Intestinal short-chain fatty acid increaser and intestinal butyrate delivery system

Abstract

To provide an intestinal short-chain fatty acid increasing agent that is effective in a smaller amount.SOLUTION: The intestinal short-chain fatty acid increasing agent includes a cellulose derivative as an active ingredient. In the cellulose derivative, the total substitution degree by an acyl group is 0.3 or more and 1.8 or less, a replacement ratio by an acyl group other than an acetyl group is 95% or more, and a 6th position replacement ratio is 40% or less. The butyric acid transmission system into the intestine includes a cellulose derivative. In the cellulose derivative, the total substitution degree by an acyl group is 0.3 or more and 1.8 or less, a replacement ratio by a butyryl group is 95% or more and, and a 6th position replacement ratio is 40% or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent, food, and medicine for increasing short-chain fatty acids in the intestine. The present invention also relates to a butyrate delivery system for delivering butyrate to the intestine. [Background technology]

[0002] Animals, including humans, harbor numerous microbiota in anatomical sites, including the mouth, esophagus, stomach, small intestine, large intestine, cecum, colon, rectum, vagina, skin, nasal cavity, ears, and lungs. The human microbiota is involved in immune system development; metabolism of carbohydrates, proteins, and xenobiotics; epithelial formation and regeneration; fat storage; hormone and vitamin production; and defense against pathogen infection.

[0003] Because altering the human microbiota plays an important role in the progression of human diseases, there are various therapies that utilize altering the human microbiota, such as antibiotics, prebiotics, probiotics, and fecal transplants.

[0004] Patent Document 1 describes a composition for treating an autoimmune disease, inflammatory disease, or infectious disease, which contains as active ingredients two or more substances selected from the group consisting of the following (a) and (b), and which induces the proliferation or accumulation of regulatory T cells: (a) a bacterium belonging to human-derived Clostridium cluster 14a or a physiologically active substance derived from said bacterium (b) a bacterium belonging to human-derived Clostridium cluster 4 or a physiologically active substance derived from said bacterium

[0005] Furthermore, according to Figure 18 of Patent Document 1, by colonizing Clostridium in germ-free mice, approximately 30% of CD4 lymphocytes were induced to differentiate into regulatory T cells, an increase from approximately 10% in the germ-free mouse group.

[0006] Non-Patent Document 1 describes that regulatory T cells (Treg) can be proliferated by oral administration of specific bacteria, such as bacteria belonging to Clostridium cluster 4 and Clostridium cluster 14a. Non-Patent Document 2 describes that butyric acid induced by bacteria belonging to the class Clostridium controls the differentiation of regulatory T cells.

[0007] Patent Document 2 discloses a pharmaceutical comprising a carrier covalently bound to a fatty acid by a bond that can be hydrolyzed in the colon to generate free fatty acids. Non-Patent Documents 2 and 3 disclose that feeding butyrated starch to mice increases the proportion of regulatory T cells in the large intestine. Patent Documents 3 and 4 disclose that cellulose butyrate (butyrated cellulose) induces regulatory T cells or type 1 helper T cells. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-128408 [Patent Document 2] Special Publication No. 9-505060 [Patent Document 3] Japanese Patent Application Publication No. 2018-158895 [Patent Document 4] Japanese Patent Publication No. 2020-066606 [Non-patent literature]

[0009] [Non-Patent Document 1] Nature, Vol. 500, p. 232-236 (2013) [Non-patent document 2] Nature, Vol. 504, p. 446-450 (2013) [Non-patent document 3] Hiroshi Ohno and two others, "Butyrate produced by intestinal bacteria is key to inducing differentiation into regulatory T cells," [online], November 14, 2013, RIKEN, [Retrieved February 17, 2014], Internet (URL: http: / / www.riken.jp / pr / press / 2013 / 20131114_1 / ) Summary of the Invention [Problem to be solved by the invention]

[0010] The method using the composition described in Patent Document 1 is a so-called probiotic approach in which butyric acid-inducing bacteria are directly administered to increase butyric acid concentration and induce the proliferation or accumulation of regulatory T cells. This method using specific bacteria has many restrictions on storage conditions and feeding methods, such as the need to seal and refrigerate the bacteria and set a relatively short shelf life of about several weeks, as in the case of storing and transporting yogurt, in order to keep the specific bacteria alive and suppress the growth of other bacteria. Furthermore, depending on the intestinal environment, the effect of increasing regulatory T cells may not be observed.

[0011] Furthermore, according to Figure 4(f) in Non-Patent Document 2, feeding butyrated starch to a mouse model of colitis induced differentiation of CD4 lymphocytes into regulatory T cells to 3.7%, compared to 1.62% in the control group. However, this required a significantly high dose of butyrated starch in the diet, at 15% (w / w). If such a high dose were required, a human would need to ingest approximately 30 g per day. Considering that a single serving of dried noodles, for example, is approximately 80 g, this is a considerable amount, making oral administration painful and, if ingested as a medicine, disrupting the enjoyment of normal eating.

[0012] According to the cellulose butyrates described in Patent Documents 2 and 3, it is possible to increase intestinal butyrate at a relatively low dose and induce regulatory T cells or type 1 helper T cells. However, in order to more efficiently induce regulatory T cells or type 1 helper T cells, there is a need for a technology for increasing short-chain fatty acids, particularly n-butyrate, in the intestine at a lower dose.

[0013] An object of the present invention is to provide an agent for increasing intestinal short-chain fatty acids and a butyrate delivery system into the intestine that can sufficiently increase regulatory T cells or type 1 helper T cells at a lower dose. [Means for solving the problem]

[0014] The agent for increasing intestinal short-chain fatty acids according to the present disclosure contains a cellulose derivative as an active ingredient. The cellulose derivative has a total degree of substitution with acyl groups of 0.3 to 1.8, a substitution rate with acyl groups other than acetyl groups of 95% or more, and a substitution rate at the 6-position of 40% or less. Preferably, the acyl groups other than acetyl groups are butyryl groups.

[0015] The intestinal short chain fatty acid increasing agent may be cellulose butyrate or cellulose acetate butyrate.

[0016] The 6-position substitution rate of the cellulose derivative may be 30% or less.

[0017] The degree of substitution of the cellulose derivative with acetyl groups may be 0.10 or less.

[0018] The content of the cellulose derivative in the agent for increasing intestinal short-chain fatty acids may be 0.2% by weight or more and 5% by weight or less.

[0019] The food product according to the present disclosure contains any one of the aforementioned agents for increasing intestinal short-chain fatty acids. The medicine according to the present disclosure contains any one of the aforementioned agents for increasing intestinal short-chain fatty acids.

[0020] The medicament according to the present disclosure may be for the prevention and / or treatment of an allergic disease caused by fluctuations in short-chain fatty acids in the intestine. The allergic disease may be chronic allergy.

[0021] The medicament according to the present disclosure may be for the prevention and / or treatment of inflammatory bowel disease caused by fluctuations in short-chain fatty acids in the intestine. The inflammatory bowel disease may be ulcerative colitis.

[0022] The medicament according to the present disclosure may be used for the prevention and / or treatment of an autoimmune disease caused by fluctuations in short-chain fatty acids in the intestine. The autoimmune disease may be Crohn's disease.

[0023] The intestinal butyric acid delivery system according to the present disclosure comprises a cellulose derivative as an active ingredient. The cellulose derivative has a total degree of acyl substitution of 0.3 to 1.8, a butyryl substitution rate of 95% or more, and a 6-position substitution rate of 40% or less. Preferably, the acetyl substitution rate of the cellulose derivative is 0.1 or less. [Effects of the Invention]

[0024] This agent for increasing intestinal short-chain fatty acids reduces restrictions on storage conditions and feeding methods, and can sufficiently increase intestinal short-chain fatty acids at lower doses. Furthermore, this intestinal butyrate delivery system allows sufficient delivery of butyrate to the intestine at lower doses. This efficiently induces regulatory T cells and type 1 helper T cells in the intestine. Furthermore, of the short-chain fatty acids produced by intestinal bacteria, most acetic acid and propionic acid are absorbed by the colonic mucosa and do not serve as an energy source for the colonic mucosal epithelium. On the other hand, butyrate serves as an energy source for the colonic mucosal epithelium, and is therefore expected to improve the intestinal microflora. DETAILED DESCRIPTION OF THE INVENTION

[0025] An example of a preferred embodiment will be described in detail below. Each configuration and combination thereof in each embodiment is merely an example, and addition, omission, substitution, and other modifications of configurations are possible as appropriate within the scope of the present disclosure. The present disclosure is not limited by the embodiments, but only by the scope of the claims. Furthermore, each aspect disclosed in this specification can be combined with any other feature disclosed in this specification.

[0026] [Increasing intestinal short-chain fatty acids] The agent for increasing intestinal short-chain fatty acids (hereinafter sometimes simply referred to as "increaser") of the present disclosure contains a cellulose derivative as an active ingredient. This cellulose derivative has a total degree of acyl substitution of 0.3 to 1.8, a substitution rate of 95% or more with acyl groups other than acetyl groups, and a substitution rate at the 6-position of 40% or less.

[0027] This cellulose derivative is not degraded by mammalian digestive enzymes, but is partially or completely fermented and degraded by intestinal bacteria. The cellulose derivative is efficiently delivered to the intestine by the agent for increasing short-chain fatty acids of the present disclosure. Furthermore, the fermentation and degradation of this cellulose derivative by intestinal bacteria results in the production of many short-chain fatty acids. Specifically, organic acids derived from acyl groups, such as acetic acid, propionic acid, and butyric acid derived from glucose residues, are produced. The cellulose derivative of the present disclosure has a low substitution rate at the 6-position, which is less susceptible to degradation by intestinal bacteria. In other words, this cellulose derivative has a high substitution rate at the 2- and 3-positions, which are easily degraded by intestinal bacteria. Therefore, an agent for increasing short-chain fatty acids in the intestine containing this cellulose derivative can produce acyl-derived organic acids more efficiently at a low dose.

[0028] [Cellulose derivatives] As described above, the cellulose derivative contained in the increasing agent of the present disclosure has a total degree of substitution with acyl groups of 0.3 or more and 1.8 or less, a substitution rate with acyl groups other than acetyl groups of 95% or more, and a substitution rate at the 6-position of 40% or less.

[0029] Here, the acyl group is a functional group represented by the general formula RCO-, where R represents a hydrocarbon group which may have a substituent. Specific examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, a carboxyl group, a carboxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a methyl group. From the viewpoint of delivering short-chain fatty acids which have excellent effects in the digestive tract such as the large intestine, preferred acyl groups are a butyryl group and a propionyl group, and a more preferred acyl group is a butyryl group.

[0030] The cellulose derivative contained in the thickener of the present disclosure may be a cellulose acylate substituted with two or more acyl groups including a butyryl group. The cellulose derivative substituted with an acyl group including a butyryl group has increased hydrophobicity. From the viewpoint of promoting decomposition by intestinal bacteria in the digestive tract and increasing the amount of butyric acid released, it is preferable to impart hydrophilicity to the cellulose derivative. From this viewpoint, examples of the acyl group introduced together with the butyryl group include an acetyl group, a carboxymethyl group, a carboxyl group, and the like, which have lower hydrophobicity than the butyryl group. An acetyl group is more preferred.

[0031] Here, when a cellulose derivative is substituted only with butyryl groups, the cellulose derivative is called cellulose butyrate (butyrated cellulose), and when a cellulose derivative is substituted with butyryl groups and acetyl groups, the cellulose derivative is called cellulose acetate butyrate (butyrated cellulose acetate or acetate-butyrated cellulose).

[0032] [Total substitution degree] The cellulose derivative contained in the agent for increasing short-chain fatty acids of the present disclosure has a total degree of substitution with acyl groups of 0.3 to 1.8, preferably 0.3 to 1.5, more preferably 0.3 to 1.4, and even more preferably 0.5 to 1.3. In this specification, the total degree of substitution refers to the sum of the degrees of substitution with all acyl groups contained as substituents in the cellulose derivative of the present disclosure. If the total degree of substitution is less than 0.3, depending on the dosage, generally less short-chain fatty acids are liberated in the digestive tract, making it difficult to achieve the desired increasing effect. Furthermore, if the total degree of substitution exceeds 1.8, degradation by bacteria such as enterobacteria in the digestive tract is inhibited, presumably due to excessive hydrophobicity, making it difficult to achieve the increasing effect of short-chain fatty acids.

[0033] [Substitution rate and degree of acyl groups other than acetyl groups] The cellulose derivative contained in the increasing agent of the present disclosure has a substitution rate of 95% or more with acyl groups other than acetyl groups. This substitution rate refers to the ratio (%) of the degree of substitution with acyl groups other than acetyl groups to the total degree of substitution with acyl groups. From the viewpoint of achieving a large effect of increasing short-chain fatty acids in the intestine, the substitution rate with acyl groups other than acetyl groups is preferably 96% or more, more preferably 98% or more, even more preferably 99% or more, and ideally 100%.

[0034] The degree of substitution of this cellulose derivative with acyl groups other than acetyl groups is preferably 0.3 to 1.8, more preferably 0.3 to 1.5, even more preferably 0.3 to 1.4, and particularly preferably 0.5 to 1.3.

[0035] [Acetyl group substitution degree] From the viewpoint of a significant effect of increasing short-chain fatty acids in the intestine, it is preferable that the degree of substitution with acyl groups other than acetyl groups is the same as the total degree of substitution with acyl groups described above. However, for example, when commercially available cellulose acetate butyrate is used as a raw material and a portion of its butyryl groups and acetyl groups are hydrolyzed to obtain the cellulose derivative of the present disclosure, acetic acid is used as a medium for the hydrolysis reaction, and as a result, acetyl groups may remain or be introduced into the resulting cellulose derivative. Furthermore, when this cellulose derivative is obtained from cellulose as a raw material, acetic acid is used as a cellulose activation treatment agent or a medium for the acylation reaction, and as a result, acetyl groups may be introduced into the resulting cellulose derivative. From the viewpoint of the effect of increasing short-chain fatty acids in the intestine, the degree of substitution with acetyl groups of the cellulose derivative is preferably 0.10 or less, more preferably 0.08 or less, and even more preferably 0.05 or less.

[0036] For example, when the cellulose derivative contained in the thickener of the present disclosure is the aforementioned cellulose acetate butyrate or cellulose butyrate, the total degree of substitution, which is the sum of the butyryl substitution degree and the acetyl substitution degree, is 0.3 to 1.8, and the ratio of the butyryl substitution degree to the total degree of substitution (i.e., butyryl substitution rate) is 95% or more. In the cellulose acetate butyrate or cellulose butyrate, the butyryl substitution degree may be 0.3 to 1.8, and the acetyl substitution degree may be 0.1 or less. Depending on the production method, the cellulose butyrate may contain acetyl groups as trace components.

[0037] [6-position substitution rate] Here, the degree of substitution refers to the sum of the number of substituents substituting the hydrogen atoms of the hydroxyl groups at the 2nd, 3rd, and 6th positions per repeating unit (glucopyranose unit) of cellulose, and the substitution rate at the 6th position refers to the ratio (%) of the degree of substitution at the 6th position to the total degree of substitution at the 2nd, 3rd, and 6th positions.

[0038] The cellulose derivatives contained in the increasing agent of the present disclosure have a 6-position substitution rate of 40% or less, preferably 30% or less, and more preferably 20% or less. This is because metabolic degradation of cellulose derivatives by intestinal bacteria begins with hydrolysis of acyl groups such as butyryl groups attached to cellulose, and acyl groups attached to the 6-position are most resistant to this metabolic degradation.

[0039] The 6-position substitution rate of this cellulose derivative may be 0% or 0.01% or more. The 6-position substitution rate of the cellulose derivative may be 2% or more, 3% to 40% or less, 3% to 30% or less, or 3% to 20% or less. The 6-position substitution rate of the cellulose derivative can be adjusted to 3% or less by selecting a reaction solvent or adjusting the starting materials.

[0040] From the viewpoint of the effect of increasing short-chain fatty acids in the intestine, the substitution rate at the 6-position of the cellulose derivative with an acyl group other than an acetyl group is preferably 40% or less, more preferably 30% or less, more preferably 20% or less, and even more preferably 3% or more and 20% or less. Here, the substitution rate at the 6-position with an acyl group other than an acetyl group refers to the ratio (%) of the degree of substitution at the 6-position with an acyl group other than an acetyl group to the total degree of substitution at the 2-, 3-, and 6-positions with an acyl group other than an acetyl group.

[0041] Furthermore, when the increasing agent of the present disclosure contains the above-mentioned cellulose butyrate or cellulose acetate butyrate as a cellulose derivative, the percentage (%) of the degree of butyryl substitution at the 6-position with butyryl groups relative to the total degree of butyryl substitution at the 2-, 3-, and 6-positions is preferably 40% or less, more preferably 30% or less, more preferably 20% or less, and even more preferably 3% or more and 20% or less.

[0042] [Method for measuring degree of substitution] The degree of substitution of a cellulose derivative can be measured by the following method. For example, it can be measured by NMR according to the method of Tezuka (Tezuka, Carbonydr. Res. 273, 83 (1995)). That is, the free hydroxyl groups of the cellulose derivative are acylated with a carboxylic acid anhydride in pyridine. The type of carboxylic acid anhydride used here should be selected depending on the purpose of the analysis. For example, when analyzing the degree of butyryl substitution of cellulose butyrate, acetic anhydride is suitable. In addition, when analyzing the degree of butyryl substitution of cellulose acetate butyrate, acetic anhydride is suitable, and when analyzing the degree of acetyl substitution, butyric anhydride is suitable. The obtained sample is dissolved in deuterated chloroform, and 13 C-NMR spectrum is measured. For example, when the substituent is an acetyl group or a butyryl group, the carbon signals of the acetyl group appear in the region from 169 ppm to 171 ppm in the order of 2, 3, and 6 from the upfield, and the carbon signals of the butyryl group appear in the region from 171 ppm to 173 ppm in the order of 2, 3, and 6 from the upfield. As another example, when a cellulose derivative having a propionyl group or a cellulose derivative not having a propionyl group is treated with propionic anhydride to analyze the degree of propionyl substitution, the signals of the carbonyl carbon of the propionyl group appear in the same order in the region from 172 ppm to 174 ppm. The total degree of substitution of a cellulose derivative treated with carboxylic acid anhydride by Tezuka's method or a method similar thereto is 3.0, so if the sum of the areas of the carbonyl carbon signals of the acyl groups originally possessed by the cellulose derivative and the carbonyl signals of the acyl groups introduced by the carboxylic acid anhydride treatment is normalized to 3.0, and the abundance ratios of acetyl groups, butyryl groups, and propionyl groups at the corresponding positions (in other words, the area ratios of each signal) are calculated, this can be used to determine the degrees of acetyl, butyryl, or propionyl substitution at the 2nd, 3rd, and 6th positions of the glucose ring in the cellulose derivative. Needless to say, the only substituents containing acyl groups that can be analyzed by this method are those that do not correspond to the carboxylic acid anhydride used in the treatment for analysis. Also, 13 In addition to C-NMR, 1 It can also be analyzed by H-NMR.

[0043] However, if it is known in advance that the total degree of substitution at the 2nd, 3rd, and 6th positions of the glucose ring of the sample cellulose derivative is 3.0 and that all of the substituents are limited substituents such as acetyl groups and butyryl groups, the propionylation step can be omitted and the sample can be directly dissolved in deuterated chloroform and NMR spectra measured. If all of the substituents are acetyl groups and butyryl groups, the carbon signals of the acetyl groups will appear in the 169 to 171 ppm region from the high magnetic field in the order of 2nd, 3rd, and 6th positions, and the carbon signals of the butyryl groups will appear in the same order in the 171 to 173 ppm region, just as in the case where the propionylation step is included. Therefore, the degree of acetyl substitution and the degree of butyryl substitution at the 2nd, 3rd, and 6th positions of the glucose ring of the cellulose derivative can be calculated from the abundance ratio of the acetyl groups and the butyryl groups at the corresponding positions (in other words, the area ratio of each signal).

[0044] [Effects and uses of intestinal short-chain fatty acid enhancers] By administering, particularly orally, the agent for increasing intestinal short-chain fatty acids of the present disclosure, the cellulose derivative, which is the active ingredient of this agent for increasing intestinal short-chain fatty acids, is delivered to the large intestine and other areas where many intestinal bacteria reside. As described above, this cellulose derivative is partially or completely fermented and decomposed by intestinal bacteria, and the metabolic products produced are organic acids derived from acyl groups; and short-chain fatty acids (SCFAs) such as acetic acid, propionic acid, and butyric acid derived from glucose residues. In particular, the increase in butyric acid is significant.

[0045] The intestinal short-chain fatty acid enhancer disclosed herein has the effect of increasing the concentration of short-chain fatty acids by decomposing its active ingredient, a cellulose derivative, with intestinal bacteria, liberating short-chain fatty acids in the intestine. Ingestion of the enhancer disclosed herein increases the number of Bacteroidetes bacteria in the intestine, suggesting that Bacteroidetes bacteria are involved in this increase in short-chain fatty acids. A relatively large number of Bacteroidetes bacteria are known to hydrolyze the acyl groups of polysaccharides containing acyl groups, such as acetyl and 3-phenylpropionyl groups (Dylan Dodd et al., "Xylan degradation, a metabolic property shared by rumen and human colonic bacteroidetes," Mol. Microbiol., 2011, January, Vol. 79(2), pp. 292-304). Furthermore, according to Non-Patent Document 2, an increase in butyrate in the intestine induces the differentiation of immature T cells into regulatory T cells, thereby increasing the number of regulatory T cells in the intestine.

[0046] In contrast to the probiotic approach of directly administering specific bacteria as described in Patent Document 1, administering the agent for increasing the amount of cellulose in the present disclosure utilizes originality and ingenuity in the use of cellulose as dietary fiber to provide short-chain fatty acids in the intestine, and is a prebiotic approach that addresses the environment of intestinal bacteria.

[0047] Here, probiotics and prebiotics are not in conflict with each other, but are expected to exert synergistic effects or to exert complementary effects, such as one acting effectively when the other is ineffective.

[0048] As described above, the increasing agent of the present disclosure can take a prebiotic approach in contrast to the probiotic approach described in Patent Document 1. The increasing agent of the present disclosure is characterized by easy storage of the cellulose derivative, which is the active ingredient, and a wide range of dosage options. For example, the increasing agent of the present disclosure can be stored at room temperature for about one year. It can also be used as an additive to foods baked at temperatures below 200°C, such as bread, cakes, and biscuits.

[0049] The intestinal short-chain fatty acid-increasing agent of the present disclosure may be contained in a food or a medicine. The intestinal short-chain fatty acid-increasing agent of the present disclosure may also be used as a component of various foods or medicines. The food or medicine containing the intestinal short-chain fatty acid-increasing agent may be administered orally. The form of the food or pharmaceutical containing this enhancer is not particularly limited, and various forms can be selected. Examples include typical pharmaceutical forms such as powders, granules, tablets, sugar-coated tablets, capsules, syrups, pills, suspensions, liquids, and emulsions, as well as typical food forms such as beverages; confectionery products such as gum, chocolate, candy, yokan, and jelly; noodles; baked foods such as bread, cakes, and biscuits; canned foods; retort pouch foods; meat products; fish paste products; edible oil compositions such as margarine, dressing, and mayonnaise; dietary supplements; and dairy products such as butter, ice cream, and yogurt. Among these, a daily intake of 0.5 g to 5 g is preferred for achieving efficacy in humans. Because relatively large amounts can be ingested, sugar-coated tablets, noodles, and baked foods such as biscuits are preferred. The intestinal short-chain fatty acid enhancer of the present disclosure can also be incorporated as a thickener into pharmaceutical or food forms. When the intestinal short-chain fatty acid increaser of the present disclosure is incorporated into food as a thickener, the viscosity of the food is improved. Each food has an appropriate viscosity, and foods with high viscosity are inappropriate. If the viscosity is low, it can be compensated for with a known thickener. However, if the viscosity is high, there are few means to lower it. In this respect, the intestinal short-chain fatty acid increaser of the present disclosure, which can exert its effect with a small dosage, is excellent.

[0050] In foods containing the intestinal short-chain fatty acid increaser of the present disclosure, the content of cellulose derivatives is preferably 0.1% by weight or more of the food, more preferably 0.2% to 5% by weight, even more preferably 0.2% to 1% by weight, and may be 0.2% to less than 0.5% by weight. By setting the amount of the intestinal short-chain fatty acid increaser in the food within the above range, it is possible to increase short-chain fatty acids in the intestine and promote differentiation into regulatory T cells or type 1 helper cells without impairing the taste or texture of the food.

[0051] Foods and / or medicines containing the intestinal short-chain fatty acid increaser of the present disclosure are useful for the prevention and / or treatment (reduction or prevention of adverse effects) of autoimmune diseases, allergic diseases, infectious diseases, rejection reactions in organ transplants, etc. Specific examples of target diseases include the following:

[0052] Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, sprue, autoimmune arthritis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, graft-versus-host rejection following bone marrow transplantation, osteoarthritis, juvenile chronic arthritis, Lyme disease arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, insulin-dependent diabetes mellitus, thyroiditis, asthma, psoriasis, dermatitis scleroderma, atopic dermatitis, graft-versus-host rejection, acute or chronic immune disorders associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease (Pascedou's disease), nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Scholein purpura, microscopic vasculitis of the kidney, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, septic symptoms group, cachexia, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, polyglandular deficiency syndrome type 1 and polyglandular deficiency syndrome type 2, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, chlamydial infection, Yersinia and Salmonella infection-associated arthropathy, spondyloarthropathies, atherosclerotic arthropathy Diseases / arteriosclerosis, allergic colitis, atopic allergies, food allergies (peanut allergies, tree nut allergies, egg allergies, milk allergies, soy allergies, wheat allergies, seafood allergies, shellfish allergies, sesame allergies, etc.), autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs test-positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myosyleitis / royal Free's disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, idiopathic autoimmune hepatitis, acquired immunodeficiency syndrome, acquired immunodeficiency-related disease, hepatitis C, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, fibrotic lung disease, idiopathic fibrosing alveolitis, postinflammatory interstitial pneumonia, interstitial pneumonia, connective tissue disease-associated interstitial lung disease, mixed connective tissue-associated lung disease, systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease,Systemic lupus erythematosus-associated lung disease (Iung), dermatomyositis / polymyositis-associated lung disease, Sjogren's disease-associated lung disease, ankylosing spondylitis-associated lung disease, vasculitic diffuse lung disease, hemosiderosis-associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrate lung disease, post-infectious interstitial pneumonia, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (classical or lupus) Hepatitis type 2 (anti-LKM1 antibody hepatitis), autoimmune hypoglycemia, type B insulin resistance due to acanthosis nigricans, hypoparathyroidism, acute immune disorders associated with organ transplantation, chronic immune disorders associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, idiopathic leukopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritis, microscopic vasculitis in the kidney, discoid lupus erythematosus, idiopathic male infertility or NOS S, sperm autoimmunity, multiple sclerosis (all subtypes), insulin-dependent diabetes mellitus, sympathetic ophthalmia, connective tissue disease with pulmonary hypertension, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goiter, hypothyroidism (Hashimoto's disease), atrophy Examples of allergic reactions include atrophic autoimmune hypothyroidism, primary myxedema, lens-induced uveitis, primary vasculitis, vitiligo, allergic rhinitis (pollen allergy), anaphylaxis, pet allergy, latex allergy, drug allergy, allergic rhinitis-conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, cutaneous lupus erythematosus, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, and diarrhea.

[0053] Foods or medicines containing the increasing agent of the present disclosure are particularly useful for the prevention and / or treatment of allergic diseases, autoimmune diseases, and inflammatory bowel diseases caused by fluctuations in short-chain fatty acids in the intestine. For example, ulcerative colitis is a specific example of inflammatory bowel disease that can be prevented and / or treated by inducing regulatory T cells in the intestines, such as the small intestine, large intestine, cecum, colon, and rectum, particularly in the lamina propria of the large intestine, in response to an increase in short-chain fatty acids. Similarly, Crohn's disease is a specific example of a suitable autoimmune disease. Specific examples of allergic diseases include chronic allergies and food allergies.

[0054] Foods or medicines containing the enhancer of the present disclosure are also useful for the prevention and / or treatment of depression. For example, Schroeder FA et al. Biol Psychiatry. 2007 Jul 1;62(1):55-64. Epub 2006 Aug 30. reported that administration of butyric acid to mice resulted in an increase in the hippocampus, which controls memory, compared to administration of SSRIs (selective serotonin reuptake inhibitors), a treatment for depression. Furthermore, Bourassa MW et al. Neurosci Lett. 2016 Jun 20;625:56-63 also reports that administration of butyric acid to mice resulted in an increase in the hippocampus, which controls memory, compared to administration of SSRIs (selective serotonin reuptake inhibitors), a treatment for depression. Considering the hippocampal-enhancing effect of butyric acid administration, in addition to the above-mentioned diseases, foods or medicines containing the increasing agent of the present disclosure are suitable for treating mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, adrenoleukodystrophy, metabolic disorders, cerebral insulin resistance, autism, and psychiatric disorders (schizophrenia, bipolar disorder, panic disorder, anxiety disorder, sexual dysfunction, personality disorder). Foods or medicines containing the increasing agent of the present disclosure can prevent and / or treat these diseases by increasing intestinal short-chain fatty acids, particularly intestinal butyric acid.

[0055] The dosage of the agent for increasing intestinal short-chain fatty acids of the present disclosure is administered to an individual in an amount sufficient to achieve the desired effect of increasing regulatory T cells. Specifically, this can be empirically determined taking into account the individual's conditions, such as the individual's age, body weight, sex, health condition, and conditions of the stomach, small intestine, and large intestine, as well as the administration method and formulation. The amount per administration may be, for example, 6.5 mg / kg to 65 mg / kg body weight, 12 mg / kg to 40 mg / kg body weight, or 12 mg / kg to 20 mg / kg body weight. The agent may be administered to an individual once or more than once. When administered more than once, the agent may be administered periodically, irregularly, or as needed. The appropriate number of administrations, like the dosage, can be empirically determined taking into account the individual's conditions, administration method, formulation, and the like.

[0056] [Intestinal butyrate delivery system] The intestinal butyric acid delivery system of the present disclosure (hereinafter sometimes simply referred to as the "delivery system") contains a cellulose derivative as an active ingredient. This cellulose derivative has a total degree of acyl substitution of 0.3 to 1.8, a butyryl substitution rate of 95% or more, and a 6-position substitution rate of 40% or less. The degree of substitution of the cellulose derivative is measured according to the method described above for the intestinal short-chain fatty acid increaser.

[0057] This cellulose derivative is not degraded by mammalian digestive enzymes, but is partially or completely fermented and degraded by intestinal bacteria. The delivery system of the present disclosure allows the cellulose derivative to be efficiently delivered to the intestine. Furthermore, the fermentation and degradation of this cellulose derivative by intestinal bacteria produces many short-chain fatty acids. Specifically, butyric acid derived from the butyryl group; and acetic acid, propionic acid, and butyric acid derived from glucose residues are produced. The cellulose derivative of the present disclosure has a low substitution rate at the 6-position, which is less susceptible to degradation by intestinal bacteria. In other words, this cellulose derivative has a high substitution rate at the 2- and 3-positions, which are easily degraded by intestinal bacteria. Therefore, a delivery system containing this cellulose derivative allows for more efficient production of butyryl-derived butyric acid at a low dose.

[0058] The cellulose derivative contained in the delivery system of the present disclosure has a total degree of substitution with butyryl groups of 0.3 to 1.8, preferably 0.3 to 1.5, more preferably 0.3 to 1.4, and even more preferably 0.5 to 1.3. This cellulose derivative has a ratio of the degree of substitution with butyryl groups to the total degree of substitution with all acyl groups (degree of substitution with butyryl groups: %) of 95% or more, preferably 96% or more, more preferably 98% or more, even more preferably 99% or more, and ideally 100%.

[0059] The cellulose derivative contained in the delivery system of the present disclosure has a 6-position substitution rate of 40% or less, preferably 30% or less, and more preferably 20% or less. The 6-position substitution rate of this cellulose derivative is preferably 3% or more. The 6-position substitution rate of this cellulose derivative may be 3% or more and 40% or less, 3% or more and 30% or less, or 3% or more and 20% or less. The 6-position substitution rate with butyryl groups is preferably 40% or less.

[0060] The degree of substitution with butyryl groups in this cellulose derivative is preferably 0.3 to 1.8, more preferably 0.3 to 1.5, even more preferably 0.3 to 1.4, and particularly preferably 0.5 to 1.3.

[0061] When the cellulose derivative contained in the delivery system of the present disclosure is substituted only with butyryl groups, the cellulose derivative is called cellulose butyrate (butyrated cellulose). This cellulose derivative may have an acyl group other than butyryl groups as a substituent. This acyl group other than butyryl groups may be an acetyl group. When the cellulose derivative is substituted with butyryl groups and acetyl groups, the cellulose derivative is called cellulose acetate butyrate (acetate butyrated cellulose or acetate butyrated cellulose).

[0062] When the cellulose derivative is substituted with a butyryl group and an acetyl group, the degree of substitution with the acetyl group of the cellulose derivative is preferably 0.10 or less, more preferably 0.08 or less, and even more preferably 0.05 or less. [Example]

[0063] The present invention will be specifically explained below with reference to examples, but the technical scope of the present invention is not limited to these examples.

[0064] [Example 1] Cellulose acetate butyrate (Sigma-Aldrich, product number 419060; hereinafter referred to as "raw cellulose acetate butyrate") was dried under reduced pressure at 60°C for 3 hours. After 30 g of the dried raw cellulose acetate butyrate was dispersed in 300 ml of methanol, a sulfuric acid solution prepared by diluting 1.5 g of concentrated sulfuric acid with 15 ml of methanol was added. The resulting mixture of raw cellulose acetate butyrate, methanol, and sulfuric acid was heated to 90°C over 60 minutes while stirring in a sealed container, maintained at 90°C for 240 minutes, and then cooled to approximately 25°C over 60 minutes. After cooling, 20 ml of methanol containing 6.2 g of sodium acetate trihydrate was added to the cooled mixture for neutralization. The sodium acetate used in the neutralization was 1.5 equivalents of sulfuric acid. The neutralized mixture was added to 2 L of methyl tert-butyl ether with stirring to obtain a precipitate. The precipitate was filtered and washed three times with 1 L of methyl tert-butyl ether. The precipitate was then dried under reduced pressure at 60°C until a constant weight was reached, yielding 18 g of product. This product is designated WSCB-E1. Analysis by the measurement method described below revealed that WSCB-E1 was cellulose butyrate with an acetyl substitution degree of 0.0, a butyryl substitution degree of 0.9, and a total substitution degree of 0.9.

[0065] [Comparative Example 1] (Preparation of Regenerated Cellulose (Base-Catalyzed Deesterification of Cellulose Acetate Butyrate)) 1.5 kg of sodium hydroxide was dissolved in 29.0 L of deionized water. After purging the gas phase of the vessel with nitrogen, 2.0 kg of raw cellulose acetate butyrate (Sigma-Aldrich, product number 419060) was added, followed by the slow addition of 7.0 L of methanol. The resulting mixture was stirred at 30°C for 72 hours, after which acetic acid was added to adjust the pH to 6.2-7. The resulting solid was filtered, washed with 75 L of deionized water, and dried under reduced pressure at 80°C to obtain 880.0 g of a white powder. This white powder is referred to as Cell-WSCB. Analysis using the measurement method described below revealed that the acetyl substitution degree of the raw cellulose acetate butyrate was 0.1, the butyryl substitution degree was 2.5, and the total substitution degree was 2.6. Cell-WSCB was a regenerated cellulose lacking acetyl and butyryl groups.

[0066] (Dissolution of Cell-WSCB (regenerated cellulose)) 850.0 g of Cell-WSCB (regenerated cellulose) was suspended in a deionized water / methanol mixture (3.4 L / 1.7 L) and allowed to stand for 30 minutes, after which the liquid phase was filtered off. The resulting wet regenerated cellulose was suspended in 5.7 L of dimethylacetamide (DMAc), allowed to stand for 30 minutes, and the liquid phase was filtered off. This procedure was repeated four times to remove moisture from the wet regenerated cellulose. 1.2 kg of lithium chloride and 15.0 L of DMAc were added to the resulting wet regenerated cellulose, and the mixture was heated to 100°C under a nitrogen atmosphere and held for 1 hour. The mixture was cooled to near room temperature, further cooled to -20°C using dry ice, held for 1 hour, and then warmed to near room temperature to obtain a clear regenerated cellulose solution.

[0067] (Preparation of cellulose butyrate (WSCB)) To the resulting regenerated cellulose solution, 1.1 L of pyridine was added under a nitrogen atmosphere, followed by the slow addition of 1.221 L of butyric anhydride. The mixture was then heated to 90°C and maintained at this temperature for 5 hours. The temperature was then lowered to 50°C, and 1.0 L of ethanol was slowly added to obtain a reaction mixture. The temperature of the mixture rose due to the decomposition of butyric anhydride, but the rate of ethanol addition was adjusted to maintain the temperature below 75°C. The resulting reaction mixture was slowly added to a mixture of 110 L of tetrahydrofuran (THF) and deionized water (volume ratio: 1 / 1) to form a precipitate. The resulting precipitate was washed sequentially with 30 L of deionized water and 30 L of ethanol, then dried under reduced pressure at 80°C to obtain 925.0 g of product. This product is designated WSCB-C1. Analysis using the measurement method described below revealed that WSCB-C1 was a cellulose butyrate with an acetyl substitution degree of 0.0, a butyryl substitution degree of 1.3, and a total substitution degree of 1.3.

[0068] Comparative Example 2 Cellulose butyrate (WSCB) was prepared in the same manner as in Comparative Example 1, except that the amount of acetic anhydride was changed from 1.221 L to 0.767 L. 822.0 g of product was obtained using the same method as in Comparative Example 1. This product is designated WSCB-C2. Analysis using the measurement method described below revealed that WSCB-C2 was cellulose butyrate with an acetyl substitution degree of 0.0, a butyryl substitution degree of 0.9, and a total substitution degree of 0.9.

[0069] [Measurement of substitution degree] The degree of acetyl substitution and the degree of butyryl substitution were determined by the following method.

[0070] 15 mg of sample was dissolved in 0.75 ml of DMSO-d6. Three drops (approximately 20 mg) of trifluoroacetic acid were added to this solution using a Pasteur pipette and mixed thoroughly. The resulting mixture was transferred to a 5 mm diameter NMR measurement tube. 1 H-NMR was measured. Within 30 minutes after the addition of trifluoroacetic acid, 1 H-NMR was measured. 1 The H-NMR measurement conditions are as follows: Equipment: JEOL ECA500 Measurement probe: TH5 Measurement temperature: room temperature Pulse: zg45 (90° pulse width 11.7 μs) Accumulation count: 32 times Data acquisition time: 1.64 seconds Waiting time: 5.36 seconds

[0071] obtained 1 Based on the H-NMR spectrum, the degrees of acetyl substitution and butyryl substitution were calculated using the following formula. The degrees of acetyl substitution and butyryl substitution are the sum of the degrees of substitution at the 2-, 3-, and 6-positions of the glucose residue. In the cellulose derivatives of the Examples and Comparative Examples, the sum of the degrees of acetyl substitution and butyryl substitution is taken as the total degree of substitution. The results are shown in Table 1 below. Degree of acetyl substitution = (L-2 × K ÷ 3) ÷ 3 ÷ (N ÷ 7) Butyryl substitution degree = (K ÷ 3) ÷ (N ÷ 7) In the above formula, K is the integrated intensity of the protons of the methyl group of the butyryl group, observed at 0.6 to 0.95 ppm; L is the sum of the integrated intensity of the protons of the methylene groups of the butyryl group that are closest to the carbonyl group and the integrated intensity of the protons of the methyl group of the acetyl group, observed at 1.8 to 2.47 ppm; and N is the integrated intensity of the protons directly bonded to the glucose residues that make up cellulose, observed at 2.7 to 5.4 ppm.

[0072] [Butyryl substitution ratio at 2, 3, and 6 positions] The distribution of butyryl groups in the cellulose butyrates (WSCB) of Example 1, Comparative Example 1, and Comparative Example 2 to the 2-, 3-, and 6-positions of the glucose residues constituting the cellulose was analyzed by the following method.

[0073] According to the literature of Tezuka et al. (Carbohydrate Research, 273, 83-91 (1995)), the sample was acetylated with acetic anhydride in pyridine solvent, then dissolved in deuterated chloroform. 13 C-NMR measurements were performed. 13 The C-NMR measurement conditions are as follows:

[0074] Measurement solvent: CDCl3 (approximately 3 ml) Measurement temperature: 40℃ Sample amount: 160-180 mg (sample tube φ10 mm) Observed nucleus: 13C (1H fully decoupled) Number of data points: 32768 Pulse angle and time: 45°, 9μsec Data acquisition time: 0.9667 seconds Waiting time: 2.0333 seconds Accumulation count: 18,000 times

[0075] obtained 13 In the C-NMR spectrum, the intensities of three signals of acetyl carbonyl carbon appearing around 169.1 to 170.2 ppm and the intensities of three signals of butyryl carbonyl carbon appearing around 171.7 to 172.8 ppm were integrated.

[0076] The three butyryl carbonyl carbon signals appearing around 171.7 to 172.8 ppm are assigned to positions 2, 3, and 6, respectively, from the high magnetic field side. The intensity of each signal was integrated within a range of ±0.2 ppm from the maximum, and this was defined as the integrated intensity of the butyryl carbonyl carbon signal at each position. The butyryl substitution degree at each position was calculated using the following formula: DSi=DS×(integrated intensity of the butyrylcarbonyl carbon signal at i-position) / (sum of integrated intensities of the butyrylcarbonyl carbon signals at 2-, 3-, and 6-positions) In the above formula, DSi is the degree of butyryl substitution at the i-position of the glucose residue, where i is 2, 3, or 6, and DS is the total degree of substitution. Note that, since Example 1, Comparative Example 1, and Comparative Example 2 are cellulose butyrates with an acetyl substitution degree of 0.0, this total degree of substitution corresponds to the total butyryl substitution degree.

[0077] Subsequently, the ratio of the degree of butyryl substitution at the 6-position to the total degree of butyryl substitution (6-position substitution rate; %) was calculated using the following formula. 6th position substitution rate (%)=DS6 / DS×100 In the above formula, DS6 is the degree of butyryl substitution at the 6-position of the glucose residue, and DS is the total degree of substitution (total butyryl substitution degree).

[0078] [Number average molecular weight Mn and weight average molecular weight Mw] According to the literature of Tezuka et al. (Carbohydrate Research, 273, 83-91 (1995)), the sample was acetylated with acetic anhydride in pyridine solvent, and then the polystyrene-equivalent molecular weight (number average molecular weight Mn and weight average molecular weight Mw) was measured by GPC (SEC). The GPC measurement conditions were as follows:

[0079] Solvent: tetrahydrofuran Sample concentration: 0.2% (wt / vol) Column: Shodex KF-803 and KF-804 Temperature: 30℃ Flow rate: 1ml / min Sample injection volume: 50 μl Detection: Differential refractive index detector Standard polystyrene: Shodex SM-105 (molecular weight: 2,700,000, 1,390,000, 661,000, 323,000, 124,000, 47,200, 18,300, 6,940, 2,980, and 1,220)

[0080] [Table 1]

[0081] The analytical results of the cellulose derivatives of the Examples and Comparative Examples are shown in Table 1. Compared with Comparative Examples 1 and 2, it can be seen that WSCB-E1 obtained in Example 1 is a cellulose butyrate with a specifically low degree of substitution at the 6-position (6-position substitution rate).

[0082] [Cultivation of human fecal bacterial flora in a medium containing cellulose derivatives] Feces were collected from a healthy male volunteer (24 years old) who had not taken antibiotics for three months. One part by mass of the collected fecal sample was mixed with four parts by mass of 0.1 M PBS buffer (8 g / L NaCl, 0.2 g / L KCl, 1.15 g / L NaHPO, 0.2 g / L KHPO) to form a slurry. The slurry was filtered through two layers of surgical gauze. This procedure was performed within five minutes of fecal collection.

[0083] One milliliter of the filtered slurry was transferred to a test tube containing 9 milliliters of intestinal environment medium (2 g / L peptone water, 2 g / L yeast extract, 0.1 g / L NaCl, 0.04 g / L KHPO, 0.04 g / L KHPO, 0.01 g / L MgSO 7H O, 0.01 g / L CaCl 6H O, 0.5 g / L bile salts, 2 mL / L Tween 80, 1 mL / L 0.05% hemin solution, 0.01 mL / L vitamin K, 1 mL / L 0.1% resazurin solution, 0.5 g / L L-cysteine HCl, and 2 g / L NaHCO) in an anaerobic chamber (Coy Laboratory Products, Grass Lake, MI). To this test tube, 0.1 g of the cellulose derivative (WSCA-E1, WSCA-C1, or WSCA-C2) obtained in the Example or Comparative Example was added. The headspace of the test tube was replaced with nitrogen gas, and the tube was sealed with a butyl rubber stopper and a plastic cap. The tube was then cultured at 37°C for 24 hours. Four cultures were performed under the same conditions.

[0084] (Short-chain fatty acids (SCFA) analysis) For SCFA analysis, 160 μl of culture supernatant was mixed with 40 μl of a deproteinizing agent (99.5% isopropanol) and allowed to stand overnight at 4°C. After overnight incubation, the mixture was centrifuged (10,000 × g, 5 min, 4°C) to remove proteins. The resulting supernatant was mixed with a three-fold volume of crotonic acid (3 mmol / dL) as an internal standard to prepare the sample solution. A 1.0 μl aliquot of this sample solution was subjected to measurement using a gas chromatograph (GC-14B, SHIMADZU; column temperature: 120°C, injector temperature: 175°C, detector temperature: 250°C) equipped with a capillary column (ULBON HR-20M, 0.53 mm × 30 cm, SHIMADZU, Kyoto, Japan) and a hydrogen salt ionization detector. Helium gas was used as the carrier gas, and nitrogen gas was used as the makeup gas. Using the chromatographic pattern of a SCFA mixture with known concentrations as a reference, the concentrations of acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, and valeric acid in the sample were determined based on the ratio of crotonic acid. SCFA analysis was performed on the culture supernatants obtained from four cultures each under the same conditions, and a significance test was performed using Tukey's multiple comparison method at p=0.05. The results are shown in Table 2 below.

[0085] [Table 2]

[0086] Table 2 shows the concentrations of short-chain fatty acids produced by culturing human fecal bacterial flora. Compared to Comparative Examples 1 and 2, it can be seen that adding WSCB-E1 obtained in Example 1 to the culture medium significantly increased the concentrations of acetic acid, propionic acid, and n-butyric acid.

[0087] It is believed that cellulose butyrate undergoes metabolic degradation pathways, including hydrolysis of the butyryl group (butyric acid group), hydrolysis of cellulose, and decomposition of glucose produced by cellulose hydrolysis, mediated by extracellular and intracellular enzymes of bacteria. It is known that glucose metabolism by such bacteria produces acetic acid and propionic acid via phosphoenolpyruvate, lactic acid, succinic acid, etc. Some of the acetic acid is known to be converted to butyric acid by some bacteria via acetyl-CoA.

[0088] Due in part to its low degree of substitution at the 6-position, WSCB-E1 is susceptible to a series of metabolic degradation processes, beginning with hydrolysis of the butyryl group (debutyrylation), which is thought to result in the production of large amounts of acetic acid, propionic acid, and n-butyric acid. Factors that efficiently increase short-chain fatty acids such as acetic acid, propionic acid, and n-butyric acid using intestinal bacteria in this way are unknown, and in particular, factors that significantly increase n-butyric acid are unknown. These evaluation results clearly demonstrate the advantages of the intestinal short-chain fatty acid-increasing agent and butyric acid delivery system to the intestine, which contain the cellulose derivatives of the present disclosure.

Claims

1. Contains cellulose derivatives as active ingredients, The cellulose derivative has a total degree of substitution with acyl groups of 0.3 or more and 1.8 or less, a substitution rate with acyl groups other than acetyl groups of 95% or more, and a substitution rate at the 6-position of 40% or less, The agent for increasing intestinal short-chain fatty acids, wherein the acyl group other than the acetyl group is a butyryl group.

2. 2. The agent for increasing intestinal short-chain fatty acids according to claim 1, which is cellulose butyrate or cellulose acetate butyrate.

3. 3. The agent for increasing intestinal short-chain fatty acids according to claim 1, wherein the 6-position substitution rate is 30% or less.

4. 4. The agent for increasing intestinal short-chain fatty acids according to claim 1, wherein the degree of substitution with acetyl groups is 0.10 or less.

5. 5. The agent for increasing intestinal short-chain fatty acids according to claim 1, wherein the content of the cellulose derivative is 0.2% by weight or more and 5% by weight or less.

6. A food product comprising the agent for increasing intestinal short-chain fatty acids according to any one of claims 1 to 5.

7. Contains cellulose derivatives as active ingredients, A butyric acid delivery system into the intestine, wherein the cellulose derivative has a total degree of substitution with acyl groups of 0.3 or more and 1.8 or less, a substitution rate with butyryl groups of 95% or more, and a substitution rate at the 6-position of 40% or less.

8. 8. The intestinal butyric acid delivery system according to claim 7, wherein the degree of substitution with acetyl groups is 0.10 or less.

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