JP7722649B2 - Intestinal short-chain fatty acid increaser and intestinal butyrate delivery system - Google Patents

Description

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.

Animal species, 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.

Because alteration of the human microbiota plays an important role in the progression of human disease, various therapies exist that utilize alteration of the human microbiota. Examples of such treatments include the administration of antibiotics, the use of prebiotics, the administration of probiotics, and fecal transplants.

Patent Document 1 describes a composition for treating an autoimmune disease, an inflammatory disease, or an 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;

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.

Non-Patent Document 1 describes that regulatory T cells (Tregs) can be proliferated by orally administering 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.

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.

JP 2016-128408 A Special Publication No. 9-505060 Japanese Patent Application Laid-Open No. 2018-158895 Japanese Patent Application Laid-Open No. 2020-066606

Nature, Vol. 500, p. 232-236 (2013) Nature, Vol. 504, p. 446-450 (2013) 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/)

The method using the composition described in Patent Document 1 is a probiotic approach in which butyric acid-inducing bacteria are directly administered to increase butyric acid concentrations and induce the proliferation or accumulation of regulatory T cells. This method of using specific bacteria involves 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 a few weeks, as is the case when 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 composition may not exhibit the effect of increasing regulatory T cells.

Furthermore, according to Figure 4(f) of Non-Patent Document 2, in a mouse model of colitis, feeding butyrated starch increased the percentage of CD4 lymphocytes induced to differentiate 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 feed, at 15% (w/w). If such a high dose were required, the daily intake for a human would be approximately 30 g. Considering that, for example, one serving of dried noodles weighs approximately 80 g, this is a considerable amount, making it painful to ingest orally as a medicine, and would detract from the enjoyment of normal eating if ingested as a food product.

The cellulose butyrate described in Patent Documents 2 and 3 is said to be able to increase intestinal butyrate at a relatively low dose and induce regulatory T cells and 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 technology to increase intestinal short-chain fatty acids, particularly n-butyrate, at even lower doses.

The object of the present invention is to provide an agent for increasing intestinal short-chain fatty acids and a butyrate delivery system to the intestine that can sufficiently increase regulatory T cells or type 1 helper T cells at lower doses.

The intestinal short-chain fatty acid increaser according to the present disclosure contains a cellulose derivative as an active ingredient. This 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. Preferably, the acyl groups other than acetyl groups are butyryl groups.

This intestinal short-chain fatty acid increaser may be cellulose butyrate or cellulose acetate butyrate.

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

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

The content of cellulose derivatives in this intestinal short-chain fatty acid increaser may be 0.2% by weight or more and 5% by weight or less.

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

The pharmaceutical disclosed herein may be used 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 a chronic allergy.

The pharmaceutical disclosed herein 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.

The pharmaceutical disclosed herein 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.

The intestinal butyrate delivery system according to the present disclosure contains a cellulose derivative as an active ingredient. This 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. Preferably, the degree of substitution with acetyl groups in the cellulose derivative is 0.1 or less.

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 for 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 mucous membrane of the large intestine and do not serve as an energy source for the mucosal epithelium of the large intestine. However, butyrate serves as an energy source for the mucosal epithelium of the large intestine, and is therefore expected to have an effect of improving the intestinal flora.

Below, one example of a preferred embodiment will be described in detail. The configurations and combinations thereof in each embodiment are merely examples, and additions, omissions, substitutions, and other modifications of configurations are possible as appropriate without departing from the spirit of this 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.

[Intestinal short-chain fatty acid increaser]
The agent for increasing intestinal short-chain fatty acids of the present disclosure (hereinafter, sometimes simply referred to as "increasing agent") contains a cellulose derivative as an active ingredient, which 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.

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 increaser disclosed herein. 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 disclosed herein 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 more susceptible to degradation by intestinal bacteria. Therefore, an intestinal short-chain fatty acid increaser containing this cellulose derivative can more efficiently produce acyl-derived organic acids at a low dose.

[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.

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

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

When a cellulose derivative is substituted only with butyryl groups, the cellulose derivative is called cellulose butyrate (butyrated cellulose). 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).

[Total substitution degree]
The cellulose derivative contained in the increasing agent 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, this 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 released 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, probably due to excessive hydrophobicity, and the effect of increasing short-chain fatty acids tends to be difficult to achieve.

[Substitution rate and degree of substitution with 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 substitution rate of acyl groups other than acetyl groups to the total substitution rate of acyl groups. From the viewpoint of achieving a large effect of increasing short-chain fatty acids in the intestine, the substitution rate of 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%.

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.

[Degree of substitution with acetyl group]
From the viewpoint of a large effect of increasing short-chain fatty acids in the intestine, it is preferable that the degree of substitution by acyl groups other than acetyl groups is the same as the total degree of substitution by the above-mentioned acyl groups. For example, when commercially available cellulose acetate butyrate is used as a raw material and a portion of its butyryl groups and acetyl groups is 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 obtained 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 obtained cellulose derivative. From the viewpoint of the effect of increasing short-chain fatty acids in the intestine, the degree of substitution by 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.

For example, when the cellulose derivative contained in the increasing agent 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 substitution degree (i.e., the butyryl substitution rate) is 95% or more. In 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, cellulose butyrate may contain acetyl groups as trace components.

[6th 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 2-, 3-, and 6-positions per repeating unit (glucopyranose unit) of cellulose, and the substitution rate at the 6-position refers to the ratio (%) of the degree of substitution at the 6-position to the total degree of substitution at the 2-, 3-, and 6-positions.

The cellulose derivatives contained in the increasing agent of the present disclosure have a substitution rate at the 6-position 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.

The 6-position substitution rate of this cellulose derivative may be 0%, or may be 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 the reaction solvent or adjusting the starting materials.

From the perspective of increasing short-chain fatty acids in the intestine, the substitution rate at the 6-position of a 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.

Furthermore, when the increasing agent of the present disclosure contains the aforementioned cellulose butyrate or cellulose acetate butyrate as a cellulose derivative, the percentage of butyryl substitution at the 6-position relative to the total degree of butyryl substitution at the 2-, 3-, and 6-positions by butyryl groups is preferably 40% or less, more preferably 30% or less, more preferably 20% or less, and even more preferably 3% or more but 20% or less.

[Method for measuring substitution degree]
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. Alternatively, 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 the ^13C -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 of 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 of 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 of 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. Therefore, if the sum of the areas of the carbonyl carbon signals of the acyl groups originally present in 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, butyryl, 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 2-, 3-, and 6-positions of the glucose ring in the cellulose derivative. Needless to say, the only acyl-containing substituents that can be analyzed by this method are those that do not correspond to the carboxylic acid anhydride used in the treatment for analysis. Furthermore, analysis can also be performed by ^1H -NMR in addition to ^13C -NMR.

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

[Effects and uses of the agent for increasing intestinal short-chain fatty acids]
By administering, particularly orally, the intestinal short-chain fatty acid increaser of the present disclosure, the cellulose derivative, which is the active ingredient of this intestinal short-chain fatty acid increaser, is delivered to the large intestine, etc., where many intestinal bacteria are present. 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.

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. Because ingestion of the enhancer disclosed herein increases the number of Bacteroidetes bacteria in the intestine, it is believed 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.

In contrast to the probiotic approach described in Patent Document 1, which involves directly administering specific bacteria, administering the agent disclosed herein utilizes innovative techniques to use cellulose as dietary fiber to provide short-chain fatty acids in the intestines, and is a prebiotic approach that addresses the environment surrounding intestinal bacteria.

Here, probiotics and prebiotics are not in conflict with each other, but are expected to have a synergistic effect, or to have a complementary effect, such as one working effectively when the other is not.

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

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 can also be used as a component of various foods or medicines. The food or medicine containing the intestinal short-chain fatty acid-increasing agent can 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, and sugar-coated tablets; noodles; and baked foods such as biscuits are preferred because they allow for relatively large intakes. 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.

For 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.

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:

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, scleroderma 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 (Pasedu'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, sepsis syndrome, cachexia, acquired immune deficiency 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-related arthropathy disease, spondyloarthropathy, atherosclerosis/arteriosclerosis, allergic colitis, atopic allergies, food allergies (peanut allergy, tree nut allergy, egg allergy, milk allergy, soy allergy, wheat allergy, seafood allergy, shellfish allergy or sesame allergy, etc.), autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs test-positive hemolytic anemia, acquired malignancies anemia, juvenile pernicious anemia, myosyleitis/Royal-Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, idiopathic autoimmune hepatitis, acquired immune deficiency syndrome, acquired immune deficiency-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, total lung disease Systemic sclerosis-related interstitial lung disease, rheumatoid arthritis-related interstitial lung disease, systemic lupus erythematosus-related lung disease, dermatomyositis/polymyositis-related lung disease, Sjogren's disease-related lung disease, ankylosing spondylitis-related lung disease, vasculitic diffuse lung disease, hemosiderosis-related 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 autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (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 of the kidney, discoid lupus erythematosus Idiopathic male infertility or NOS, 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), 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.

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 association with an increase in short-chain fatty acids. Similarly, a suitable example of an autoimmune disease is Crohn's disease. Specific examples of allergic diseases include chronic allergies and food allergies.

Foods or medicines containing the enhancers 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. 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 diseases mentioned above, foods or medicines containing the increasing agent of the present disclosure are suitable for treating diseases such as mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, adrenoleukodystrophy, metabolic disorders, cerebral insulin resistance disorders, autism, and psychiatric disorders (schizophrenia, bipolar disorder, panic disorder, anxiety disorder, sexual dysfunction, and 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.

The dosage of the intestinal short-chain fatty acid-increasing agent 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, weight, sex, health condition, and the condition 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 of body weight, 12 mg/kg to 40 mg/kg of body weight, or 12 mg/kg to 20 mg/kg of 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, as well as the dosage, can be empirically determined taking into account the individual's conditions, administration method, formulation, etc.

[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.

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 more susceptible to degradation 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.

The cellulose derivative included 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%.

The cellulose derivative included 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. Furthermore, 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.

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.

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).

When the cellulose derivative is substituted with butyryl groups and acetyl groups, the degree of substitution with acetyl groups in the cellulose derivative is preferably 0.10 or less, more preferably 0.08 or less, and even more preferably 0.05 or less.

The present invention will be explained in detail below using examples, but the technical scope of the present invention is not limited to these examples.

[Example 1]
Cellulose acetate butyrate (Sigma-Aldrich, product number 419060; hereinafter referred to as "raw cellulose acetate butyrate") used as the raw material 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 with 1 L of methyl tert-butyl ether three times, and then dried under reduced pressure at 60°C until a constant weight was obtained, yielding 18 g of a product. This product is designated WSCB-E1. Analysis by the measurement method described below revealed that WSCB-E1 was a cellulose butyrate having an acetyl substitution degree of 0.0, a butyryl substitution degree of 0.9, and a total substitution degree of 0.9.

[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 raw cellulose acetate butyrate had an acetyl substitution degree of 0.1, a butyryl substitution degree of 2.5, and a total substitution degree of 2.6. Cell-WSCB was a regenerated cellulose lacking acetyl and butyryl groups.

(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), allowed to stand for 30 minutes, and then 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 maintained for 1 hour. This mixture was cooled to near room temperature, further cooled to -20°C using dry ice, maintained for 1 hour, and then heated to near room temperature to obtain a transparent regenerated cellulose solution.

(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. During this process, the temperature of the mixture rose due to the decomposition of butyric anhydride, but the rate of ethanol addition was adjusted so that the temperature remained 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.

[Comparative Example 2]
In the preparation of cellulose butyrate (WSCB) of Comparative Example 1, 822.0 g of a product was obtained 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. This product is designated WSCB-C2. Analysis by the measurement method described below revealed that WSCB-C2 was a 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.

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

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 and ¹ H-NMR was measured. ¹ H-NMR was measured within 30 minutes after the addition of trifluoroacetic acid. The measurement conditions for ¹ H-NMR were as follows:
Equipment: JEOL ECA500
Measurement probe: TH5
Measurement temperature: room temperature Pulse: zg45 (90° pulse width 11.7 μs)
Number of integrations: 32 Data acquisition time: 1.64 sec
Waiting time: 5.36 seconds

Based on the obtained ^1H -NMR spectrum, the degree of acetyl substitution and the degree of butyryl substitution were calculated using the following formula. The degree of acetyl substitution and the degree of 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 degree of acetyl substitution and the degree of butyryl substitution is taken as the total degree of substitution. The obtained results are shown in Table 1 below.
Degree of acetyl substitution=(L−2×K÷3)÷3÷(N÷7)
Degree of butyryl substitution=(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.

[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.

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

Measurement solvent: CDCl ₃ (approximately 3 ml used)
Measurement temperature: 40℃
Sample amount: 160-180 mg (sample tube φ10 mm)
Observed nucleus: 13C (1H fully decoupled)
Number of data points: 32,768
Pulse angle and time: 45°, 9 μsec
Data acquisition time: 0.9667 sec
Waiting time: 2.0333 seconds
Accumulation count: 18,000 times

In the obtained ¹³ C-NMR spectrum, the intensities of the three signals of acetylcarbonyl carbon appearing around 169.1 to 170.2 ppm and the intensities of the three signals of butyrylcarbonyl carbon appearing around 171.7 to 172.8 ppm were integrated.

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 degree of butyryl substitution at each position was calculated using the following formula:
DSi=DS×(integrated intensity of the butyrylcarbonyl carbon signal at position i)/(sum of integrated intensities of the butyrylcarbonyl carbon signals at positions 2, 3, and 6)
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, the total degree of substitution corresponds to the total butyryl substitution degree.

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).

[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)), a sample was acetylated with acetic anhydride in a 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:

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 weights: 2,700,000, 1,390,000, 661,000, 323,000, 124,000, 47,200, 18,300, 6,940, 2,980, and 1,220)

Table 1 shows the analytical results of the cellulose derivatives of the Examples and Comparative Examples. Compared to 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).

Cultivation of human fecal bacterial flora in a medium containing a cellulose derivative
Feces were collected from a healthy male volunteer (24 years old) who had not taken antibiotics for three months. One part by weight of each collected fecal sample was mixed with four parts by weight of 0.1 M PBS buffer (8 g/L NaCl, 0.2 g/L KCl, _1.15 g/L _Na2HPO3 , 0.2 g/ _{L KH2PO3} ) to form a slurry. The slurry was filtered through two layers of surgical gauze. This procedure was performed within five minutes of fecal collection.

One mL of the filtered slurry was transferred to a test tube containing 9 mL of intestinal environment medium (2 g/L peptone water, 2 g/L yeast extract, 0.1 g/L NaCl _, 0.04 g/L K2HPO4, 0.04 g/L _KH2PO4 , 0.01 _g /L MgSO4.7H2O, 0.01 g/L _CaCl4.6H2O , 0.5 g _/ L bile salts, ₂ mL/L Tween ₈₀ , ₁ mL/L 0.05% hemin solution, 0.01 mL/L vitamin K1, 1 mL/L 0.1% resazurin solution, 0.5 g/L L-cysteine HCl, 2 g/L _NaHCO3 ) in an anaerobic chamber (Coy Laboratory Products, Grass Lake, MI). To this test tube was added 0.1 g of the cellulose derivative (WSCA-E1, WSCA-C1, or WSCA-C2) obtained in the Examples or Comparative Examples. 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, followed by incubation at 37°C for 24 hours. Four incubations were performed under the same conditions.

(Short-chain fatty acid (SCFA) analysis)
For SCFA analysis, 160 μl of culture supernatant was mixed with 40 μl of a deproteinizer (99.5% isopropanol) and allowed to stand overnight at 4°C. After overnight standing, 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 a sample solution. This sample solution (1.0 μl) was then 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 whose concentration was known in advance 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 by culturing four times under the same conditions, and a significance test was performed using TUKEY's multiple comparison at p = 0.05. The results are shown in Table 2 below.

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

Cellulose butyrate is thought to undergo metabolic degradation by extracellular and intracellular enzymes of bacteria, including hydrolysis of the butyryl group (butyric acid group), hydrolysis of cellulose, and decomposition of the glucose produced by cellulose hydrolysis. The metabolism of glucose by such bacteria is known to produce acetic acid and propionic acid via phosphoenolpyruvate, lactic acid, or succinic acid. Some of the acetic acid is known to be converted to butyric acid by some bacteria via acetyl-CoA.

WSCB-E1, due in part to its low degree of substitution at the 6-position, 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. There are no known factors that efficiently increase short-chain fatty acids such as acetic acid, propionic acid, and n-butyric acid using intestinal bacteria, and in particular, no known factors that significantly increase n-butyric acid. These evaluation results clearly demonstrate the advantages of the intestinal short-chain fatty acid increaser and butyric acid delivery system to the intestine, which contain the cellulose derivatives of the present disclosure.

Claims (8)

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. The agent for increasing intestinal short-chain fatty acids according to claim 1, which is cellulose butyrate or cellulose acetate butyrate. The agent for increasing intestinal short-chain fatty acids according to claim 1 or 2, wherein the 6-position substitution rate is 30% or less. The agent for increasing intestinal short-chain fatty acids according to any one of claims 1 to 3, wherein the degree of substitution with acetyl groups is 0.10 or less. The agent for increasing intestinal short-chain fatty acids according to any one of claims 1 to 4, wherein the content of the cellulose derivative is 0.2% by weight or more and 5% by weight or less. A food product containing the intestinal short-chain fatty acid increaser according to any one of claims 1 to 5. 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. The intestinal butyric acid delivery system according to claim 7 , wherein the degree of substitution with acetyl groups is 0.10 or less.