JP2023139878A - Gastrointestinal stem cell activator - Google Patents

Abstract

To provide a novel gastrointestinal stem cell activator.SOLUTION: A gastrointestinal stem cell activator includes at least one selected from the group consisting of a compound represented by the general formula (1) and a salt thereof as an active ingredient. [In the general formula (1), R1 represents a hydrogen atom or a hydroxy group, R2 represents a hydrogen atom or a hydroxy group, and n represents a natural number of 1-9].SELECTED DRAWING: None

Description

The present invention relates to a gastrointestinal stem cell activator.

Decline in gastrointestinal function is caused by a decline in the self-renewal ability of gastrointestinal stem cells with aging (for example, Non-Patent Document 1). It has been reported that the stemness of gastrointestinal stem cells is controlled by Paneth cells (for example, Non-Patent Document 2).

The role of stem cell niche inintestinal aging Mech Aging Dev. 2020 Oct;191:111330. Paneth cells constitute theniche for Lgr5 stem cells in intestinal crypts, Nature, 2011 Jan20;469(7330):415-418.

An object of the present invention is to provide a novel gastrointestinal stem cell activator.

［一般式（１）中、Ｒ^１は、水素原子、又はヒドロキシ基を示し、Ｒ^２は、水素原子、又はヒドロキシ基を示し、ｎは１～９の自然数を示す。］ The present invention relates to a gastrointestinal stem cell activating agent containing as an active ingredient at least one selected from the group consisting of compounds represented by the following general formula (1) and salts thereof.

[In general formula (1), R ¹ represents a hydrogen atom or a hydroxy group, R ² represents a hydrogen atom or a hydroxy group, and n represents a natural number from 1 to 9. ]

At least one selected from the group consisting of compounds represented by the above general formula (1) and salts thereof, 10-hydroxydecanoic acid, 8-hydroxyoctanoic acid, 12-hydroxydodecanoic acid, 3,10-dihydroxydecanoic acid, It may be at least one selected from the group consisting of acids, capric acids, and salts thereof.

The present invention also relates to a gastrointestinal stem cell activator containing royal jelly as an active ingredient.

The present invention provides a novel gastrointestinal stem cell activator.

These are photographs and graphs showing the results of organoid culture from intestinal crypts (Crypt), (A) shows the control, (B) shows the results when using enzymatically degraded royal jelly (enzymatically degraded RJ), ( C) shows the results when raw royal jelly (raw RJ) was used, and (D) shows the results when enzymatically decomposed royal jelly (enzymatically decomposed RJ) and raw royal jelly (raw RJ) were used when the number of control organoids was set to 1. The number (ratio) of organoids is shown. It is a graph showing the results of the number of organoids when Paneth cells were co-cultured with stem cells isolated from mice to which raw royal jelly (raw RJ) (500 mg/kg BW) was orally administered for one month or more. (A) and (B) are photographs showing the results of hematoxylin and eosin staining (HE staining) of the intestinal tract in mice administered with royal jelly (500 mg/kg BW), and (C) is a graph showing the results of Crypt size. . (A) and (B) are photographs showing the results of Lysozyme antibody staining of the intestinal tract of mice administered with royal jelly (500 mg/kg BW), and (C) is a graph showing the results of the number of Lysozyme-positive cells. 1 is a graph showing the results of culturing organoids from intestinal crypts (Crypt) supplemented with 10-hydroxydecanoic acid or 10-hydroxydecenoic acid. 2 is a graph showing the results of an investigation on the addition of RJ or 10-hydroxydecanoic acid to a co-culture system of stem cells isolated from wild-type mice and Paneth cells. It is a graph showing the results of the number of organoids when Paneth cells were co-cultured with stem cells isolated from mice to which 10-hydroxydecanoic acid (dose: 10 mg/kg BW) was orally administered for one month or more. (A) and (B) are photographs showing the results of Lysozyme antibody staining of the intestinal tract of mice administered with 10-hydroxydecanoic acid (10 mg/kg BW), and (C) is a graph showing the results of the number of Lysozyme-positive cells. be. (A) to (E) are graphs showing the results of examination of royal jelly components in Crypt. FIG. 2 is a graph showing the results of a test in which capric acid was added to an organoid culture system from Crypt. It is a graph showing the results of organoid culture from stem cells and Paneth cells isolated from mice administered with capric acid (20 mg/kg BW).

EMBODIMENT OF THE INVENTION Hereinafter, the form for implementing this invention is demonstrated in detail. However, the present invention is not limited to the following embodiments.

The gastrointestinal stem cell activator of the present invention effectively activates at least one compound selected from the group consisting of a compound represented by the following general formula (1) (hereinafter also referred to as "compound (1)") and a salt thereof. Contained as an ingredient.

In the general formula (1), R ¹ represents a hydrogen atom or a hydroxy group, R ² represents a hydrogen atom or a hydroxy group, and n represents a natural number from 1 to 9.

The lower limit of n may be 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more. The upper limit of n may be 9 or less, or 8 or less.

When an optical isomer exists, compound (1) may be either an R-form or an S-form.

Compound (1) is more specifically selected from the group consisting of 10-hydroxydecanoic acid, 8-hydroxyoctanoic acid, 12-hydroxydodecanoic acid, 3,10-dihydroxydecanoic acid and capric acid (decanoic acid). It may be at least one type.

The salt of compound (1) may be a salt acceptable for food or pharmaceutical use. Examples of the salt of compound (1) include salts with alkali metals, alkaline earth metals, other metals, ammonium, and the like. More specific examples of the salt of compound (1) include potassium salt, sodium salt, calcium salt, and magnesium salt.

Compound (1) and its salts may be obtained by purification from natural products such as royal jelly, for example. Furthermore, as the compound (1) and its salt, commercially available products may be purchased and used, or chemically synthesized products may be used.

The gastrointestinal stem cell activator of the present invention may contain the above-mentioned compound (1) and its salts singly, or may contain two or more of them in combination.

Compound (1) and its salt have the effect of activating gastrointestinal stem cells. Therefore, the gastrointestinal stem cell activator of the present invention has an effect of increasing the number of gastrointestinal stem cells by containing at least one selected from the group consisting of compound (1) and a salt thereof as an active ingredient. It has the effect of improving the self-renewal ability of cells, or promoting the proliferation of gastrointestinal stem cells. Here, the gastrointestinal cells are, for example, intestinal epithelial stem cells. By ingesting the gastrointestinal stem cell activator of the present invention, gastrointestinal stem cells can be activated, and, for example, it is possible to suppress the decline in gastrointestinal function, and to anti-aging and rejuvenate the gastrointestinal tract.

The gastrointestinal stem cell activating agent of the present invention can exert a gastrointestinal stem cell activation effect through activation of Paneth cells (increase in Paneth cells, etc.). Paneth cells constitute the stem cell niche, which plays an important role in maintaining stem cell numbers and function. The agent for activating gastrointestinal stem cells of the present invention can also be referred to as an agent for activating gastrointestinal stem cells through activation of Paneth cells.

The gastrointestinal stem cell activator of the present invention may contain only the above-mentioned active ingredients, or may further contain other ingredients as long as they do not impede the effects of the present invention. Other ingredients include, for example, pharmaceutically acceptable ingredients (e.g., excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizing agents, suspending agents). , ingredients acceptable as foods (e.g. minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, colorants) , fragrances, stabilizers, preservatives, sustained release modifiers, surfactants, solubilizers, wetting agents).

The gastrointestinal stem cell activator of the present invention may contain a composition containing the above compound (1) as an active ingredient. The composition may be, for example, royal jelly. One embodiment of the present invention provides a gastrointestinal stem cell activator containing royal jelly as an active ingredient.

Royal jelly is a milky substance produced by the addition of fatty acids secreted from the mandibular glands to a protein-rich transparent liquid secreted by worker bees from the hypopharyngeal glands, or is derived from this. Royal jelly is known to contain water, protein, carbohydrates, lipids, ash, free amino acids, vitamins, minerals, and the like. Royal jelly may be collected as it is (raw royal jelly), or may be a processed royal jelly obtained by processing raw royal jelly. Raw royal jelly can be obtained, for example, as a beekeeping product according to conventional methods. The type of bees used to collect raw royal jelly is not particularly limited.

Processed royal jelly products include royal jelly concentrates or diluted products obtained by concentrating or diluting raw royal jelly, royal jelly powder obtained by drying and powdering raw royal jelly, enzymatically decomposed royal jelly obtained by treating raw royal jelly with proteolytic enzymes, raw royal jelly treated with ethanol, etc. Examples include royal jelly organic solvent extracts such as royal jelly ethanol extracts extracted with organic solvents, fermented royal jelly which is a fermented product of royal jelly, and the like. Fermented royal jelly is obtained by reacting Lactobacillus bacteria with 10-hydroxy-2-decenoic acid and converting 10-hydroxy-2-decenoic acid into 10-hydroxydecanoic acid (10-hydroxydecanoic acid). (royal jelly) containing a high content of The processed royal jelly may be one that has been subjected to a plurality of treatments. The royal jelly may be enzymatically decomposed royal jelly, or may be an enzymatically decomposed royal jelly powder obtained by drying and powdering enzymatically decomposed royal jelly.

Royal jelly concentrate can be obtained, for example, by removing water from raw royal jelly. A diluted royal jelly can be obtained, for example, by adding water to raw royal jelly.

Royal jelly powder can be obtained, for example, by pulverizing raw royal jelly by methods known in the art, such as freeze drying and spray drying. Alternatively, after freeze-drying or spray-drying, the royal jelly powder may be obtained by pulverizing with a pulverizer (eg, pin mill, hammer mill, ball mill, jet mill).

Enzyme-degraded royal jelly can be obtained, for example, by treating raw royal jelly with a proteolytic enzyme. Examples of proteolytic enzymes include enzymes having endopeptidase action, enzymes having exopeptidase action, and enzymes having both endopeptidase action and exopeptidase action. The proteolytic enzyme may be any enzyme that has at least one of an endopeptidase action and an exopeptidase action, preferably an enzyme that has at least an endopeptidase action, and an enzyme that has both an endopeptidase action and an exopeptidase action. Enzymes are more preferred. Here, the endopeptidase action is an action that breaks down peptide bonds of non-terminal amino acids, and the exopeptidase action is an action that breaks down peptide bonds of terminal amino acids.

Proteolytic enzymes include enzymes having only exopeptidase action, enzymes having only endopeptidase action, and enzymes having both endopeptidase action and exopeptidase action. An enzyme that has both endopeptidase and exopeptidase actions is classified as an "enzyme with endopeptidase action" if the endopeptidase action is stronger, and an "exopeptidase action" if the exopeptidase action is stronger. If the exopeptidase action and the endopeptidase action are the same or almost the same, the enzyme is said to be an "enzyme that has both the endopeptidase action and the exopeptidase action." Note that "equivalent or almost equivalent" means that the ratio of endopeptidase action to exopeptidase action (activity ratio) is 0.8 to 1.2 times.

Specific examples of enzymes having both endopeptidase and exopeptidase actions include pancreatin, pepsin, and the like. More specific examples of enzymes that have both endopeptidase and exopeptidase actions include peptidase produced by Streptomyces griseus (trade name: actinase AS), peptidase produced by Aspergillus oryzae, Examples include peptidase (trade name: Protease A, Flavorzam) and peptidase produced by Aspergillus melleus (trade name: Protease P).

Specific examples of enzymes having exopeptidase activity include carboxypeptidase, aminopeptidase, and exopeptidase derived from microorganisms such as lactic acid bacteria, Aspergillus spp., and Rhizopus spp. More specific examples of enzymes having exopeptidase activity include peptidase produced by Aspergillus oryzae (trade name: Umamizyme G, Promod 192P, Promod 194P, Sumitem FLAP), Aspergillus soe. jae) produced peptidase (trade name: Sternzyme B15024), peptidase produced by the genus Aspergillus (trade name: Coclase P), and peptidase produced by Rhizopus oryzae (trade name: Peptidase R).

Specific examples of enzymes having endopeptidase activity include animal-derived endopeptidases (e.g., trypsin, chymotrypsin, etc.), plant-derived endopeptidases (e.g., papain, etc.), or lactic acid bacteria, yeast, molds, Bacillus subtilis, etc. Examples include endopeptidases derived from microorganisms such as actinomycetes. More specific examples of enzymes having endopeptidase activity include peptidase produced by Bacillus subtilis (trade name: Orientase 22BF, Nucleisin), peptidase produced by Bacillus licheniformis (trade name) :Alcalase), Peptidase produced by Bacillus stearothermophilus (Product name: Protease S), Peptidase produced by Bacillus amyloliquefaciens (Product name: Neutrase), Bacillus peptidases produced by the genus ( (Product name: Protamex).

The reaction conditions (amount of proteolytic enzyme used, temperature during reaction, pH, reaction time, etc.) when treating raw royal jelly with proteolytic enzymes can be set appropriately depending on the type of proteolytic enzyme used, etc. good. As specific reaction conditions, for example, when using actinase AS (Kaken Pharmaceutical Co., Ltd.), which has both endopeptidase action and exopeptidase action as a protease, the amount of protease used is 1 g per 100 g of royal jelly, and the temperature during the reaction is Examples include 45 to 55°C, pH 8.5 to 9.5, and reaction time 2 to 4 hours.

Royal jelly organic solvent extract can be obtained, for example, by extracting raw royal jelly using an organic solvent such as ethanol, methanol, propanol, acetone, or the like. The extraction time can be appropriately set depending on the form of raw royal jelly used as a raw material, the type and amount of solvent, the temperature during extraction, stirring conditions, etc. After extraction, solid content may be removed by filtration, centrifugation, etc. Further, the extracted solution may be used as it is, or the solvent may be removed from the solution and used as a concentrated liquid or powder. The royal jelly organic solvent extract is preferably a royal jelly ethanol extract.

Commercially available royal jelly may be used. Specific examples of commercially available royal jelly include enzymatically decomposed royal jelly king (manufactured by Yamada Bee Farm Co., Ltd.).

The gastrointestinal stem cell activator of the present invention can be used at a dose of 1 mg or more and 10 g or less per day for adults weighing 60 kg, preferably at a dose of 5 mg or more and 8 g or less, and 10 mg or more, in terms of active ingredient amount. It is more preferable to use it at a dose of 3 g or less, it is even more preferable to use it at a dose of 15 mg or more and 1.5 g or less, it is even more preferable to use it at a dose of 20 mg or more and 1 g or less, and it is preferably used at a dose of 22 mg or more and 500 mg or less. It is even more preferred, and it is especially preferred to use it at a dose of 24 mg or more and 250 mg or less. When the gastrointestinal stem cell activator of the present invention is used in children, the dosage is, for example, 3/5 the adult dose for children aged 6 to 13 years, 2/5 the adult dose for the children 1 to 6 years old, and If the dose is less than 1/5, the dose may be 1/5. The dose can be appropriately set within the above range depending on factors such as the health condition of the person taking it, the method of administration, and the combination with other agents.

The gastrointestinal stem cell activating agent of the present invention may be administered orally (ingested) or parenterally (for example, intranasally). The gastrointestinal stem cell activator of the present invention may be administered once a day, or multiple times, such as twice a day or three times a day, as long as the daily amount of the active ingredient is within the above-mentioned range. It may be administered in divided doses. Furthermore, the agent for activating gastrointestinal stem cells of the present invention is preferably administered continuously. By continuously administering it, the gastrointestinal stem cell activation effect is even more pronounced.

The gastrointestinal stem cell activating agent of the present invention may be in any form such as solid, liquid, or paste. The form of the gastrointestinal stem cell activator of the present invention may be, for example, plain tablets, sugar-coated tablets, granules, powders, tablets, or capsules (hard capsules, soft capsules, seamless capsules). The agent for activating gastrointestinal stem cells of the present invention can be prepared, for example, by mixing the active ingredient, the compound of the present invention or a salt thereof, with other ingredients as necessary, and forming the mixture into the above-mentioned dosage form. I can do it.

The gastrointestinal stem cell activator of the present invention can be used as a drug, quasi-drug, or food composition itself, or by being added to a drug, quasi-drug, or food composition. The food composition is preferably a food that emphasizes the tertiary function (physical condition regulating function) of the food. Examples of foods with emphasized tertiary functions include health foods, foods with functional claims, nutritional supplements, supplements, and foods for specified health uses.

A pharmaceutical, quasi-drug, or food composition comprising the gastrointestinal stem cell activator of the present invention, or a pharmaceutical, quasi-drug, or food composition containing the gastrointestinal stem cell activator of the present invention has the ability to activate gastrointestinal stem cells. It may be for commercial purposes.

The content of the gastrointestinal stem cell activator of the present invention in pharmaceuticals, quasi-drugs, and food compositions is such that the amount of active ingredient ingested per day is within the above-mentioned range. It may be set appropriately depending on the type of composition, etc.

When the gastrointestinal stem cell activator of the present invention is used as a food composition itself or added to a food composition, the form of the food composition is not particularly limited. soft drinks, milk drinks, lactic acid bacteria drinks, yogurt drinks, carbonated drinks, etc.); spreads (custard cream, etc.); pastes (fruit paste, etc.); Western sweets (chocolate, donuts, pies, cream puffs, gum, jelly, Candies, cookies, cakes, puddings, etc.); Japanese sweets (daifuku, mochi, manju, castella, anmitsu, yokan, etc.); Frozen confections (ice cream, popsicles, sorbet, etc.); Foods (curry, gyudon, rice porridge, etc.) miso soup, soup, meat sauce, pasta, pickles, jam, etc.); seasonings (dressing, furikake, flavor seasoning, soup stock, etc.).

The gastrointestinal stem cell activator of the present invention can be used as a food itself (for example, a health food, a food with functional claims, a nutritional supplement, a supplement, or a food for specified health use) in which the tertiary function of the food is emphasized, or as a tertiary function of the food. When added to food with an emphasized function, the form of the food with an emphasized tertiary function includes, in addition to the above-mentioned food forms, for example, uncoated tablets, sugar-coated tablets, granules, powders, tablets, It may be a capsule (hard capsule, soft capsule, seamless capsule).

When the gastrointestinal stem cell activator of the present invention is used as a drug or quasi-drug itself, or added to a drug or quasi-drug, the form of the drug or quasi-drug is not particularly limited, and for example, It may be a plain tablet, sugar-coated tablet, granule, powder, tablet, or capsule (hard capsule, soft capsule, seamless capsule).

The method for producing a pharmaceutical, quasi-drug, or food composition containing the gastrointestinal stem cell activator of the present invention is not particularly limited, and any known method can be followed as appropriate. For example, pharmaceuticals, quasi-drugs, or quasi-drugs used for the above purposes can be obtained by mixing the gastrointestinal stem cell activator of the present invention with intermediate products or final products in the manufacturing process of pharmaceuticals, quasi-drugs, or food compositions. Or a food composition can be obtained.

The present invention described above can also be considered as a compound represented by the above general formula (1) or a salt thereof for use in activating gastrointestinal stem cells. The present invention can also be considered as an application of at least one compound selected from the group consisting of the compound represented by the above general formula (1) and salts thereof in the production of a gastrointestinal stem cell activating agent.

The present invention described above also provides an effective amount of a gastrointestinal stem cell activating agent containing as an active ingredient at least one selected from the group consisting of the compound represented by the general formula (1) and salts thereof. It can also be viewed as a method for activating gastrointestinal stem cells, including the step of administering them to a subject in need. The subject may be rodents, ungulates, carnivores, marsupials, and primates. The subject is preferably a mammal such as a cynomolgus monkey or a human, and more preferably a human.

As one embodiment of the present invention, there is provided a Paneth cell activating agent containing as an active ingredient at least one selected from the group consisting of the compound represented by the above general formula (1) and its salt. The Paneth cell activator of the present invention contains as an active ingredient at least one selected from the group consisting of the compound represented by the above general formula (1) and its salt, thereby increasing the number of Paneth cells; Or it has the effect of promoting the increase of Paneth cells. Regarding the Paneth cell activating agent or the Paneth cell increasing agent, the above-described embodiments can be applied without limit.

Hereinafter, the present invention will be explained more specifically based on Examples. However, the present invention is not limited to the following examples.

<Test Example 1>
We analyzed the effects of royal jelly on intestinal epithelial stem cells or niche Paneth cells. Specifically, we revealed changes in the number of organoids caused by royal jelly in a co-culture system (organoid culture system) of Paneth cells and stem cells, and histological changes in villus height, intestinal crypts, etc. caused by royal jelly in vivo. did.

It was found that addition of raw royal jelly (raw RJ) or enzymatically decomposed royal jelly (enzymatically decomposed RJ) to the intestinal crypt culture system promoted organoid formation (FIGS. 1(A) to (D)).

Next, royal jelly (500 mg/kg BW) was administered to mice for over 1 month, and stem cells and Paneth cells were isolated from the royal jelly-administered mice and co-cultured. Paneth cells isolated from mice treated with royal jelly (500 mg/kg BW) increased organoid formation of stem cells from mice not treated with royal jelly (Figure 2). This indicates that royal jelly increases stem cell self-renewal through Paneth cell activation.

Royal jelly's ability to increase stem cell self-renewal ability was confirmed by tissue staining of mice treated with royal jelly, which showed an increase in intestinal crypts (Fig. 3 (A) to (C)). Immunostaining with a lysozyme antibody revealed that Paneth cells increased in mice administered royal jelly (Fig. 4 (A) to (C)).

<Test Example 2>
Analysis similar to Test Example 1 was conducted focusing on 10-hydroxydecanoic acid or other fatty acid components contained in royal jelly.

When organoids were cultured from intestinal crypts by adding 10-hydroxydecanoic acid, organoid formation was promoted. On the other hand, when 10-hydroxy-2-decenoic acid was added, no clear organoid formation promoting effect was observed (FIG. 5).

Addition of 10-hydroxydecanoic acid to stem cells isolated from LgR5-EGFP-IRES-creERT2 mice suppressed organoid formation. On the other hand, when isolated stem cells and equal amounts of Paneth cells were mixed and 10-hydroxydecanoic acid was added, organoid formation was promoted (Figure 6).

10-hydroxydecanoic acid (10 mg/kg BW) was administered to mice for over 1 month, and stem cells and Paneth cells were isolated from the mice after administration and co-cultured. Paneth cells isolated from mice treated with 10-hydroxydecanoic acid (10 mg/kg BW) increased organoid formation of stem cells from mice not treated with 10-hydroxydecanoic acid (Figure 7).

From the above, it was found that 10-hydroxydecanoic acid acts on Paneth cells and increases organoid formation from stem cells. Tissue staining of mice administered with 10-hydroxydecanoic acid confirmed that 10-hydroxydecanoic acid increased the number of Paneth cells (FIGS. 8(A) to (C)).

3,10-Dihydroxydecanoic acid, 8-Hydroxyoctanoic acid, 2-Decene-1,10-dioic acid , Sebacic acid, and 12-hydroxydodecanoic acid were added to intestinal crypts isolated from wild-type mice to perform organoid culture.

No obvious effect of increasing organoids was observed with sebacic acid and 2-decene-1,10-dioic acid. On the other hand, the effect of increasing organoids was observed with 3,10-dihydroxydecanoic acid, 8-hydroxyoctanoic acid, and 12-hydroxydodecanoic acid (FIGS. 9(A) to (E)).

<Test Example 3>
The gastrointestinal cell activation effect of capric acid was confirmed by the following method. The results are shown in FIGS. 10 and 11.
When organoid culture was performed by adding capric acid to intestinal crypts isolated from wild-type mice, organoid formation was promoted (Figure 10). Capric acid (10 mg/kg BW) was administered to mice for over 1 month, and stem cells and Paneth cells were isolated from the mice after administration and co-cultured. Paneth cells isolated from mice treated with capric acid (10 mg/kg BW) increased organoid formation of stem cells from mice not treated with capric acid (Figure 11).

As shown in FIGS. 10 and 11, even when capric acid was used, the effect of increasing the number of organoids was observed, confirming that capric acid has a gastrointestinal cell activating effect.

Claims (3)

A gastrointestinal stem cell activator containing as an active ingredient at least one selected from the group consisting of compounds represented by the following general formula (1) and salts thereof.

[In general formula (1),
R ¹ represents a hydrogen atom or a hydroxy group,
R ² represents a hydrogen atom or a hydroxy group,
n represents a natural number from 1 to 9. ] At least one selected from the group consisting of compounds represented by the general formula (1) and salts thereof is 10-hydroxydecanoic acid, 8-hydroxyoctanoic acid, 12-hydroxydodecanoic acid, and 3,10-dihydroxydecanoic acid. The gastrointestinal stem cell activator according to claim 1, which is at least one selected from the group consisting of acid, capric acid, and salts thereof. A gastrointestinal stem cell activator containing royal jelly as an active ingredient.

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