Compositions for improving nicotinamide mononucleotide production

Abstract

A composition for improving the production of nicotinamide mononucleotide (NMN), characterized by containing, as an active ingredient, at least one carbohydrate selected from the group consisting of monosaccharides (excluding glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols, and dietary fibers.

Description

Technical Field

[0001] The present invention relates to a composition for improving the production of nicotinamide mononucleotide, and more particularly, to a composition for improving the production of nicotinamide mononucleotide achieved by intestinal flora. Background Art

[0002] Nicotinamide MonoNucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide (NAD) and is a substance that has received particular attention in recent years.

[0003] For example, in order to control aging, it is important to maintain the activity of deacetylase, which is called a longevity gene, but with the passage of years (aging), the concentration of NAD required for its activity in tissues decreases, which becomes a cause of aging. Therefore, it is said that the administration or ingestion of NMN, which is a precursor of NAD, brings about an anti-aging effect.

[0004] More specifically, for example, Mills Kathryn F. et al., Cell metabolism, 24.6, 2016, p.795-806 (non-patent document 1) reported that by administering NMN to aged mice, it was confirmed that obesity caused by aging, energy metabolism was improved, and insulin resistance, lipid metabolism, eye function, bone density and immune function were improved; changes in gene expression caused by aging in skeletal muscle, fat and liver were inhibited. In addition, type II diabetes is a lifestyle disease caused by decreased glucose tolerance due to aging, but Jun Yoshino et al., Cell Metab., 2011 Oct5, 14 (4), p.528-536 (non-patent document 2) reported that by administering NMN, in mice induced with type II diabetes by giving a high-fat diet, glucose intolerance and improvement of insulin sensitivity in the liver, as well as restoration of gene expression related to oxidative stress, inflammatory response and circadian rhythm were confirmed.

[0005] In addition, for example, in Luis Rajman et al., Cell Metab., 2018 Mar 6, 27 (3), p. 529-547 (non-patent document 3), Xiaonan Wang et al., Brain Research, Volume 1643, 15 July 2016, p. 1-9 (non-patent document 4), it is reported that the administration of NMN improves liver function, kidney function, skeletal muscle function and heart function, and Alzheimer's dementia that are reduced due to aging. Furthermore, for example, in Zhu et al., Signal Transduction and Targeted Therapy, 2017, e17017 (non-patent document 5), it is reported that constipation is improved by administering NMN to aged mice.

[0006] Therefore, in recent years, supplements for taking NMN have been commercially available. However, a method for easily producing a sufficient amount of NMN industrially has not yet been established, and it is difficult to obtain raw materials, so it has a problem of being expensive for daily intake.

[0007] As a method for producing NMN, in addition to production by chemical synthesis, there are also known methods for producing using nicotinamide riboside (NR) as a raw material, methods for producing using Escherichia coli, methods for producing using yeast, etc. In addition, it is reported that Escherichia coli produces NMN from glucose and xylose (S. Shoji et al, Metabolic Engineering, 65, 2021, p. 167-177 (non-patent document 6); Y. Liu et al., Microbial biotechnology, 2021, 14 (6), p. 2581-2591 (non-patent document 7); U. Ngivprom, ChemBioChem, 2022, 23, e202200071 (non-patent document 8)), and yeast extracts containing NMN are produced using a medium containing glucose (International Publication No. 2017 / 022768 (Patent Document 1)). Furthermore, it has been reported that a certain lactic acid bacteria produces NMN (Sugiyama Kazane et al., Scientific reports, 11.1, 2021, p.1-8 (non-patent document 9)). In addition, for example, in Japanese Patent Publication No. 2022-505262 (Patent Document 2), oxidized NAD (NAD + ) levels, describing a pet food composition comprising protein, carbohydrates, insoluble fiber and soluble fiber.

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: International Publication No. 2017 / 022768

[0011] Patent Document 2: Japanese Patent Application No. 2022-505262

[0012] Non-patent literature

[0013] Non-patent literature 1: Mills Kathryn F. et al., Cell metabolism, 24.6, 2016, p.795-806

[0014] Non-patent document 2: Jun Yoshino et al., Cell Metab., 2011 Oct 5, 14(4), p.528-536

[0015] Non-patent document 3: Luis Rajman et al., Cell Metab., 2018 Mar 6, 27(3), p.529-547

[0016] Non-patent literature 4: Xiaonan Wang et al., Brain Research, Volume 1643, 15 July 2016, p. 1-9

[0017] Non-patent literature 5: Zhu et al., Signal Transduction and Targeted Therapy, 2017, e17017

[0018] Non-patent document 6: S. Shoji et al, Metabolic Engineering 65, 2021, p. 167-177

[0019] Non-patent document 7: Y. Liu et al., Microbial biotechnology, 2021, 14(6), p. 2581-2591 Non-patent document 8: U. Ngivprom, ChemBioChem, 2022, 23, e202200071

[0020] Non-patent literature 9: Sugiyama Kazane et al., Scientific reports, 11.1, 2021, p.1-8 Summary of the invention

[0021] Problem that the invention aims to solve

[0022] A large number of bacteria live in the intestines (especially the large intestine) of animals including humans, and their collection is called intestinal flora. It is believed that the intestinal flora plays a variety of roles such as digestive assistance, immune response regulation, and anti-inflammatory. In addition, it is also known that the host absorbs metabolites produced by the intestinal flora, thereby bringing various health effects to the host. In view of the problems of the above-mentioned prior art, the inventors of the present invention believe that when the intestinal flora produces NMN, it is absorbed by the host, which can bring the same effect as giving NMN to the host or causing the host to ingest NMN. The present invention is completed in view of such problems and insights, and its purpose is to provide a composition having the effect of improving the production of nicotinamide mononucleotide (NMN) achieved by intestinal flora.

[0023] Solutions for solving problems

[0024] The present inventors have repeatedly conducted in-depth research to achieve the above-mentioned purpose. First, it was found that although there are differences due to individual differences in the host, the intestinal flora produces NMN. Therefore, the present inventors have explored the prebiotics that can improve the NMN production achieved by intestinal flora from various previously known prebiotics (i.e., not decomposed / absorbed in the upper part of the digestive tract, becoming a selective nutrient source for intestinal bacteria in the large intestine, improving the composition of intestinal flora to maintain a healthy balance, and contributing to the health of the host. Food ingredients (Gibson et al., J Nutr., 1995, 125, p. 1401-1412, etc.)). As a result, it was newly discovered that specific carbohydrates, i.e., at least one carbohydrate selected from the group consisting of monosaccharides (wherein, glucose and xylose are excluded), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fibers, have the effect of increasing the NMN production achieved by intestinal flora in vitro and in vivo. It can be seen that by administering a composition with the aforementioned carbohydrate as an active ingredient to a host or causing the host to ingest it, the amount of NMN produced by its intestinal flora can be improved. In addition, the host can thereby ingest more NMN via the large intestine, so in addition to the NMN, the in vivo concentration of NAD and its metabolites with NMN as a precursor can also be increased. Furthermore, the intake of NMN can improve various diseases caused by aging (non-patent literature 1 to 4), constipation can be improved (non-patent literature 5), and NAD as a metabolite of NMN is effective for improving inflammatory bowel disease (Navarro et al., Br J Pharmacol., 2022, 179, p. 1839-1856), so it can be seen that by administering or ingesting a composition with the aforementioned carbohydrate as an active ingredient, diseases caused by aging, constipation and inflammatory bowel disease can also be prevented or improved, thereby completing the present invention. The embodiment of the present invention obtained based on this insight is as follows. [1]

[0026] A composition for improving nicotinamide mononucleotide (NMN) production, comprising as an active ingredient at least one carbohydrate selected from the group consisting of monosaccharides (excluding glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fiber. [2]

[0028] The composition according to [1], comprising a monosaccharide as the carbohydrate, wherein the monosaccharide is tagatose. [3]

[0030] The composition according to [1] or [2], comprising a disaccharide as the carbohydrate, wherein the disaccharide is at least one selected from the group consisting of cellobiose, lactulose, trehalose and sialyllactose. [4]

[0032] The composition according to any one of [1] to [3], comprising a trisaccharide as the carbohydrate, wherein the trisaccharide is at least one selected from the group consisting of kestose, lactoligosaccharide, raffinose and fucosyllactose. [5]

[0034] The composition according to any one of [1] to [4], comprising a tetrasaccharide as the carbohydrate, wherein the tetrasaccharide is at least one selected from the group consisting of stachyose and saccharide. [6]

[0036] The composition according to any one of [1] to [5], comprising a pentasaccharide as the carbohydrate, wherein the pentasaccharide is cane pentasaccharide. [7]

[0038] The composition according to any one of [1] to [6], comprising a sugar alcohol as the carbohydrate, wherein the sugar alcohol is at least one selected from the group consisting of reduced isomaltulose, lactitol, sorbitol, mannitol, and xylitol. [8]

[0040] The composition according to any one of [1] to [7], characterized in that it contains dietary fiber as the carbohydrate, and the dietary fiber is inulin. [9]

[0042] The composition according to any one of [1] to [8], which is an oral composition or an enteral composition.

[10]

[0044] The composition according to any one of [1] to [9], which is a food and beverage composition, a pharmaceutical composition, or a quasi-drug composition.

[11]

[0046] The composition according to any one of [1] to

[10] , which is a composition for improving the nicotinamide adenine dinucleotide (NAD) concentration in a living body.

[12]

[0048] The composition according to any one of [1] to

[10] , which is a composition for preventing or improving constipation.

[13]

[0050] The composition according to

[11] or

[12] , wherein the dosage for human administration is 10 to 1000 mg of the carbohydrate per kg of body weight per day.

[14]

[0052] The composition according to any one of [1] to

[10] , which is a composition for preventing or improving inflammatory bowel disease.

[15]

[0054] The composition according to

[14] , wherein the dosage for human administration is 10 to 1000 mg of the carbohydrate per kg body weight per day.

[16]

[0056] The composition according to any one of [1] to

[10] , which is a composition for preventing or ameliorating diseases caused by aging.

[17]

[0058] The composition according to

[16] , wherein the dosage for human administration is 10 to 1000 mg of the carbohydrate per kg of body weight per day.

[18]

[0060] Use of at least one carbohydrate selected from the group consisting of monosaccharides (excluding glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fiber in improving NMN production.

[19]

[0062] Use of at least one carbohydrate selected from the group consisting of monosaccharides (excluding glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fiber in producing a composition for improving NMN production.

[20]

[0064] A method for improving NMN production, wherein an effective amount of at least one carbohydrate selected from the group consisting of monosaccharides (excluding glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fiber is administered to a subject. [twenty one]

[0066] The use of the carbohydrate according to

[18] is further used for improving the NAD concentration in a living body. [twenty two]

[0068] The use of carbohydrates according to

[19] , wherein the composition for improving NMN production is a composition for improving NAD concentration in vivo. [twenty three]

[0070] The method for improving NMN production according to

[20] is further a method for improving NAD concentration in a living body. [twenty four]

[0072] The use of carbohydrates according to

[18] is further used for preventing or improving constipation.

[25]

[0074] The use of carbohydrates according to

[19] , wherein the composition for improving NMN production is a composition for preventing or improving constipation.

[26]

[0076] The method for improving NMN production according to

[20] is further a method for preventing or improving constipation.

[27]

[0078] The use of carbohydrates according to

[18] is further used for preventing or improving inflammatory bowel disease.

[28]

[0080] The use of carbohydrates according to

[19] , wherein the composition for improving NMN production is a composition for preventing or improving inflammatory bowel disease.

[29]

[0082] The method for improving NMN production according to

[20] is further a method for preventing or improving inflammatory bowel disease.

[30]

[0084] The use of the carbohydrate according to

[18] is further for preventing or ameliorating diseases caused by aging.

[31]

[0086] The use of carbohydrates according to

[19] , wherein the composition for improving NMN production is a composition for preventing or improving diseases caused by aging.

[32]

[0088] The method for improving NMN production according to

[20] is further a method for preventing or improving diseases caused by aging.

[0089] Effects of the Invention

[0090] According to the present invention, a composition having an effect of improving the production of nicotinamide mononucleotide (NMN) achieved by gut microbiota can be provided. In addition, the composition of the present invention can also be provided as a dietary composition, and thus is easy to ingest and easy to get used to ingesting. Furthermore, by increasing the amount of NMN produced by gut microbiota, the composition of the present invention can be used for improving the NAD concentration in vivo, preventing or improving diseases caused by aging, and preventing or improving constipation and inflammatory bowel disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 It is a graph showing the NMN concentration in the culture solution obtained in Test Example 1 by culturing human feces (#1 to 3) in a GAM medium containing 0.5% glucose.

[0092] Figure 2 It is a graph showing the average value of the NMN concentration in the culture solution when human feces (#1 to 3) are respectively cultured in an evaluation medium containing each carbohydrate in Test Example 2.

[0093] Figure 3 It is a graph showing the average value of the amount of NMN (the amount obtained by multiplying the NMN concentration by the weight of cecal contents (total, total amount)) in the cecal contents of the control group and the FOS group obtained in Test Example 3.

[0094] Figure 4 It is a graph showing the average value of the NMN concentration in the feces of humanized microbiota mice on each feces collection day obtained in Test Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0095] Hereinafter, the present invention will be described in detail in conjunction with preferred embodiments.

[0096] <Composition for Improving NMN Production>

[0097] The present invention provides a composition for improving the production of nicotinamide mononucleotide (NMN) (in this specification, sometimes referred to as "composition for improving NMN production" or simply as "the composition of the present invention"), which contains at least one carbohydrate selected from the group consisting of monosaccharides (excluding glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols, and dietary fibers as an active ingredient.

[0098] In the present invention, nicotinamide mononucleotide refers to β-nicotinamide mononucleotide, and is also simply referred to as NMN. β-Nicotinamide mononucleotide is a compound in which nicotinamide and nicotinamide riboside are converted into nicotinamide adenine dinucleotide (NADH, NAD +, referred to as "NAD" in this specification as appropriate. Nicotinamide adenine dinucleotide is known to play a central role in dehydrogenation reactions in vivo as a redox coenzyme. The present inventors have found that the production of nicotinamide mononucleotide by intestinal flora and the increase in the production of nicotinamide mononucleotide by the carbohydrates of the present invention have an excellent effect of improving the production of nicotinamide mononucleotide.

[0099] In the present invention, intestinal flora refers to a group of bacteria present in the intestines (especially the large intestine) of animals, also referred to as intestinal flora, intestinal microbial flora. Among the microorganisms contained in the intestinal flora of the present invention, in addition to the intestinal bacteria that constitute most of it, other intestinal microorganisms (bacteriophages, viruses, archaea, fungi, parasites) are also included. For example, in the human large intestine, it is generally said that the aforementioned intestinal bacteria exist in 600 to 1000 trillion and more than 1000 species. The composition of the intestinal flora varies greatly between individuals and also changes according to the aging and health status of the host. Therefore, it cannot be generalized, but for example, the microbial flora obtained by culturing human and animal feces in a GAM medium containing 0.5% glucose at 37°C and anaerobic conditions for 12 hours can also be used as the intestinal flora of the present invention.

[0100] The active ingredient contained in the composition for improving NMN production of the present invention is at least one carbohydrate selected from the group consisting of monosaccharides (except glucose and xylose), disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fiber. As the carbohydrate of the present invention, it is preferably a saccharide, more preferably a saccharide, further preferably at least one selected from the group consisting of disaccharides, trisaccharides, tetrasaccharides and pentasaccharides, and further preferably at least one selected from the group consisting of trisaccharides and tetrasaccharides, and further preferably trisaccharides and tetrasaccharides in that order. In addition, as the carbohydrate of the present invention, it is preferred not to contain fucose as a constituent sugar, and more preferably to use 1 to 3 selected from the group consisting of glucose, galactose and fructose as constituent sugars.

[0101] (monosaccharide)

[0102] The monosaccharide of the present invention may be linear or cyclic, may be an aldose containing an aldehyde group or a ketose containing a ketone group, and may be any one of them when both the D form and the L form exist. The number of carbon atoms in the monosaccharide of the present invention is preferably 4 to 7, more preferably 6 (i.e., the monosaccharide is a hexose).

[0103] Among them, glucose and xylose are excluded from the monosaccharides of the present invention. Glucose and xylose are 100% absorbed into the body in the small intestine and therefore do not reach the large intestine (Yamada Kazuhiko et al., Journal of Nutrition, 2001, Vol. 59, No. 4, p. 169-176; Keio University Hospital, "D-xylose test", [on line], February 22, 2018, [retrieved on August 3, 2023], Internet<https: / / kompas.hosp.keio.ac.jp / contents / 000347.html> ), does not contribute to the improvement of NMN production by intestinal bacteria present in the large intestine.

[0104] More specifically, monosaccharides of the present invention include tagatose, arabinose, allose, psicose, galactose, fructose, and mannose, and may be one of them or a combination of two or more thereof. Among them, the monosaccharide of the present invention is preferably at least one selected from the group consisting of tagatose, arabinose, allose, and psicose, and tagatose is preferred from the viewpoint that it is easier to reach intestinal bacteria that produce NMN in the body, that is, it is easier to reach the large intestine as a prebiotic without being decomposed / absorbed in the upper part of the digestive tract.

[0105] (Disaccharide)

[0106] The disaccharide of the present invention refers to a sugar in which two molecules of the above-mentioned monosaccharide are bonded by dehydration condensation. In addition, when both the D-body and the L-body are present, any one of them may be used. In addition, the disaccharide of the present invention also includes modified sugars formed by modifying the disaccharide. As the modification of the above-mentioned disaccharide, for example, sialylation can be listed, and the modification site can be one or more. When it is multiple, it can be one modification or a combination of two or more modifications.

[0107] The monosaccharides constituting the above-mentioned disaccharide may be the same or different from each other, and examples thereof include tagatose, glucose, galactose, fructose, mannose, xylose, arabinose, allose, and psicose, and tagatose, glucose, galactose, fructose, mannose, and xylose are preferred. Among them, the disaccharide of the present invention is preferably a disaccharide composed of one or two kinds selected from the group consisting of glucose, galactose, and fructose as constituent sugars.

[0108] As the disaccharide of the present invention, more specifically, for example, cellobiose, lactulose, trehalose, lactose, isomaltulose can be listed, and it can be one of them or a combination of two of them. Among them, as the disaccharide of the present invention, from the viewpoint that it is easier to reach the intestinal bacteria that produce NMN in the body, that is, it is easier to reach the large intestine without being decomposed / absorbed in the upper part of the digestive tract as a prebiotic, it is preferably at least one selected from the group consisting of cellobiose, lactulose, trehalose and sialyllactose (3'-sialyllactose, etc.), more preferably a disaccharide that has not been modified as described above, further preferably at least one selected from the group consisting of cellobiose, lactulose and trehalose, and particularly preferably cellobiose.

[0109] (Trisaccharide)

[0110] The trisaccharide of the present invention refers to a sugar in which three molecules of the above-mentioned monosaccharide are bonded by dehydration condensation. In addition, when both the D-body and the L-body exist, it can be any one of them. In addition, the trisaccharide of the present invention also includes a modified sugar formed by modifying the trisaccharide. As the modification of the above-mentioned trisaccharide, the same modification as the modification of the above-mentioned disaccharide can be listed, and the modification site can be one or more. When it is multiple, it can be one modification or a combination of two or more modifications.

[0111] The monosaccharides constituting the trisaccharide may be all the same, partly the same, or all different, and examples thereof include tagatose, glucose, galactose, fructose, mannose, xylose, arabinose, allose, psicose, and fucose, and preferably tagatose, glucose, galactose, fructose, mannose, xylose, and fucose. Among them, the trisaccharide of the present invention is preferably a trisaccharide composed of one to three constituent sugars selected from the group consisting of glucose, galactose, fructose, and fucose, and more preferably a trisaccharide composed of one to three constituent sugars selected from the group consisting of glucose, galactose, and fructose.

[0112] As the trisaccharide of the present invention, more specifically, for example, nitose (1-nitose, etc.), lactulose oligosaccharide, raffinose, fucosyllactose (2'-fucosyllactose, etc.), galactosyl lactose (4'-galactosyl lactose, etc.) can be listed, and it can be one of them or a combination of two or more. Among them, as the trisaccharide of the present invention, from the viewpoint that it is easier to reach the intestinal bacteria that produce NMN in the body, that is, it is easier to reach the large intestine without being decomposed / absorbed in the upper part of the digestive tract as a prebiotic, it is preferably at least one selected from the group consisting of nitose, lactulose oligosaccharide, raffinose, fucosyllactose and galactosyl lactose, and more preferably at least one selected from the group consisting of nitose, lactulose oligosaccharide and raffinose.

[0113] (Tetrasaccharide)

[0114] The tetrasaccharide of the present invention represents a sugar in which four molecules of the aforementioned monosaccharide are bonded by dehydration condensation. In addition, when both the D-body and the L-body are present, any one of them may be used. In addition, the tetrasaccharide of the present invention also includes a modified sugar obtained by modifying the tetrasaccharide. As the modification of the aforementioned tetrasaccharide, the same modification as the modification of the aforementioned disaccharide may be listed, and the modification site may be one or more, and when it is more than one, it may be one modification or a combination of two or more modifications.

[0115] The monosaccharides constituting the tetrasaccharide may be all the same, partly the same, or all different, and examples thereof include tagatose, glucose, galactose, fructose, mannose, xylose, arabinose, allose, and psicose, preferably tagatose, glucose, galactose, fructose, mannose, and xylose. Among them, the tetrasaccharide of the present invention is preferably a tetrasaccharide composed of one to three constituent sugars selected from the group consisting of glucose, galactose, and fructose.

[0116] The tetrasaccharide of the present invention may be one or a combination of two or more. Among them, the tetrasaccharide of the present invention is preferably at least one selected from the group consisting of stachyose and nicotinose from the viewpoint that it is easier to reach the intestinal bacteria that produce NMN in the body, that is, it is easier to reach the large intestine as a prebiotic without being decomposed / absorbed in the upper part of the digestive tract.

[0117] (Pentasaccharide)

[0118] The pentasaccharide of the present invention represents a sugar in which 5 molecules of the above-mentioned monosaccharide are bonded by dehydration condensation. In addition, when both the D-body and the L-body are present, any one of them may be used. In addition, the pentasaccharide of the present invention also includes modified sugars obtained by modifying the pentasaccharide. As the modification of the above-mentioned pentasaccharide, the same modification as the modification of the above-mentioned disaccharide can be listed, and the modification site may be one or more, and when it is more than one, it may be one modification or a combination of two or more modifications.

[0119] The monosaccharides constituting the pentasaccharide may be all the same, partly the same, or all different, and examples thereof include tagatose, glucose, galactose, fructose, mannose, xylose, arabinose, allose, and psicose. Among them, the pentasaccharide of the present invention is preferably a pentasaccharide composed of one to three constituent sugars selected from the group consisting of glucose, galactose, and fructose.

[0120] The pentasaccharide of the present invention may be one or a combination of two or more. Among them, the pentasaccharide of the present invention is preferably sucrose pentasaccharide (1-fructofuranosyl-D-sucrose tetraose, etc.) from the viewpoint that it is easier to reach the intestinal bacteria that produce NMN in the body, that is, it is easier to reach the large intestine as a prebiotic without being decomposed / absorbed in the upper part of the digestive tract.

[0121] (Sugar Alcohol)

[0122] The sugar alcohol of the present invention is a compound in which the carbonyl group of a sugar compound is reduced. Examples of the sugar compound include the monosaccharides, disaccharides, trisaccharides, tetrasaccharides and pentasaccharides.

[0123] As the sugar alcohol of the present invention, more specifically, for example, lactitol, sorbitol, mannitol, xylitol, and reduced isomaltulose can be listed, and they can be one kind or a combination of two or more kinds. Among them, as the sugar alcohol of the present invention, it is preferably a sugar alcohol in which the above-mentioned monosaccharide or disaccharide is reduced, and from the viewpoint that it is easier to reach the intestinal bacteria that produce NMN in the body, that is, it is easier to reach the large intestine without being decomposed / absorbed in the upper part of the digestive tract as a prebiotic, it is more preferably at least one selected from the group consisting of lactitol, sorbitol, mannitol, xylitol and reduced isomaltulose, and it is further preferably at least one selected from the group consisting of lactitol and sorbitol.

[0124] (Dietary Fiber)

[0125] The dietary fiber of the present invention refers to a carbohydrate that is not decomposed by human digestive enzymes (amylase, protease, maltase, etc.), and refers to a sugar in which more than 6 molecules of the aforementioned monosaccharides are bonded by dehydration condensation. As the aforementioned dietary fiber, it can be straight-chain or branched. In addition, the molecular weight of the dietary fiber of the present invention is preferably 500 to 50,000, and more preferably 1,000 to 30,000.

[0126] The monosaccharides constituting the dietary fiber may be all the same, partly the same, or all different, and examples thereof include tagatose, glucose, galactose, fructose, mannose, xylose, arabinose, allose, and psicose. Among them, the dietary fiber of the present invention is preferably a dietary fiber composed of one to three constituent sugars selected from the group consisting of glucose, galactose, and fructose.

[0127] More specifically, the dietary fiber of the present invention includes, for example, inulin, indigestible dextrin, and guar gum degradation products, and the dietary fiber may be one kind or a combination of two or more kinds thereof. Among them, inulin is preferred as the dietary fiber of the present invention.

[0128] As the carbohydrate of the present invention, as described above, it can be a combination of two or more selected from the group consisting of monosaccharides, disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fibers. In this case, the combination of carbohydrates of the present invention is not particularly limited, but is more preferably a combination of two or more saccharides selected from the group consisting of disaccharides, trisaccharides, tetrasaccharides and pentasaccharides, more preferably trisaccharides, tetrasaccharides and pentasaccharides (in this specification, referred to as "mixed sugars" depending on the situation). Examples of such combinations include: fructooligosaccharides composed of nitrosyl triose (trisaccharide), nitrosyl tetraose (tetrasaccharide) and nitrosyl pentose (pentasaccharide); galacto-oligosaccharides containing galactosyl lactose (trisaccharide); soybean oligosaccharides containing raffinose (trisaccharide) and stachyose (tetrasaccharide); lactofructooligosaccharides containing lactulose oligosaccharides (trisaccharide); xylooligosaccharides containing xylobiose (disaccharide); isomaltose oligosaccharides containing isomaltose (disaccharide), isomaltotriose (trisaccharide) and panose (trisaccharide); and a mixture of disaccharides to decasaccharides in which mannose is linked in a straight chain in a β1,4-mannosidic bond, namely coffee bean manno-oligosaccharides.

[0129] Among them, as the mixed sugar of the present invention, from the viewpoint of being easier to reach the intestinal bacteria that produce NMN in the body, that is, being easier to reach the large intestine without being decomposed / absorbed in the upper part of the digestive tract as a prebiotic, it is preferably at least one selected from the group consisting of oligofructose and oligogalactose, and oligofructose is more preferred.

[0130] In the composition of the present invention, the content of the carbohydrate (when the carbohydrate is a combination of two or more, it is the total amount thereof, the same applies hereinafter) is appropriately adjusted depending on the form of the composition, the dosage or intake, the purpose and method of administration or intake, etc., and is not particularly limited. It can be 0.001 to 100% by mass, for example, in the range of 0.001 to 99% by mass, 0.005 to 95% by mass, 0.01 to 80% by mass, 0.1 to 70% by mass, 1 to 60% by mass, 5 to 50% by mass, or 10 to 50% by mass, relative to the total mass of the composition.

[0131] The dosage or intake amount (hereinafter also referred to as "dosage") of the composition of the present invention can be appropriately determined according to each case in consideration of the form of the composition, the purpose and method of administration or intake, the type, age, weight, sex, degree of symptoms, etc. of the subject. Therefore, it is not particularly limited, and for example, as a dosage for humans (preferably adults), the amount of the aforementioned carbohydrates (when the aforementioned carbohydrates are a combination of two or more, the total amount thereof, the same below) is preferably 1 to 1000 mg per kg of the subject's body weight and per day, and more preferably 10 to 1000 mg, for example, 20 to 800 mg, 30 to 700 mg, or 50 to 500 mg can be used.

[0132] As long as the composition of the present invention does not hinder the effect of the present invention, in addition to the aforementioned carbohydrate, it can also contain other acceptable ingredients in food or medicine. As the aforementioned other ingredients, there are no particular restrictions, and examples thereof include water, lipids, minerals, vitamins, proteins, peptides, amino acids, organic acids, lactic acid bacteria (Lactobacillus, Bifidobacterium, etc.), yeast, processed materials (crushed processed materials, heat-treated materials, etc.) of the aforementioned lactic acid bacteria and / or yeast, fermented materials of the aforementioned lactic acid bacteria and / or yeast, and formulation adjuvants. In addition, as the aforementioned other ingredients, other sugars and other active ingredients other than the aforementioned carbohydrate can also be used.

[0133] The lipids are not particularly limited, and more specifically include natural oils such as soybean oil, corn oil, palm oil, perilla seed oil, canola oil, safflower oil, sunflower oil, sesame seed oil, rice oil, grape seed oil, fish oil, safflower oil, rapeseed oil and peanut oil; and synthetic oils such as medium-chain fatty acid triglycerides (MCT) having about 6 to 12 carbon atoms.

[0134] The minerals are not particularly limited, and more specific examples thereof include calcium, magnesium, sodium, potassium, phosphorus, iron, manganese, copper, zinc, iodine, zinc, selenium, chromium, and molybdenum.

[0135] The vitamins are not particularly limited, and more specific examples include vitamins A, B1, B2, B5, B6, B7, B9, B12, C, D, E, and K.

[0136] The aforementioned formulation auxiliary agent is not particularly limited, and more specifically, for example, a solvent, a dispersant, an emulsifier, a thickener, a thickening stabilizer, a gelling agent, a surfactant, a buffer, a stabilizer, an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, a solubilizing agent, a suspending agent, a coating agent, a carrier (a solid carrier, a liquid carrier such as water), a preservative, a flavoring agent, a colorant, and a pH adjuster can be listed.

[0137] The sugars other than the aforementioned carbohydrates are not particularly limited, and more specific examples thereof include starch and maltodextrin.

[0138] The other active ingredients other than the carbohydrates are not particularly limited, and more specifically include, for example, fruits and vegetables and processed products thereof, animal and plant extracts, and naturally derived polymers (collagen, hyaluronic acid, chondroitin, etc.).

[0139] As above-mentioned other components, can only contain 1 kind, also can contain 2 or more combinations.In addition, when containing these other components, the content of these other components is not particularly limited, can be suitably adjusted according to the form, dosage, purpose, method etc. of giving or taking of composition.

[0140] The administration method of the composition of the present invention is not particularly limited, and oral administration, enteral administration, intraperitoneal administration, etc. can be listed, and the composition of the present invention can be prepared into a composition corresponding to each administration method. Among them, as the composition of the present invention, it is preferably administered or ingested orally or enterally, and accordingly, it is preferably prepared into an oral composition or an enteral composition. In particular, from the viewpoint of its ease, it is more preferably administered or ingested orally, and it is more preferably prepared into an oral composition. In addition, the composition of the present invention can be prepared into, for example, a pharmaceutical composition, a quasi-drug composition, a dietary composition, or a feed composition, depending on the purpose, object, method, dosage, etc. of administering or ingesting the composition.

[0141] The pharmaceutical composition and quasi-drug composition of the present invention may be prepared, for example, in the form of a preparation, and the form thereof is not particularly limited, and examples thereof include solid preparations such as tablets, pills, granules, powders, powders, and capsules; liquid preparations such as general liquid preparations, suspensions, emulsions, and syrups; jellies; enteral preparations; external preparations such as suppositories, etc. The preparations may be prepared, for example, by adding one or more of the aforementioned formulation aids to the aforementioned carbohydrates, and further adding one or more of the aforementioned other ingredients as required, by a known method or a method based on the method.

[0142] The form of the dietary composition of the present invention is not particularly limited, and examples thereof include solid forms such as sticks, liquid forms such as beverages and liquid foods, paste forms, semi-liquid forms, gel forms (jelly forms), gel-like fats (semi-solid fats), powder forms, etc. In addition, the dietary composition may be taken by oral / enteral nutrition patients, the elderly, infants, etc. in the form of liquid foods, powdered liquid foods, nutritional pastes, oral / tube nutrition agents, beverages, gel-like foods, etc.

[0143] Examples of the dietary composition of the present invention are not particularly limited, and examples thereof include beverages (tea, carbonated beverages, cocoa, coffee, lactic acid bacteria beverages, soy milk beverages, fruit juice / vegetable juice beverages, refreshing beverages, nutritional beverages, alcoholic beverages, etc.), processed foods (chocolate, chewing gum, gummy candy, jelly, baked snacks (bread, cake, cookies, biscuits, etc.), candies, etc.), dairy products (formulated milk powder (milk powder, etc.), formula milk, milk beverages, fermented milk, yogurt, ice cream, cheese, cream, butter, margarine, condensed milk, etc.), seasonings (sauce, soup, salad dressing, mayonnaise, mayonnaise-type seasonings, cream, etc.), supplements, edible oils, and functional edible fats and oils. Such a dietary composition can be produced, for example, by a method of blending the carbohydrate of the present invention into an existing food or beverage or an intermediate product of its raw material or manufacturing process. The carbohydrate blended in this case may be in the form of the aforementioned pharmaceutical composition or quasi-drug composition.

[0144] In addition, the dietary composition of the present invention may be, for example, ordinary food, health food, functional food, health functional food (e.g., food for specific health use, nutritional functional food, nutritional supplement food, functional labeled food, etc.), special purpose food (e.g., food for infants, food for pregnant women, food for patients, etc.), medical food (food prescribed by the U.S. Food and Drug Administration (FDA) and the Orphan Drug Act under the management of a doctor), therapeutic food (food for achieving therapeutic purposes, food prepared based on a menu prepared by a nutritionist or the like according to a doctor's diet sheet), and diet therapy food. In addition, in the aforementioned dietary composition, the effects / efficacy achieved by the carbohydrate of the present invention in its product may also be shown (e.g., prevention or improvement of diseases caused by aging, prevention or improvement of constipation, prevention or improvement of inflammatory bowel disease).

[0145] Examples of the feed composition of the present invention include feed compositions obtained by appropriately modifying the above-mentioned dietary composition according to the purpose, target, method, dosage, etc. of administration or ingestion of the feed composition.

[0146] The composition of the present invention is preferably packaged (preferably sealed) in a packaging container from the time of manufacture to administration or ingestion. The packaging container is not particularly limited, and examples thereof include wrapping paper, packaging bags, soft bags, tubes, aluminum foil packaging, paper containers, cans, bottles, and capsules.

[0147] The composition of the present invention can be used to improve the production of NMN by intestinal flora by containing the above-mentioned carbohydrate as an effective ingredient, and is more preferably used to improve the production of NMN by intestinal flora in a living body. Therefore, the present invention also provides the use of the above-mentioned carbohydrate in improving NMN production, and the use of the above-mentioned carbohydrate in manufacturing a composition for improving NMN production.

[0148] In addition, the production of NMN by intestinal flora is improved, and the host (subject) absorbs the produced NMN, thereby improving the concentration of NMN in the body, and also improving the production of NAD and its metabolites (nicotinamide, nicotinic acid, NAMN, NAAD, etc.) using the NMN as a precursor, thereby improving the concentration in the body. Therefore, the composition of the present invention can be used to improve the NAD concentration in the body, and the present invention also provides the use of the aforementioned carbohydrates in improving the NAD concentration in the body, and the use of the aforementioned carbohydrates in the manufacture of a composition for improving the NAD concentration in the body.

[0149] Furthermore, the composition of the present invention can also be used to prevent or improve various diseases and symptoms reported to be prevented or improved by administering or taking NMN and NAD as its metabolite, i.e., diseases caused by aging (non-patent literature 1 to 4), constipation (non-patent literature 5), inflammatory bowel disease (Navarro et al., Br J Pharmacol., 2022, 179, p. 1839-1856), etc., by improving the NMN concentration and / or NAD concentration in the body, preferably for preventing or improving diseases caused by aging, preventing or improving constipation, or preventing or improving inflammatory bowel disease. The present invention also provides the use of the aforementioned carbohydrates in preventing or improving these diseases, and the use of the aforementioned carbohydrates in preparing compositions for preventing or improving these diseases.

[0150] Examples of the aforementioned diseases caused by aging include various diseases reported to be caused by aging (preferably over 40 years old, more preferably over 50 years old, and even more preferably over 60 years old for humans), such as obesity, decreased insulin resistance, decreased lipid metabolism ability, decreased eye function, decreased bone density, decreased immune function, decreased glucose tolerance, increased oxidative stress, inflammation, circadian rhythm disorders, decreased liver function, decreased kidney function, decreased skeletal muscle function, decreased cardiac function, Alzheimer's dementia, and decreased central nervous system function.

[0151] In the present invention, the improvement of NMN production by intestinal flora in the body can be confirmed, for example, by collecting feces, measuring the NMN concentration in the feces, and taking the subject before administration or the group not administered with the composition of the present invention or the carbohydrate of the present invention as a benchmark, and the above-mentioned NMN concentration becomes higher. The above-mentioned NMN concentration can be measured by a suitable known method or a method based on the method, for example, it can be measured by a method using a liquid chromatography mass spectrometer (LC-MS / MS) described in the following examples.

[0152] <Methods for improving NMN production>

[0153] By administering the above-mentioned carbohydrates to the subject, the NMN production of the subject using the intestinal flora can be improved. In addition, this can improve the NAD concentration in the organism, prevent or improve the aforementioned various diseases and symptoms (preferably diseases caused by aging, constipation, and inflammatory bowel disease). Therefore, the present invention also provides a method for improving NMN production, a method for improving NAD concentration in the organism, and a method for preventing or improving the aforementioned various diseases (preferably diseases caused by aging, constipation, and inflammatory bowel disease) by administering an effective amount of the above-mentioned carbohydrates to a subject (hereinafter collectively referred to as "the method of the present invention" according to the circumstances).

[0154] The method of the present invention includes a step of administering an effective amount of the carbohydrate of the present invention to the subject. As the subject of the method of the present invention, humans or non-human mammals can be listed, and as the aforementioned non-human mammals, mice, sheep, cattle, pigs, horses, monkeys, dogs, cats, rabbits, etc. can be listed. As described above, there are individual differences in the intestinal flora, and there may be a situation where NMN is not produced. Therefore, as the aforementioned subject, it is preferred that its intestinal flora produces NMN. It should be noted that there are individual differences in the production of NMN by the intestinal flora, so it cannot be generalized. For example, it can be determined by detecting NMN in the culture medium containing 0.5% glucose in the feces of the subject (preferably 1 mg) at 37 ° C and anaerobic conditions for 12 hours (preferably by using a liquid chromatography mass spectrometer (LC-MS / MS) method (such as the method described in the following examples) When measured, the quantitative limit value (e.g., 1 ng / mL) is detected. In addition, the aforementioned subjects may be people who have already suffered from the aforementioned various diseases (for example, diseases due to aging, constipation, inflammatory bowel disease), or people whose purpose is to prevent the onset of the diseases.

[0155] In the method of the present invention, the carbohydrate can be administered directly, more preferably as the composition of the present invention, preferably orally or enterally to the subject, more preferably orally. It should be noted that in the present invention, oral administration also includes ingestion of the dietary composition, the feed composition, etc.

[0156] In the method of the present invention, the effective amount of the aforementioned carbohydrate is appropriately determined according to the respective circumstances in consideration of the purpose and method of administration; the type, age, weight, sex, disease, degree of symptoms, etc. of the subject, and is therefore not particularly limited, and is the same as the dosage of the composition of the present invention described above. For example, for humans (preferably adults), the amount of the aforementioned carbohydrate is preferably 1 to 1000 mg per kg of the subject's body weight and per day, more preferably 10 to 1000 mg, and can be, for example, 20 to 800 mg, 30 to 700 mg, or 50 to 500 mg. In the method of the present invention, the number of administrations can be divided into once a day to an appropriate number of times.

[0157] Example

[0158] The present invention will be described in more detail below based on test examples, but the present invention is not limited to the following examples. It should be noted that in each of the following test examples, "%" represents weight / volume (w / v: g / mL) % unless otherwise specified.

[0159] <Test Example 1> NMN production capacity of human intestinal flora

[0160] 1 mg of human feces (#1-3) collected from different people was added to 1 mL of GAM medium supplemented with glucose at a final concentration of 0.5%, and cultured in an anaerobic glove box at 37°C for 12 hours, and the NMN concentration in the culture medium was measured. The aforementioned GAM medium uses a semi-fluid medium for GAM sugar decomposition (made by Nissui Pharmaceutical) dissolved in water at a predetermined concentration, filtered with a 0.8μm filter, and sterilized in an autoclave at 115°C for 15 minutes. In addition, the aforementioned NMN concentration was determined by the following method. That is, first, the supernatant obtained by centrifuging the culture solution was filtered with a 0.22μm filter, and the filtrate was mixed with methanol (final concentration 80v / v%) and left to stand on ice for 30 minutes. Then, the supernatant obtained by centrifugation was dried with a centrifugal evaporator. Then, the obtained dried solid was dissolved with an ammonium acetate solution, provided to a liquid chromatography mass spectrometer (LC-MS / MS), and analyzed under the following conditions to determine the NMN concentration. Figure 1 The NMN concentration (ng / mL) in each human feces (#1 to 3) is shown.

[0161] (LC-MS / MS analysis conditions)

[0162] Detector: QTRAP4500 (manufactured by SCIEX)

[0163] HPLC system: Made by Shimadzu Corporation

[0164] Chromatographic column: Hypercarb 3μm, 2.1mm×100mm column

[0165] Mobile phase

[0166] Solution A: 7.5 mM ammonium acetate aqueous solution containing 0.05 (v / v)% ammonium hydroxide

[0167] Solution B: Acetonitrile solution containing 0.05 (v / v)% ammonium hydroxide

[0168] The ratio of liquid A and liquid B: the flow of mobile phase begins → 0 minutes: liquid A 95v / v% - liquid B 5v / v%; 0 minutes → 1.8 minutes: liquid A 95v / v% - liquid B 5v / v%; 1.8 minutes → 14 minutes: liquid A 95v / v% - liquid B 5v / v% → liquid A 46v / v% - liquid B 54v / v%; 14 minutes → 14.1 minutes: liquid A 46v / v% - liquid B 54v / v% → liquid A 10v / v% - liquid B 90v / v%; 14.1 minutes → 17.1 minutes: liquid A 10v / v% - liquid B 90v / v%; 17.1 minutes → 17.2 minutes: liquid A 95v / v% - liquid B 5v / v%; 17.2 minutes → 32.2 minutes: liquid A 95v / v% - liquid B 5v / v%

[0169] Column temperature: 60°C

[0170] Flow rate: 0.2mL / min

[0171] Injection volume: 2μL

[0172] Ionization: ESI positive mode

[0173] m / z of NMN

[0174] Precursor ion (Q1 Mass, (Da)): 335.1

[0175] Product ion (Q3 Mass, (Da)): 123.0.

[0176] like Figure 1 As shown, NMN was detected in human feces #1 to 3, confirming that human intestinal flora produces NMN. In addition, it was confirmed that the human feces culture system in the aforementioned GAM medium can evaluate the NMN production ability achieved by the intestinal flora derived from the human feces.

[0177] <Test Example 2> Evaluation of improvement in NMN production using carbohydrates

[0178] First, any one of the carbohydrates shown in the following Table 1 was added to the aforementioned GAM medium (without the addition of glucose) at a final concentration of 0.5%, and each evaluation medium was prepared. In addition, as a comparative example, an evaluation medium was prepared in which distilled water (DW) was added instead of carbohydrates. Next, 1 mg of human feces #1 to 3, the same as in Experimental Example 1, was added to 1 mL of the aforementioned evaluation medium, and cultured at 37°C in an anaerobic glove box for 12 hours. After culture, the NMN concentration in the culture medium was measured using a liquid chromatography-mass spectrometer (LC-MS / MS) by the method described in Experimental Example 1. The average values ​​of the NMN concentrations when human feces #1 to 3 were cultured are shown in Figure 2In addition, the calculation results of the average values ​​of the above-mentioned average values ​​for each carbohydrate category (except glucose and sucrose) are shown in Table 2 below.

[0179] [Table 1]

[0180]

[0181] [Table 2]

[0182]

[0183] like Figure 2 As shown, NMN was detected in the evaluation medium to which each carbohydrate was added, unlike the evaluation medium (DW) to which no carbohydrate was added. In particular, nitrosaccharide, cellobiose, oligofructose, lactoligosaccharide, and raffinose showed higher NMN concentrations than glucose and sucrose, which are general sugars used in culture (wherein they are decomposed / absorbed in the upper part of the digestive tract in the body). In addition, as shown in Table 2, the average value of NMN concentration of each carbohydrate classification was the highest in trisaccharides, followed by mixed sugars (a mixture of tri- to pentasaccharides), tetrasaccharides, and disaccharides. However, as Figure 2 As shown in the figure, even for disaccharides, sialyllactose, which is a sialylated modified sugar, has a low NMN concentration. Furthermore, even for trisaccharides, fucosyllactose, which contains fucose in its constituent sugar, has a low NMN concentration.

[0184] <Test Example 3> Evaluation of improvement of NMN production in the intestine of mice

[0185] Among the carbohydrates that have been confirmed to have excellent NMN production improvement effects in Test Example 2, oligofructose (a mixture of FOS, 1-fructotriose, fructotetraose and 1-fructofuranosyl-D-fructotetraose, manufactured by Meiji Food Materia Co., Ltd., product name: Meioligo P) was used to evaluate the NMN production improvement effect in the mouse intestine (in the large intestine). First, 7-week-old male ICR mice (manufactured by Japan SLC, Inc.) were divided into 2 groups, each with 8 individuals, one group freely ingested a 5% FOS aqueous solution as the FOS group, and the other group freely ingested water as the control group, and they were raised for 10 days respectively. After the feeding period, the cecal contents were collected after fasting for 3 hours and their weight was measured. In addition, 20 mg of the collected cecal contents were weighed in a microtube, mixed with methanol in a manner that the final concentration was 80 v / v% and allowed to stand on ice for 30 minutes. Next, the supernatant obtained by centrifugation is transferred to another microtube, and then 80 v / v% methanol is added to the pellets to mix, and centrifugation is performed again, and the obtained supernatant is mixed with the supernatant previously transferred to another microtube. Next, the mixed supernatant is dried with a centrifugal evaporator, and the obtained dry matter is dissolved with an ammonium acetate solution, filtered with a 0.22 μm filter, and the NMN concentration in the filtrate is measured by a liquid chromatography-mass spectrometer (LC-MS / MS) using the method described in Experimental Example 1 to calculate the NMN concentration in the cecal contents. Furthermore, the amount obtained by multiplying the measured NMN concentration by the weight of the cecal contents (total amount, total (μg)) is calculated, and the average value of total in each group is calculated. The results are shown in Figure 3 .

[0186] like Figure 3 As shown, the amount of NMN in the cecal contents in the FOS group that ingested oligofructose was greater than that in the control group that ingested water, and a significant difference test was performed between the control group and the FOS group by t-test, and the result was p<0.01, confirming that there was a significant difference between the two groups. Therefore, it was confirmed that oligofructose also increases the amount of NMN produced by intestinal flora in vivo (in vivo), and it is suggested that at least one selected from the group consisting of nitrosaccharide, nitrosaccharide, and nitrosaccharide contained therein also exerts the same effect.

[0187] <Test Example 4> Evaluation of improvement in NMN production in the intestines of humanized bacterial flora mice

[0188] Using nitrosaccharide (Meiji Food Materia Co., Ltd.), the improvement effect of NMN in the intestine (in the large intestine) of humanized bacterial flora mice transplanted with human intestinal flora in germ-free mice was evaluated. First, human feces were orally administered to 8-week-old male germ-free mice (C57BL / 6N, CLEA Japan, Inc., 3 individuals), and feces were collected after 3 weeks of acclimatization (Day0, Day 0). During this period, water was freely ingested. After feces were collected, drinking water was replaced from water to a 5% nitrosaccharide aqueous solution for free intake and raised for 14 days. Feces were collected 1, 3, 9, and 14 days after the administration of nitrosaccharide (Day 1, 3, 9, 14 (Days 1, 3, 9, and 14)). In addition, 20 mg of feces collected on each feces collection day (Day) were weighed in a microtube, and methanol was mixed in a way that the final concentration became 80v / v% and stood on ice for 30 minutes. Next, the supernatant obtained by centrifugation was transferred to another microtube, and then 80 v / v% methanol was added to the pellets to mix, and centrifuged again, and the obtained supernatant was mixed with the supernatant previously transferred to another microtube. Next, the mixed supernatant was dried with a centrifugal evaporator, and the obtained dry matter was dissolved with an ammonium acetate solution, filtered with a 0.22 μm filter, and the NMN concentration in the filtrate was measured by liquid chromatography-mass spectrometry (LC-MS / MS) using the method described in Test Example 1, and the NMN concentration (ng / mL) in the feces was calculated. The average value of the NMN concentration of the three individuals on each fecal collection day is shown in Figure 4 .

[0189] like Figure 4 As shown, the fecal NMN concentration on Day 1, 3, and 9 during the kestose administration period was higher than that on Day 0 before the kestose administration period. On Day 1 and 9, p < 0.10 ( Figure 4 #) or p<0.05( Figure 4 denoted by * in the figure). Therefore, it was confirmed that kestose increases the amount of NMN produced by human intestinal flora in vivo.

[0190] Industrial Applicability

[0191] As described above, according to the present invention, a composition having the effect of improving the production of nicotinamide mononucleotide (NMN) by intestinal flora can be provided. In addition, the composition of the present invention can also be provided as a dietary composition, so it is easy to ingest and easy to get used to. Furthermore, the composition of the present invention can be used to improve the NAD concentration in the body, prevent or improve diseases caused by aging, and prevent or improve constipation and inflammatory bowel disease by increasing the amount of NMN produced by intestinal flora.

Claims

1. A composition for improving the production of nicotinamide mononucleotide (NMN), characterized in that It contains at least one carbohydrate selected from the group consisting of monosaccharides, disaccharides, trisaccharides, tetrasaccharides, pentasaccharides, sugar alcohols and dietary fibers as an effective ingredient, wherein the monosaccharide does not include glucose and xylose.

2. The composition according to claim 1, characterized in that It contains a monosaccharide as the carbohydrate, and the monosaccharide is tagatose.

3. The composition according to claim 1, characterized in that It contains a disaccharide as the carbohydrate, and the disaccharide is at least one selected from the group consisting of cellobiose, lactulose, trehalose, and sialyllactose.

4. The composition according to claim 1, characterized in that It contains a trisaccharide as the carbohydrate, and the trisaccharide is at least one selected from the group consisting of kestose, lactulose oligosaccharide, raffinose and fucosyllactose.

5. The composition according to claim 1, characterized in that The carbohydrate contains a tetrasaccharide, which is at least one selected from the group consisting of stachyose and konjac.

6. The composition according to claim 1, characterized in that It contains pentasaccharide as the carbohydrate, and the pentasaccharide is sucrose pentasaccharide.

7. The composition according to claim 1, characterized in that The carbohydrate contains a sugar alcohol, wherein the sugar alcohol is at least one selected from the group consisting of reduced isomaltulose, lactitol, sorbitol, mannitol, and xylitol.

8. The composition according to claim 1, characterized in that The invention contains dietary fiber as the carbohydrate, and the dietary fiber is inulin.

9. The composition according to any one of claims 1 to 8, characterized in that It is an oral composition or an enteral composition.

10. The composition according to any one of claims 1 to 8, characterized in that It is a dietary composition, a pharmaceutical composition or a quasi-drug composition.

11. The composition according to any one of claims 1 to 8, characterized in that It is a composition for preventing or improving constipation.

12. The composition according to claim 11, characterized in that The dosage for humans is 10 to 1000 mg per kg of body weight per day of the carbohydrate.

13. The composition according to any one of claims 1 to 8, characterized in that It is a composition for preventing or improving inflammatory bowel disease.

14. The composition according to claim 13, characterized in that The dosage for humans is 10 to 1000 mg per kg of body weight per day of the carbohydrate.

15. The composition according to any one of claims 1 to 8, characterized in that This is a composition for preventing or improving diseases caused by aging.

16. The composition according to claim 15, characterized in that The dosage for humans is 10 to 1000 mg per kg of body weight per day of the carbohydrate.

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