solution was mixed with raw material water, pectin, sucralose, a trisaccharide fraction containing galactosyl kojibiose as the main component, and a flavoring, and heat-sterilized at 80°C for 10 minutes. The resulting solution was mixed and stirred under cooling. The blending ratio of the raw materials is shown in the table below. The resulting drinkable yogurt can be used for anti-obesity purposes.

[0110]

[0111] [Food Production Example 3: Fermented Milk 1] Raw milk was prepared by mixing 500.0 g of raw milk, 53.2 g of skim milk powder, 23.0 g of fresh cream, 403.6 g of tap water, and 50 g of sucrose. The raw milk was heat-sterilized at 95°C, and the heat-sterilized raw milk was cooled. The raw milk was then inoculated with 0.5% Liquorilactobacillus satsumensis concentrate and fermented under static conditions at 48°C for 18 hours. Lactobacillus bulgaricus and Streptococcus thermophilus were then added as lactic acid bacteria starters. The amount of lactic acid bacteria starter added was 20 g. The raw milk to which the lactic acid bacteria starter had been added was filled into a cup container (capacity: 100 ml, plastic). The raw milk filled into the cup container was subjected to static fermentation in a fermentation chamber at 43°C until the lactic acid acidity reached 0.7%. The resulting fermented milk can be used for immune regulation.

[0112] [Food Production Example 4: Fermented Milk 2] Raw milk was prepared by mixing 500.0 g of raw milk, 53.2 g of skim milk powder, 23.0 g of fresh cream, 403.6 g of tap water, and 54 g of a trisaccharide fraction containing galactosyl kojibiose as the main component. The raw milk was then heat-sterilized at 95°C, and the heat-sterilized raw milk was cooled to 43°C. Next, Lactobacillus bulgaricus and Streptococcus thermophilus were added as lactic acid bacteria starters to the heat-sterilized raw milk. The amount of lactic acid bacteria starter added was 20 g. The raw milk with the added lactic acid bacteria starter was filled into a cup container (capacity: 100 ml, plastic). The raw milk filled into the cup container was allowed to stand and ferment in a fermentation chamber at 43°C until the lactic acid acidity reached 0.7%. The resulting fermented milk can be used to improve liver function.

[0113] [Food Production Example 5: Syrup] Under the same enzymatic reaction conditions as in Production Example 1, whey powder (Meiji Co., Ltd.) (containing 75% lactose) was added at 20 w / w% instead of lactose, and the enzymatic reaction was carried out under the same conditions. After completion of the reaction, the mixture was sterilized at 100°C. A sugar solution (syrup) showing a chromatogram similar to that of Example 1 was obtained. The resulting syrup can be used to promote butyric acid production in the intestine.

[0114] The present invention supports the maintenance and improvement of people's health by providing a composition for controlling the growth of butyric acid bacteria, the composition comprising any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar. The present invention also provides a food composition and a method for producing food that support the maintenance and improvement of people's health. Furthermore, the present invention can improve the nutrition of various people, ensure healthy lifestyles, and promote welfare.

Claims

1. A composition for controlling the growth of butyric acid bacteria, comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar.

2. The composition according to claim 1, wherein the butyric acid bacteria are Faecalibacterium bacteria.

3. The composition according to claim 1 for use as a prebiotic or synbiotic.

4. A composition for treating any one selected from inflammation, asthma, food allergy, non-alcoholic fatty liver, chronic kidney disease, dementia, irritable bowel syndrome, inflammatory bowel disease, Parkinson's disease, cancer, cognitive decline, and atopic dermatitis, comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar.

5. The composition according to claim 4, wherein the treatment is mediated by controlling the proliferation of Faecalibacterium bacteria in the intestine.

6. A composition for controlling butyric acid production in the intestine, comprising any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar.

7. The composition according to claim 6, wherein the regulation of butyric acid production is mediated by regulation of the proliferation of Faecalibacterium bacteria in the intestine.

8. A composition for treating a disease or condition that is ameliorated by controlling the proliferation of intestinal Faecalibacterium bacteria, comprising kojibiose and oligosaccharides having kojibiose as a constituent sugar.

9. A composition according to any one of claims 1 to 8, which is obtained by allowing glucansucrase to act on a raw material composition containing lactose and sucrose.

10. The composition of any one of claims 1 to 3, 5, 7, and 8, wherein the growth control is growth promotion.

11. A composition described in any one of claims 1 to 3, 5, 7, and 8, wherein the butyric acid bacteria or Faecalibacterium bacteria is Faecalibacterium prausnitzii.

12. The composition according to claim 6 or 7, wherein the control of butyric acid production is promotion of butyric acid production.

13. A composition according to any one of claims 1 to 8, comprising kojibiose and an oligosaccharide having kojibiose as a constituent sugar, the oligosaccharide having the ability to promote the growth of Parabacteroides.

14. A composition according to any one of claims 1 to 8, comprising galactosyl kojibiose as a component sugar selected from kojibiose and oligosaccharides having kojibiose as a component sugar.

15. A food information providing method comprising the steps of: acquiring information on the intestinal flora of a subject; deriving information on food to be provided to the subject based on the information on the intestinal flora; and providing the derived food information to the subject, wherein in the information acquiring step, information on the presence or absence or amount of Faecalibacterium bacteria is acquired from the information on the intestinal flora, and in the food information deriving step, information on a food that is a composition containing any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar, is derived based on the information on the presence or absence or amount of Faecalibacterium bacteria.

16. A food information providing method comprising the steps of: acquiring information on the amount of intestinal butyric acid in a subject; deriving information on food to be provided to the subject based on the information on the amount of intestinal butyric acid; and providing the derived food information to the subject, wherein in the step of deriving food information, information on a food that is a composition containing any one selected from the group consisting of kojibiose and oligosaccharides having kojibiose as a constituent sugar is derived based on the information on the amount of intestinal butyric acid.

17. A method for controlling Faecalibacterium bacteria in the intestines of a subject or a method for supporting the diet or health of a subject, comprising carrying out the method according to claim 15 or 16 and providing food to the subject based on the derived food information.

18. The method of claim 15 or 16, wherein the food product is for use as a prebiotic or synbiotic.

19. The method of claim 16, further comprising the step of displaying the food information to be provided on the target terminal.

20. Use of any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar, for controlling the proliferation of Faecalibacterium bacteria in intestinal flora.

21. A method for controlling the proliferation of Faecalibacterium bacteria in intestinal flora, the method comprising a step of causing intestinal flora containing Faecalibacterium bacteria to contain any one selected from kojibiose and oligosaccharides having kojibiose as a constituent sugar.