Primary bile acid synthesis promoter

Abstract

To provide a new use of soybean isoflavone as a food material.SOLUTION: A composition as a primary bile acid production promotor contains soybean isoflavone as an active component.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a new use of soy isoflavones as a food ingredient. [Background technology]

[0002] Abnormalities in the intestinal microbiota (dysbiosis) are increasingly considered to be an important factor in the development of conditions such as obesity, type 2 diabetes, colon cancer, and inflammatory bowel disease. For example, changes in the composition of the intestinal microbiota have been cited as one of the causes of obesity. Specifically, obese individuals tend to have a high proportion of Firmicutes bacteria and a low proportion of Bacteroidetes bacteria. On the other hand, normal or lean individuals tend to exhibit the opposite tendency to obese individuals, with a high proportion of Bacteroidetes bacteria and a low proportion of Firmicutes bacteria (Non-Patent Document 1). For this reason, it has been proposed to change the composition of the intestinal microbiota from obese individuals to normal or lean individuals by ingesting health foods. For example, it has been reported that the use of an extract from a plant of the genus Salacia as an active ingredient increases the proportion of Bacteroidetes bacteria and decreases the proportion of Firmicutes bacteria (Patent Document 1). Furthermore, since the proportion of butyrate-producing bacteria is reduced in many ulcerative colitis patients compared to healthy individuals, it has been suggested that one of the causes of inflammatory bowel disease (ulcerative colitis, Crohn's disease) is a decrease in the concentration of butyrate in the intestine due to a decrease in butyrate-producing bacteria in the intestine (Non-Patent Document 2).

[0003] Bile acids have also been reported as a regulator of intestinal microbiota, and their increased levels following a high-fat diet have been shown to affect changes in the intestinal microbiota. Bile acids are the main component of bile, involved in lipid absorption. Their primary role is to promote micelle formation in the digestive tract after ingesting fat, facilitating fat absorption. Bile acids consist of primary and secondary bile acids. Primary bile acids are synthesized in the liver by conjugating cholesterol with glycine or taurine and secreted into the intestine. After completing their role in the intestine, conjugated bile acids are reabsorbed in the small intestine and returned to the liver. However, some conjugated bile acids reach the large intestine, where intestinal bacteria release the glycine or taurine (deconjugation). The deconjugated primary bile acids (e.g., cholic acid and chenodeoxycholic acid) are further converted to secondary bile acids such as deoxycholic acid and lithocholic acid. Once converted to a secondary bile acid, the hydrophobicity of the molecule increases, resulting in a stronger bactericidal activity. For example, the secondary bile acid deoxycholic acid (DCA) is known to have 10 times the bactericidal activity of the primary bile acid cholic acid (CA) (see Non-Patent Document 3).

[0004] Based on these findings, the "bile acid hypothesis" has been proposed as a mechanism by which changes in the intestinal flora occur, stating that the intake of a high-fat diet results in excessive secretion of bile acids, which in turn results in increased deoxycholic acid (DCA) concentrations by intestinal bacteria in the intestine, acting as a selective pressure (see Non-Patent Document 4). It is also known that deoxycholic acid (DCA) has a colon cancer-promoting effect (Non-Patent Document 5). Furthermore, according to the description in Patent Document 2, there are also documents pointing out that the recent increase in colon cancer in Japan is due to an increase in lipid intake due to the Westernization of dietary habits, and the resulting increase in the amount of bile acids in the intestine. Furthermore, Non-Patent Document 6 describes that when one becomes obese, there is a significant increase in intestinal bacteria (deoxycholic acid-producing bacteria) that convert primary bile acids (such as cholic acid), which aid in the digestion and absorption of lipids, into secondary bile acids (such as deoxycholic acid), and that the increased secondary bile acids in the body cause hepatic stellate cells in the liver to undergo cellular senescence, which leads to the secretion of inflammatory cytokines, thereby promoting the carcinogenesis of surrounding hepatocytes. It has been suggested that a similar mechanism is involved in the development of liver cancer associated with human obesity, and that inhibiting the growth of deoxycholic acid-producing bacteria may lead to the prevention of liver cancer.

[0005] Thus, various secondary bile acid lowering agents (secondary bile acid production inhibitors) have been proposed as methods for improving or preventing diseases (colon disease, liver disease) and their symptoms caused by secondary bile acids, such as secondary bile acid production inhibitors. Examples of such agents include a secondary bile acid lowering agent containing a plant-derived polyphenol such as curcumin as an active ingredient (Patent Document 3), a secondary bile acid production inhibitor containing an α-linked galactose-containing oligosaccharide as an active ingredient (Patent Document 4), a secondary bile acid lowering agent containing an extract of Ganoderma lucidum as an active ingredient (Patent Document 5), and a deoxycholic acid reducer containing Lactobacillus gasseri cells and / or a culture thereof as an active ingredient (Patent Document 2). These lactic acid bacteria are particularly advantageous in that they inhibit the conversion of primary bile acids to secondary bile acids, thereby suppressing the production of secondary bile acids without reducing the amount of useful primary bile acids, i.e., selectively reducing the amount of secondary bile acids. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2015-127340 [Patent Document 2] Japanese Patent Application Laid-Open No. 2017-66086 [Patent Document 3] Japanese Patent Application Laid-Open No. 2009-227609 [Patent Document 4] Japanese Patent Application Laid-Open No. 2004-244365 [Patent Document 5] Japanese Patent Application Publication No. 2018-43955 [Non-patent literature]

[0007] [Non-Patent Document 1] Ley RE, et al., Nature, 2006, Vol.444, No.7122. pp.1022-1023 [Non-patent document 2] Machiels K., et al., Gut, 2014, Vol.63, No.8, pp.1275-1283 [Non-patent document 3] Kurdi et al., J Bacteriol., 188(5), 1979-1986 (2006) [Non-patent document 4] Yokota et al., Gut Microbes., 3(5):455-459 (2012) [Non-patent document 5] H. Bernstein et al., Mutat. Res., Vol. 589, pp. 47-65, 2005 [Non-patent document 6] Japan Science and Technology Agency website: "Joint announcement: Obesity-related changes in gut bacteria promote the development of liver cancer" (JST, June 27, 2013, joint publication by the Japan Foundation for Cancer Research and the Japan Science and Technology Agency) (http: / / www.jst.go.jp / pr / announce / 20130627-2 / ) Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to provide a new use of soy isoflavones as a food ingredient. Specifically, the objective is to provide a new functional use of soy isoflavones as a food ingredient based on the beneficial bioregulatory function (tertiary function) that ingesting soy isoflavones exerts on the body. [Means for solving the problem]

[0009] The inventors have conducted extensive research to solve the above-mentioned problems and have found that the deterioration of the intestinal flora (changes in the composition of the intestinal flora) that occurs in mice when they are fed a diet simulating a high-fat diet (a diet supplemented with primary bile acids) is significantly improved by simultaneously feeding them soy isoflavones; furthermore, the decrease in equol-producing bacteria, short-chain fatty acid-producing bacteria such as butyric acid bacteria, and / or lactic acid bacteria, which are considered to be beneficial intestinal bacteria, is suppressed and even increased.

[0010] They also found that the intake of soy isoflavones significantly reduced the increase in secondary bile acid production that occurs when a primary bile acid-supplemented diet is consumed, while confirming that the amount of primary bile acids, which are useful for fat absorption, did not decrease but rather increased.

[0011] The present invention was completed based on this finding and includes the following embodiments. (I) Intestinal flora improver (I-1) An agent for improving intestinal flora containing soy isoflavone as an active ingredient. (I-2) The agent for improving intestinal flora according to (I-1), which exhibits at least one effect selected from the group consisting of the following (a) to (e): (a) Increase in the Shannon index, (b) A decrease in the ratio of Firmicutes to Bacteroidetes in the intestinal flora. (c) Increase in the proportion of equol-producing bacteria (Adlercreutzia) in the intestinal flora. (d) Increase in the proportion of short-chain fatty acid-producing bacteria in the intestinal flora, (e) Increase in the proportion of lactic acid bacteria (Lactobacillus) in intestinal bacteria.

[0012] (II) Secondary bile acid production inhibitors, primary bile acid production promoters (II-1) A secondary bile acid production inhibitor containing soy isoflavone as an active ingredient. (II-2) A secondary bile acid production inhibitor according to (II-1), which increases the amount of primary bile acid produced. (II-3) A primary bile acid synthesis promoter containing soy isoflavone as an active ingredient. (II-4) A primary bile acid production promoter according to (II-3), wherein the primary bile acid is at least one selected from the group consisting of cholic acid and taurocholic acid.

[0013] (III) Additives for intestinal flora improvers, additives for secondary bile acid production inhibitors, additives for primary bile acid production promoters (III-1) An additive for an agent for improving intestinal flora or an agent for inhibiting secondary bile acid production, containing soy isoflavone as an active ingredient. (III-2) An additive for a primary bile acid production promoter containing soy isoflavone as an active ingredient.

[0014] (IV) How to use soy isoflavones (IV-1) A method of using soy isoflavones to impart to an oral composition at least one effect selected from the group consisting of an effect of improving the intestinal flora, an effect of inhibiting secondary bile acid production, and an effect of increasing the amount of primary bile acid produced, by incorporating soy isoflavones or the additive described in (III-1) into the oral composition. [Effects of the Invention]

[0015] The present invention provides an intestinal microbiota-improving agent containing soy isoflavones as an active ingredient. The intestinal microbiota-improving agent of the present invention can exhibit at least one effect selected from the group consisting of (a) an increase in the Shanon index, (b) a decrease in the ratio of Firmicutes bacteria to Bacteroidetes bacteria in intestinal bacteria, (c) an increase in the proportion of equol-producing bacteria (Adlercreutzia) in intestinal bacteria, (d) an increase in the proportion of short-chain fatty acid-producing bacteria in intestinal bacteria, and (e) an increase in the proportion of lactic acid bacteria (Lactobacillus) in intestinal bacteria. The effect of (a) indicates that the intestinal microbiota-improving agent of the present invention can improve the diversity of intestinal microbiota reduced by the intake of a high-fat diet. Furthermore, the effect of (b) indicates that by changing the composition of the intestinal microbiota, it is possible to change the body type from obese to normal or lean. The effect of (c) indicates that the production of equol, which has estrogen-like effects, in the body can compensate for the female hormones that tend to become deficient with age. The action and effect of (d) makes it possible to prevent or improve diseases and pathologies caused by a decrease in short-chain fatty acids in the intestines, such as inflammatory bowel disease. Furthermore, the action and effect of (e) makes it possible to prevent or improve autoimmune diseases and colds by using lactic acid bacteria, and to improve intestinal regulation, diarrhea, bowel movements, etc. by increasing good bacteria and suppressing bad bacteria.

[0016] The present invention also provides a secondary bile acid production inhibitor containing soybean isoflavone as an active ingredient. The secondary bile acid production inhibitor of the present invention is excellent in reducing the amount of secondary bile acids in the intestine. Therefore, it can be useful in preventing or ameliorating diseases and pathologies caused by secondary bile acids (e.g., colon diseases, liver diseases, etc.). Furthermore, the secondary bile acid production inhibitor of the present invention inhibits the production of secondary bile acids from primary bile acids in the intestine, thereby increasing rather than reducing the production of primary bile acids, which are important for lipid absorption, and can selectively reduce the production of secondary bile acids.

[0017] Furthermore, the secondary bile acid production inhibitor of the present invention uses soy isoflavones, which have been confirmed to be safe for consumption, as its active ingredient, so there is no need to worry about side effects.It can be taken without difficulty by incorporating it into your daily diet, and you can enjoy the effects described above.

[0018] Furthermore, according to the method of using the additive for an intestinal flora improver, the additive for an inhibitor of secondary bile acid production, or the soy isoflavone of the present invention, by adding it to a food composition or the like, the intestinal flora improver and / or secondary bile acid production inhibitor of the present invention can be easily prepared and provided. [Brief explanation of the drawings]

[0019] [Figure 1] This shows the results of a comparison of the Shanon index (mean ± SEM (n = 6), Tukey-HSD test) from the "analysis of intestinal microbiota in cecal contents" in an experimental example between the control group, CA group (cholic acid administration group), CA + 3% raffinose group, CA + 0.5% curcumin group, and CA + 0.8% isoflavone group. Different letters in each graph indicate significant differences between groups (p < 0.05). [Figure 2] In the "analysis of intestinal microbiota in cecal contents" experiment, (A) the phylum-level intestinal microbiota composition (n=6) was compared between the control group, CA group (cholic acid administration group), CA + 3% raffinose group, CA + 0.5% curcumin group, and CA + 0.8% isoflavone group. (B) The ratio of the Firmicutes phylum to the Bacteroidetes phylum (Firmicutes / Bacteroidetes ratio) was compared between each group. [Figure 3] This figure compares the abundance (%) of equol-producing bacteria (genus Adlercreutzia) in the cecal contents of each group from the results of the "analysis of intestinal bacterial flora in cecal contents" in the experimental example. Mean ± standard error (n = 6) (the same applies to Figures 4 to 7 below). Different letters in each graph indicate significant differences between groups (Tukey-HSD test, p < 0.05). [Figure 4]This is a graph comparing the abundance ratio (%) of lactic acid bacteria (genus Lactobacillus) in the cecal contents of each group from the results obtained in the "analysis of intestinal bacterial flora in cecal contents" in the experimental example. [Figure 5] These figures compare the abundance ratios (%) of various short-chain fatty acid-producing bacteria in the cecal content of each group from the results of the "intestinal microbiota analysis in cecal content" in the experimental example. A compares the abundance ratios (%) of butyrate-producing bacteria (Coprococcus genus) in the cecal content of each group; B compares the abundance ratios (%) of butyrate-, propionate-, and isovalerate-producing bacteria (Prevotella genus) in the cecal content of each group; C compares the abundance ratios (%) of succinate-producing bacteria (Parabacteroides genus) in the cecal content of each group; and D compares the abundance ratios (%) of acetic acid- and lactic acid-producing bacteria (Blautia genus) in the cecal content of each group. [Figure 6] This figure compares the abundance (%) of bacteria belonging to the phylum Firmicutes in the cecal contents of each group, based on the results obtained in the "analysis of intestinal microbiota in cecal contents" in the experimental example. A shows the abundance (%) of bacteria in the genus Turicibacter, and B shows the abundance (%) of bacteria in the genus Dorea. In Figure A, different letters in each graph indicate significant differences between groups (Tukey-HSD test, p<0.05). In Figure B, * indicates a significant difference compared to the CA group, based on the Welch test (p<0.05). [Figure 7] This figure compares the abundance (%) of Proteobacteria (family Desulfovibrionaceae) bacteria in the cecal contents of each group from the results of "analysis of intestinal bacterial flora in cecal contents" in an experimental example. Different letters in each graph indicate significant differences between groups (Tukey-HSD test, p<0.05). DETAILED DESCRIPTION OF THE INVENTION

[0020] (I) Intestinal flora improver The intestinal flora improving agent of the present invention (hereinafter also simply referred to as "the present flora improving agent") is characterized by containing soy isoflavone as an active ingredient.

[0021] Soy isoflavones are a type of flavonoid found in large amounts in soybeans, mainly in the germ, and are a general term for compounds with the basic structure shown in the formula below: [ka]

[0022] Known soy isoflavones include compounds having the above basic structure (soy isoflavone aglycones), glycosides in which sugars are bound to the soy isoflavone aglycones (soy isoflavone glycosides), and acetylated and malonylated versions of these glycosides. The term "soy isoflavones" used herein includes these soy isoflavone aglycones, soy isoflavone glycosides, and their acetylated and malonylated versions without distinction. Specifically, soy isoflavone aglycones include genistein, daidzein, and glycitein. Soy isoflavone glycosides include genistin, daidzin, and glycitin. Acetylated versions of soy isoflavone glycosides include acetylgenistin, acetyldaidzin, and acetylglycitin, and malonylated versions include malonylgenistin, malonyldaidzin, and malonylglycitin. These soy isoflavones may be used singly or in combination of two or more. In the present invention, the soy isoflavones may be those purified from soybeans, or may be crudely purified products, such as those extracted from soybeans (extracts), or crushed or shredded soybeans. Methods for purifying or extracting isoflavones from soybeans are known, and in the present invention, purified products or extracts of soy isoflavones obtained according to known methods can be used. Commercially available soy isoflavones can also be used.

[0023] The present microbiota improver can be in any form as long as it is administered orally. Furthermore, as long as it is administered orally (orally ingested), its use (drugs, quasi-drugs, food and drink [including health functional foods and supplements such as foods for specified health uses, foods with functional claims, and nutritional functional foods]) is not particularly limited. Food and drink are preferred, and foods for specified health uses or foods with functional claims that can claim their actions or effects.

[0024] Specific oral dosage forms include those prepared in the form of liquids (including extracts and syrups) or jellies; powders, fine granules, or granules formulated into powder or granule form using conventional methods; capsules (hard capsules, soft capsules) in which liquids, powders, or granules are filled into capsules; and those in which powders or granules are further compressed into tablets (solid preparations).

[0025] The present bacterial flora improver can also be prepared in various dosage forms (oral administration forms) by combining the soy isoflavones with conventionally known edible carriers, excipients, etc. that are pharmaceutically or food-acceptable.

[0026] When the present bacterial flora improver is in the form of a liquid preparation, it can be frozen and stored, or it may be stored after removing water by freeze-drying, etc. Freeze-dried preparations, dry syrups, etc. can be reconstituted by adding sterilized water, etc., at the time of use.

[0027] When the present bacterial flora improver is in the form of a solid preparation, for example, a tablet, a wide variety of carriers conventionally known in the art can be used. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, crystalline cellulose, hydroxypropylcellulose, hypromellose, and sodium alginate; dry starch, powdered agar, powdered laminaran, sodium bicarbonate, and polio. Disintegrants such as ethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, crospovidone, povidone, and low-substituted hydroxypropyl cellulose can be used. Disintegration inhibitors such as stearin, cocoa butter, and hydrogenated oils can be used. Absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate can be used. Wettable tablets can be coated with conventional coatings, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, and film-coated tablets, or can be double- or multi-layered tablets. Furthermore, capsules containing the active ingredient can be prepared by filling conventional capsules made from materials such as gelatin, pullulan, starch, gum arabic, and hydroxypropylmethylcellulose (HPMC).

[0028] When the formulation is in the form of pills, a wide variety of carriers conventionally known in the art can be used, including excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, and talc, binders such as powdered gum arabic, powdered tragacanth, gelatin, and ethanol, and disintegrants such as laminaran and agar.

[0029] In addition to the above, additives such as surfactants, absorption enhancers, adsorbents, fillers, preservatives, stabilizers, emulsifiers, solubilizers, etc. may be appropriately selected and used depending on the form of the preparation.

[0030] All of these forms can be prepared by conventional methods in the art, for example, tablets can be obtained by adding the above-mentioned active ingredient and other excipients necessary for obtaining tablets as appropriate, mixing and dispersing them well, and then compressing them into tablets, while powders can be obtained by adding the above-mentioned active ingredient and other excipients necessary for obtaining powders as appropriate, mixing them by a suitable method, and pulverizing them.

[0031] The present microbiota-improving agent may be in the form of a formulation as described above, or may be in the form of a regular food or drink. Such food or drink can be produced by adding the soy isoflavones described above or an additive containing soy isoflavones described below to various foods or drinks. The food or drink may be in any form that can be orally ingested, such as a solution, suspension, emulsion, jelly (gel), sol, powder, or solid molding, and is not particularly limited. Specific examples include instant foods such as instant noodles, retort pouch foods, canned foods, microwave foods, instant soups and miso soups, and freeze-dried foods; beverages such as soft drinks, fruit juice drinks, vegetable drinks, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, nutritional drinks, and alcoholic beverages; flour products such as bread, pasta, noodles, cake mix, fried chicken flour, and breadcrumbs; sweets such as candy, caramel, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, and dessert sweets; sauces, processed tomato seasonings, and flavors. Examples include condiments such as seasonings, cooking mixes, sauces, dressings, soups, and curry and stew bases; processed oils and fats such as butter, margarine, and mayonnaise; dairy products such as milk drinks, yogurt, cheese, fermented milk, lactic acid bacteria drinks, ice cream, and cream; processed egg products such as pudding and mayonnaise; processed seafood products such as fish ham and sausage, and fish paste products; processed livestock products such as meat ham and sausage; processed agricultural products such as canned agricultural products, jams and marmalades, pickles, boiled beans, and cereals; frozen foods and nutritional foods.

[0032] (Effect of intestinal flora improver) The target subjects of this microbiota improver are humans or non-human animals, preferably humans. Non-human animals include pets (companion animals), laboratory animals, and animals kept in zoos and aquariums. By administering (ingesting) this microbiota improver to humans or non-human animals, it is possible to adjust the composition of the intestinal microbiota of said humans or non-human animals, and in particular, to improve changes in the composition of the intestinal microbiota caused by ingestion of a high-fat diet, returning it to a state before or close to the state before ingestion of the high-fat diet, or even to an even better state. For example, ingestion of this microbiota improver induces the following changes in the intestinal microbiota:

[0033] (A) Increase in the Shanon index When humans or non-human animals ingest this microbiota improver, it can increase the Shanon index (increase in the Shanon index), which is reduced by consuming a high-fat diet. The Shanon index is an index that takes into account the number of bacterial species and the frequency of each species, and is used to determine the diversity of the intestinal microbiota. In other words, when humans or non-human animals ingest this microbiota improver, it can improve the diversity of the intestinal microbiota that has been reduced by consuming a high-fat diet, returning it to a normal state (intestinal microbiota diversity) or a state close to that before consuming a high-fat diet.

[0034] (B) Changes in the composition of gut microbiota at the phylum level When humans or non-human animals ingest this microbiota-improving agent, the ratio of Firmicutes bacteria to Bacteroidetes bacteria present in the intestine (the "Firmicutes bacteria / Bacteroidetes bacteria" ratio) decreases. This decrease in abundance ratio may be caused by an increase in the ratio of Bacteroidetes bacteria to Firmicutes bacteria, or by an increase in the ratio of Firmicutes bacteria to Bacteroidetes bacteria, or by a decrease in the ratio of Firmicutes bacteria and an increase in the ratio of Bacteroidetes bacteria. As described in Non-Patent Document 1, the "Firmicutes bacteria / Bacteroidetes bacteria" ratio tends to be high in obese or obese-prone subjects and low in normal or lean subjects. As will be shown in the experimental examples described below, ingestion of this microbiota improver can change the composition of the intestinal microbiota from obese to normal or thin (non-obese), and therefore it is believed that this microbiota improver can reduce or prevent obesity, or maintain a non-obese state. In other words, this microbiota improver can be expected to have diet effects such as suppressing weight gain and weight loss.

[0035] (C) Increase in the proportion of beneficial bacteria (1) Increase in the proportion of equol-producing bacteria (Adlercreutzia) in the intestinal flora Ingestion of this microbiota improver by humans or non-human animals can increase the proportion of Adlercreutzia, an equol-producing bacterium, present in the intestine. This bacterium converts ingested isoflavones into equol, which has higher estrogen-like activity. In other words, when this microbiota improver, which contains soy isoflavones as its active ingredient, is taken into the body, it increases the proportion of equol-producing bacteria (Adlercreutzia) present in the intestine, thereby promoting the metabolism and activation of isoflavones and producing equol. Therefore, by improving the human intestinal microbiota (by adjusting the composition of the intestinal microbiota), this microbiota improver increases the production of equol from isoflavones, enabling it to exert its equol-based effects. The effects of equol can be expected to include, but are not limited to, at least one effect selected from the following: alleviation of menopausal symptoms (hot flashes, headache, dizziness, autonomic nervous system disorder-like symptoms, tachycardia, blood pressure fluctuations, etc.); suppression of lipid peroxide production; suppression of excessive sebum secretion (prevention or improvement of acne and pimples); prevention of cancer (breast cancer, uterine cancer, prostate cancer, stomach cancer, etc.); prevention or improvement of type II diabetes (fasting blood glucose level, insulin resistance); prevention or improvement of lifestyle-related diseases (diabetes, hyperlipidemia, arteriosclerosis, high cholesterol, etc.); prevention or improvement of osteoporosis, increase in bone density, increase in bone mineral concentration; prevention or improvement of skin aging (loss of skin firmness and elasticity, age spots, wrinkles, sagging); improvement of blood flow (prevention or improvement of cold sensitivity, stiff shoulders, tension headaches, dullness and dryness of skin, etc.); and prevention or improvement of male pattern baldness.

[0036] (2) Increase in the proportion of short-chain fatty acid-producing bacteria in the intestinal flora Ingestion of this microbiota improver by humans or non-human animals can increase the proportion of short-chain fatty acid-producing bacteria in the intestine. Specifically, short-chain fatty acid-producing bacteria include bacteria of the genus Coprococcccus that produce butyrate, bacteria of the genus Parabacteroides that produce succinate, bacteria of the genus Prevotella that produce butyrate, propionate, and isovalerate, and bacteria of the genus Blautia that produce acetic acid and lactic acid. These short-chain fatty acid-producing bacteria can increase the amount of short-chain fatty acids present in the intestine, which have useful functions in the intestine. The role of short-chain fatty acids in the intestine and their relationship to health is explained below.

[0037] a. Strengthening the barrier function against harmful substances Acetic acid is said to enhance the barrier function of the large intestine, while butyric acid is also said to activate the MUC2 gene in intestinal cells, promoting the secretion of mucin, a mucosal substance, and protecting the large intestine.

[0038] b. Cancer prevention Short-chain fatty acids are said to prevent colon cancer by making the intestines slightly acidic, making it harder for harmful secondary bile acids to form. Butyric acid is also said to suppress the onset of colon cancer by suppressing abnormal colon cell proliferation, promoting apoptosis, and suppressing colon cell lesions. Research has shown that propionic acid acts on short-chain fatty acid receptors on liver cancer cells, inhibiting their proliferation.

[0039] c. Preventing obesity Short-chain fatty acids act on the short-chain fatty acid receptors in fat cells to suppress the uptake of energy into fat cells and prevent fat cells from enlarging. They also act on the short-chain fatty acid receptors in nerve cells to promote energy consumption via the sympathetic nervous system, thus regulating energy balance.

[0040] d. Prevention of diabetes Butyric acid acts on L cells in the intestinal tract to promote the secretion of the intestinal hormone GLP-1. GLP-1 has the effect of preventing and improving diabetes, suppressing the decrease in the number of pancreatic beta cells that secrete insulin, and promoting insulin secretion.

[0041] e. Appetite suppression Butyrate and propionate induce the secretion of gut hormones such as GLP-1 and PYY from the L-cells in the intestinal tract. GLP-1 and PYY act on the brain to suppress appetite, prolonging the feeling of fullness and preventing overeating.

[0042] f. Regulation of immune function Approximately 60% of the body's immune cells are concentrated in the intestines, and it is said that an imbalance in the immune system (especially an excessive immune response) in the intestines affects the entire body. Butyrate has the effect of increasing immune cells called Treg cells, which suppress excessive immune responses, and it is known that this is related to butyrate's ability to promote histone acetylation in colonic epithelial cells. Butyrate is also said to be effective in inflammatory bowel disease, an intestinal immune disorder.

[0043] (3) Increase in the proportion of lactic acid bacteria in the intestinal flora Ingestion of this microflora improver by humans or non-human animals can increase the proportion of lactic acid bacteria present in the intestines. This increase in lactic acid bacteria is expected to prevent or improve autoimmune diseases and colds caused by lactic acid bacteria, and to improve intestinal conditions, diarrhea, bowel movements, etc. by increasing good bacteria and suppressing bad bacteria.

[0044] The subject to which the present microbiota-improving agent is applied may be any person who needs to enjoy the above-mentioned effects, and is not particularly limited insofar as such, but preferably includes a wide range of subjects who consume a high-fat diet, which is a factor that alters the composition of the intestinal microbiota. The subject is preferably a person who prefers to consume a high-fat diet, and more preferably a person who is obese or has a tendency toward obesity. Note that a fatty diet is a diet that contains a lot of fat, and although it is not strictly defined, it can include a diet in which the proportion of fat in the total energy intake (fat energy ratio) is approximately 30 to 40% or more. For example, foods high in fats tend to be high in fats, such as beef belly, beef loin, ground beef, corned beef, pork belly, pork loin, bacon, and pork sausage; seafood such as monkfish liver, fatty tuna, grilled eel, saury, and yellowtail; eggs and dairy products such as egg yolk, cream (milk fat), and Camembert cheese; grains such as croissants, Danish pastries, corn snacks, and potato chips; nuts such as macadamia nuts, peanuts, almonds, and cashews; and foods high in fat-containing ingredients such as fried tofu, soybean flour, mayonnaise, French dressing, olive oil, sesame oil, salted butter, and margarine. Obesity is assessed based on BMI (Body Mass Index: weight [kg] / height [m] squared). A BMI of 30 or higher is considered obese, while a BMI of 25 to 30 is considered slightly obese.

[0045] Whether or not taking (administering, ingesting) the microbiota-improving agent improves the intestinal microbiota can be evaluated and confirmed by analyzing the intestinal bacteria contained in feces.

[0046] Furthermore, as shown in the experimental examples below, soy isoflavones, the active ingredient in this microbiota improver, are thought to suppress the conversion of primary bile acids to secondary bile acids in the intestine by changing the composition of the intestinal microbiota and / or increasing the abundance of beneficial intestinal bacteria. As a result, this microbiota improver does not decrease the production of primary bile acids, which are useful for lipid absorption, but rather increases it, while significantly suppressing the production of secondary bile acids, which can cause colon cancer and liver cancer, and reducing their abundance in the intestine.

[0047] The dosage (intake) of the microbiota improver can be adjusted depending on the condition and severity of symptoms of the subject. However, the daily dosage (intake) for an adult (body weight 50 kg) is typically approximately 10 to 150 mg, calculated as the amount of soy isoflavones (dry weight) contained in the microbiota improver. It is typically administered orally once or two to three times a day. The time of administration is not particularly limited, and examples include one or more of the following: breakfast, lunch, and dinner. Furthermore, although not limited, it is preferable to administer it with a meal or within 30 minutes before or after a meal, as this affects the absorption of lipids contained in food.

[0048] (II) Inhibitors of secondary bile acid production The secondary bile acid production inhibitor of the present invention (hereinafter also referred to simply as "the production inhibitor") is characterized by containing soy isoflavone as an active ingredient.

[0049] As with the aforementioned microbiota improver, the present growth inhibitor can be in any form as long as it is administered orally. Furthermore, as long as it is administered orally (orally ingested), there are no particular limitations on its intended use (drugs, quasi-drugs, food and drink [including health functional foods and supplements such as foods for specified health uses, foods with functional claims, and nutritional functional foods]). Food and drink are preferred, and foods for specified health uses or foods with functional claims that can claim to have certain actions or effects.

[0050] The present production inhibitor may be in the form of various formulations or ordinary foods and drinks, which can be produced by adding the soy isoflavones described above or the additive containing soy isoflavones described below to various foods and drinks.

[0051] The dosage (intake) of the present production inhibitor can be adjusted as appropriate depending on the condition and severity of symptoms of the subject, but the daily dosage (intake) for an adult (body weight 50 kg) is typically approximately 10 to 150 mg, calculated as the amount of soy isoflavones (dry weight) contained in the present production inhibitor. It is typically administered orally once a day or in two to three divided doses. The time of administration is not particularly limited, and examples include one or more of the following time periods: morning, lunch, and dinner. Furthermore, although not limited, it is preferable to take it with a meal, or within 30 minutes either before or after a meal, since it affects the absorption of lipids contained in food.

[0052] The target population for the present production inhibitor is not particularly limited as long as it is a person who needs to reduce the amount of secondary bile acid production, but it can broadly include people who consume a high-fat diet, which is a factor that increases the amount of secondary bile acid production, preferably people who prefer to consume a high-fat diet, more preferably people who are obese or have a tendency to become obese.

[0053] Whether or not taking (administering, ingesting) this production inhibitor inhibits the production of secondary bile acids and reduces their production levels can be evaluated and confirmed by analyzing and measuring the amount of bile acids in feces. This production inhibitor is thought to inhibit the production of secondary bile acids from primary bile acids in the intestine. As a result, as shown in the experimental examples described below, this production inhibitor does not decrease, but rather increases, the production of primary bile acids useful for lipid absorption, while significantly inhibiting the production of secondary bile acids that can cause colon cancer and liver cancer, and reducing their presence in the intestine.

[0054] (III) Intestinal flora improving additive or additive for inhibiting the production of secondary bile acids The additive of the present invention is characterized in that it contains soybean isoflavones, preferably edible soybean isoflavones, as an active ingredient.

[0055] The additive of the present invention is an additive used to impart an intestinal flora-improving effect to a target oral composition based on the intestinal flora-improving effect of its active ingredient, soy isoflavone. The additive of the present invention can also be used to further enhance the effect of an oral composition that has an intestinal flora-improving effect.

[0056] The additive of the present invention can also be an additive used to impart the effect of inhibiting secondary bile acid production to a target oral composition, based on the inhibitory effect of soybean isoflavone, its active ingredient, on secondary bile acid production. The additive of the present invention can also be used to further enhance the effect of an oral composition that has the effect of inhibiting secondary bile acid production. The additive of the present invention can also be an additive used to impart the effect of increasing the production of primary bile acids and decreasing the production of secondary bile acids to a target oral composition, based on the effect of soybean isoflavone, its active ingredient. The additive of the present invention can also be used to further enhance the effect of an oral composition that has these effects.

[0057] Here, the oral compositions targeted by the present invention include compositions that are orally administered to or ingested by humans, specifically oral pharmaceuticals, oral quasi-drugs, and food and beverages, preferably food and beverages.

[0058] The types of soy isoflavones used as raw materials for the additive of the present invention, their preparation methods, etc. are as explained in (I) above, and can be used by reference in this section (III).

[0059] The additive of the present invention may be soy isoflavone itself, or may be prepared by combining soy isoflavone with a conventionally known edible carrier, excipient, etc. that is pharmaceutically and food-acceptable. The additive of the present invention is used to prepare the aforementioned secondary bile acid production inhibitor by adding it to the above-mentioned oral pharmaceuticals, oral quasi-drugs, and / or foods and drinks. Therefore, to that extent, the form thereof is not particularly limited, and it may be in the form of a liquid (including an extract or syrup) or a jelly, or the liquid may be formulated into a powder or granule form by a conventional method to form a powder, fine granule, or granule; a capsule (hard capsule, soft capsule) in which the liquid, powder, or granule is filled into a capsule, or the powder or granule may be further compressed into a tablet form (solid preparation).

[0060] The amount of the additive of the present invention to be added and incorporated into oral pharmaceuticals, oral quasi-drugs, and / or foods and beverages can be increased so that the daily administration (intake) of the intestinal flora improver or secondary bile acid production inhibitor prepared by incorporating the additive of the present invention is usually about 10 to 150 mg, converted into the amount of soy isoflavone (dry amount).

[0061] The additive of the present invention can be used as one of the raw materials together with other raw materials in the process of preparing the oral composition (oral pharmaceuticals, oral quasi-drugs, and / or food and drink), or can be added to the oral composition immediately when the oral composition is taken (administered or ingested).

[0062] (IV) How to use soy isoflavones The present invention also provides a method for using soy isoflavones. This method is for imparting to an oral composition the effects of improving the intestinal flora, inhibiting the production of secondary bile acids, and / or increasing the production of primary bile acids and decreasing the production of secondary bile acids, and can be carried out by incorporating soy isoflavones into the oral composition. Note that instead of soy isoflavones, the aforementioned additives containing soy isoflavones as an active ingredient can also be used.

[0063] Details of the subject oral composition and the method of using soy isoflavones are as described above.

[0064] Hereinafter, in this specification, the terms "comprise" and "contain" include the meanings of "consist of" and "consist essentially of." [Example]

[0065] The present invention will be described below using experimental examples to aid in understanding the configuration and effects of the present invention. However, the present invention is not limited by these experimental examples. Unless otherwise specified, the following experiments were carried out at room temperature (25±5°C) and atmospheric pressure.

[0066] Experimental example: Bile acid intake test Test animals (mice) were fed soy isoflavones in addition to primary bile acids (cholic acid), and body weight, food intake, cecal content weight, and bile acid amounts in the cecal content (primary bile acids, secondary bile acids, and total bile acids) were measured. Genomic DNA was also extracted from the cecal content and used for intestinal microbiota analysis.

[0067] (1) Test animals Animals: Male C57BL / 6J mice, 8 weeks old (purchased from SLC Japan) Breeding period: After the animals were brought in, they were allowed to acclimate for two weeks with normal solid food, and then divided into the following test groups so that the average weight of each group was equal. Rearing environment: Room temperature 25°C, humidity 55%, indoor fluorescent lights were lit on a 12-hour cycle from 7:00 AM to 7:00 PM.

[0068] Test area: After the acclimatization period, the test animals were divided into the following test groups (n=6 or 7 per group), and the bile acid administration groups (b) to (e) were given 0.3% (w / v) cholic acid (CA) aqueous solution as drinking water, and were also given free access to feed in which each material was mixed into control food for two weeks. (a) Control group: Control diet (regular solid diet sample D12450J: Research Diet) + drinking water (distilled water, the same below). (b) Bile acid administration group (CA group): Control diet + drinking water containing 0.3% cholic acid. (c) 3% raffinose + bile acid administration group (CA + 3% raffinose group): Intake of control diet + 3% raffinose + 0.3% cholic acid-added drinking water. (d) 0.5% curcumin + bile acid administration group (CA + 0.5% curcumin group): Control diet + 0.5% curcumin + 0.3% cholic acid-added drinking water was consumed. (e) 0.8% soy isoflavone + bile acid administration group (CA + 0.8% isoflavone group): Intake of control diet + 0.8% soy isoflavone + 0.3% cholic acid-added drinking water. The soy isoflavone used was Isoflavone P40 (manufactured by Fujicco Co., Ltd.). Isoflavone P40 contains 37% or more by mass of isoflavones. Of the total isoflavones, the glycosides of the three isoflavones genistein, daidzein, and glycitein account for approximately 85% or more by mass, and the aglycones account for approximately 15% by mass. The "0.8%" mentioned above is the amount converted into the isoflavone content contained in Isoflavone P40.

[0069] (2) Test method and results 1. Body weight, food intake, and cecal content After the two-week administration period, the body weight, cecal content volume, and daily food intake (g / day / mice) of the test animals in each test group were measured. The results are shown in Table 1 as the mean + standard error (n = 6-7) for each group.

[0070] [Table 1]

[0071] As shown in Table 1 above, although food intake did not change significantly, a significant decrease in body weight was observed in the (e) CA + 0.8% isoflavone group compared to the control and CA groups. In contrast, no significant weight loss was observed in either the (c) CA + 3% raffinose group or the (d) CA + 0.5% curcumin group. Furthermore, compared to the control and CA groups, a tendency for an increase in cecal contents was observed in the (c) CA + 3% raffinose group and the (e) CA + 0.8% isoflavone group, with a particularly significant increase observed in the (e) CA + 0.8% isoflavone group.

[0072] 2. Bile acid content in cecal contents The amount of bile acids in the cecal contents was quantified. The bile acid content was measured according to the method described by Hagio et al. (Hagio, M., M. Matsumoto, and S. Ishizuka. 2011. Bile acid analysis in various biological samples using ultraperformance liquid chromatography / electrospray ionization-mass spectrometry (UPLC / ESI-MS). Methods Mol. Biol. 708: 119-129.) Samples were prepared from the cecal contents and bile acid components were analyzed and quantified using LC-MS.

[0073] The results of comparing the amounts of each primary bile acid, secondary bile acid, and total bile acid for the control group, CA group, CA + 3% raffinose group, CA + 0.5% curcumin group, and CA + 0.8% isoflavone group are shown in Table 2. Table 2 also shows the results of the Tukey HSD test. The letters in the upper right corner of each value indicate that different letters indicate significant differences between groups (p<0.05), and that the same letters indicate no significant differences.

[0074] [Table 2]

[0075] As shown in Table 2, the CA group that received cholic acid had a decreased amount of primary bile acids and a significant increase in the amount of secondary bile acids, including the highly toxic deoxycholic acid (DCA), compared to the control group. In contrast, the CA + 0.8% isoflavone group, which received soy isoflavones in addition to cholic acid, had a marked increase in the amount of primary bile acids compared to both the control and CA groups. Furthermore, compared to the CA group, which had increased amounts of deoxycholic acid (DCA) and secondary bile acids, the amount of deoxycholic acid (DCA) and the amount of secondary bile acids were significantly reduced.

[0076] The above bile acid administration test confirmed that soy isoflavones have the effect of suppressing the increase in secondary bile acids caused by CA intake, in other words, by consuming a high-fat diet, i.e., a secondary bile acid reducing effect (secondary bile acid production inhibitory effect). On the other hand, in the CA + 0.8% isoflavone group, the production of primary bile acids such as cholic acid (CA) and taurocholic acid (TCA) increased, confirming that soy isoflavones have the effect of suppressing the production and increase of secondary bile acids and reducing the production of secondary bile acids without impairing (rather enhancing) the effects of primary bile acids (e.g., promoting fat emulsification, cholesterol excretion, etc.).

[0077] As shown in Table 1, the cecal content volume increased in the CA + 0.8% isoflavone group, and this increase in cecal content was due to the increase in the amount of short-chain fatty acids that have beneficial effects on the host. It is known that soy isoflavone intake is associated with an increase in the production of primary bile acids. This suggests that the CA + 0.8% isoflavone group experienced an increase in metabolites of specific beneficial bacteria that produce short-chain fatty acids, resulting in a decrease in intestinal pH and / or an improvement in the diversity of the intestinal microflora, resulting in an increase in primary bile acid production and a decrease in secondary bile acid production. Furthermore, as shown in Table 1, weight loss was observed in the CA + 2% isoflavone group, suggesting that its anti-obesity effect is related to changes in the intestinal microflora caused by soy isoflavone intake.

[0078] Recently, it has been reported that an antioxidant called Tempole suppresses obesity caused by a high-fat diet, reducing the Firmicutes phylum, which increases with a high-fat diet, and increasing the Bacteroidets phylum, which decreases with a high-fat diet (Li et al., Microbiome remodeling leads to inhibition of intestinal farnesoid X receptor signaling and decreased obesity. Nat Commun., 4:2384. doi: 10.1038 / ncomms3384 (2013)). It has been suggested that administration of Tempole increases the conjugated bile acid called tauro-β-muricholic acid (TβMCA), which acts as an antagonist to the nuclear receptor farnesoid X receptor (FXR) in the gastrointestinal tract, thereby inhibiting FXR activation and suppressing obesity. Although the mechanism of anti-obesity effect of isoflavone intake is unclear, the significant increase in the primary bile acid tauro-β-muricholic acid (TβMCA) in this study suggests that obesity may be suppressed through an increase in the production of primary bile acids due to an improvement in the intestinal flora.

[0079] 3. Composition of intestinal microbiota in cecal contents DNA was extracted from the cecal contents of the test animals in each test group after the two-week administration period according to standard methods, and the V3-V4 region of the 16S rRNA gene was amplified by Seibu Giken Co., Ltd. Meta-16S bacterial flora analysis was performed using Illumina MiSeq. A total of 1,511,039 reads (average 50,368 reads) from the 30 samples obtained were used for bacterial flora analysis using QIIME (Quantitave Insights Into Microbial Ecology).

[0080] From the results of the bacterial flora analysis, we calculated the Shanon index (an index that takes into account the number of bacterial species and the frequency of each species), the bacterial flora composition at the phylum level, and the bacterial flora composition at the family and genus level. The Shanon index is used as an index to judge the diversity of the bacterial flora.

[0081] [Shanon index] The results of the Shanon index (mean ± SEM (n = 6), Tukey-HSD test) are shown in Figure 1. As shown in Figure 1, a significant decrease in the Shanon index (decreased microbiota diversity) was observed in the CA group compared to the control group, but a significant improvement (improved microbiota diversity) was observed in the CA + 0.8% isoflavone group.

[0082] [Phylum-level bacterial flora composition] Figure 2A shows the phylum-level composition of the intestinal microbiota in the cecal contents (n = 6). As shown in Figure 2A, CA administration increased the Proteobacteria phylum and decreased the Bacteroidetes phylum. Figure 2B shows the ratio of the Firmicutes phylum to the Bacteroidetes phylum (Firmicutes / Bacteroidetes ratio). As shown in Figures 2A and 2B, particularly in the CA + 0.8% Iso group, the Firmicutes / Bacteroidetes ratio tended to decrease as the Bacteroidetes phylum increased. As described in Non-Patent Document 1, the intestinal microbiota of obese humans is known to have a low proportion of bacteria belonging to the Bacteroidetes phylum and a high proportion of bacteria belonging to the Firmicutes phylum. On the other hand, with weight loss, i.e., as individuals become normal or lean, the proportion of bacteria belonging to the Bacteroidetes phylum increases and the proportion of bacteria belonging to the Firmicutes phylum decreases. The results in Figure 2B correlated with the weight loss in the CA+0.8%Iso group shown in Table 1, confirming that intake of soy isoflavones changes the composition of the intestinal flora and leads to a leaner constitution.

[0083] [Family and genus level bacterial flora composition] The family and genus composition of the intestinal microbiota in the cecal contents (n = 6) is shown in Figures 3, 4, 5A-D, and 6-8. As shown in Figure 3, the equol-producing Adlercreutzia genus, which was decreased by CA administration, was significantly increased by isoflavone administration. As shown in Figure 4, the lactic acid bacteria Lactobacillus genus, which was decreased by CA administration, was significantly increased by isoflavone administration. Furthermore, as shown in Figures 5A-D, the short-chain fatty acid-producing Coprococcus genus (butyric acid-producing bacteria) (Figure 5A) and Prevotella genus (butyric acid, propionic acid, and isovaleric acid-producing bacteria) (Figure 5B), which were decreased by CA administration, were significantly increased by isoflavone administration. In particular, the Prevotella genus is known to be a bile acid-sensitive bacterium within the Bacteroidetes phylum. Furthermore, as shown in Figures 5C and 5D, it was confirmed that the short-chain fatty acid-producing bacteria Parabacteroides (succinic acid-producing bacteria) and Blautia (acetic acid- and lactic acid-producing bacteria) also increased with isoflavone administration. Furthermore, as shown in Figures 6 and 7, it was confirmed that the Firmicutes phylum (Turicibacter, Dorea) (Figures 6A and 6B) and Proteobacteria phylum (Desulfovibrionaceae) (Figure 7), which increased with CA administration, both decreased with soy isoflavone administration.

[0084] 4. Discussion It is generally known that a high-fat diet increases secondary bile acids, as well as increasing the Firmicutes phylum and decreasing the Bacteroidetes phylum, leading to the development of obesity and metabolic syndrome. It has also been suggested that an increase in secondary bile acids due to a high-fat diet is associated with colon and liver diseases (Non-Patent Document 2). This study confirmed that the increase in secondary bile acids due to CA administration was reduced by the administration of soy isoflavones. Furthermore, it was confirmed that the diversity of the intestinal flora, which was reduced by CA administration, was improved by the administration of soy isoflavones (for example, the Bacteroidetes phylum, which was reduced by CA administration, was increased by soy isoflavone administration; the Firmicutes phylum (Turicibacter genera, Dorea genera) and Proteobacteria phylum (Desulfovibrionaceae family), which were increased by CA administration, were both reduced by soy isoflavone administration, and the ratio of the Firmicutes phylum to the Bacteroidetes phylum (Firmicutes / Bacteroidetes ratio) was reduced).It was also confirmed that the administration of soy isoflavones increased beneficial bacteria in the intestines, such as butyric acid-producing bacteria (Coprococcus genus), various short-chain fatty acid-producing bacteria, equol-producing bacteria (Adlercreutzia genus), and lactic acid bacteria (Lactobacillus genus).

[0085] Although the details of the relationship between these intestinal bacteria and bile acids are unknown, it is thought that the administration of soy isoflavones improved the diversity of the intestinal flora, which was reduced by CA administration, resulting in the suppression of secondary bile acid production and an increase in primary bile acids. Thus, it is thought that the effects of consuming soy isoflavones on improving the intestinal flora and / or reducing secondary bile acids (inhibiting secondary bile acid production) may improve or prevent other diseases and conditions, such as obesity, metabolic syndrome, colon disease, and liver disease.

Claims

1. A primary bile acid production promoter containing soy isoflavone as an active ingredient, The primary bile acid production promoter is an orally administered agent for increasing primary bile acid production in the intestine, The primary bile acid is at least one selected from the group consisting of cholic acid, glycocholic acid, α-muricholic acid, and tauro-β-muricholic acid. The primary bile acid production promoter.

2. An additive for a primary bile acid production promoter containing soy isoflavone as an active ingredient, the primary bile acid production promoter is an orally administered agent for increasing primary bile acid production in the intestine, The primary bile acid is at least one selected from the group consisting of cholic acid, glycocholic acid, α-muricholic acid, and tauro-β-muricholic acid. An additive for the primary bile acid production promoter.

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