阅读说明：本技术 肠道屏障功能改善用组合物 (Composition for improving intestinal barrier function ) 是由 有江秀行 八木田友纪 小野佳子 于 2020-03-10 设计创作，主要内容包括：本发明的目的在于提供可用于改善肠道屏障功能的新型肠道屏障功能改善用组合物等。本发明涉及一种肠道屏障功能改善用组合物,其特征在于,含有选自乌苏烷型三萜、其衍生物及它们的盐中的至少1种的化合物作为有效成分。(The purpose of the present invention is to provide a novel composition for improving intestinal barrier function, which can be used for improving intestinal barrier function. The present invention relates to a composition for improving the barrier function of the intestinal tract, which is characterized by containing at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof as an active ingredient.)

1. A composition for improving the barrier function of the intestinal tract, which comprises at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof as an active ingredient.

2. The composition for improving the barrier function of the intestinal tract according to claim 1, wherein the compound is at least 1 compound selected from the group consisting of acetylursolic acid, ursolic acid glycoside, and salts thereof.

3. The composition for improving the barrier function of the intestinal tract according to claim 1 or 2, wherein the compound is acetylursolic acid and/or a salt thereof.

4. The composition for improving the barrier function of the intestinal tract according to claim 2 or 3, wherein the acetylursolic acid is 3-acetylursolic acid.

5. The composition for improving the barrier function of the intestinal tract according to any one of claims 1 to 4, which is a composition for oral administration.

6. The composition for improving the barrier function in the intestinal tract according to claim 5, wherein the composition for oral administration is a food, drink, drug or quasi drug.

7. The intestinal barrier function improving composition according to any one of claims 1 to 6, which is used for intestinal regulation.

8. The composition for improving the barrier function of the intestinal tract according to any one of claims 1 to 7, wherein the composition is provided with a marker for the purpose of having an intestinal tract regulating effect.

9. Use of at least 1 compound selected from ursane-type triterpenes, derivatives and salts thereof for improving the intestinal barrier function.

Technical Field

The present invention relates to a composition for improving the barrier function of the intestinal tract. The invention also relates to methods of improving intestinal barrier function, and the like.

Background

In recent years, awareness of intestinal health has been increasing, and functional foods related to intestinal tracts are also being sold in large quantities. The intestinal function is mainly a nutrient absorption function and a barrier function (intestinal barrier function) for preventing the invasion (permeation) of harmful substances. Among them, it is known that the intestinal barrier function is closely related to chronic inflammatory diseases which increase with age.

There are many cells of the immune system like macrophages, dendritic cells, T cells, B cells, etc. under the intestinal epithelium. Generally, intestinal epithelial cells are firmly bound to each other by a structure called tight junction, and are strictly controlled in such a manner that high molecular weight substances cannot permeate through intercellular spaces. Furthermore, transport proteins for the excretion of hydrophobic foreign substances from the cells are also present in the intestinal epithelial cells. These tight junction structures or transporters and the like serve as intestinal barriers to prevent the invasion of foreign substances. However, when the intestinal barrier is impaired and the permeability of the intestines is increased due to aging, living disorder, stress, or the like, high molecular substances such as bacteria or bacterial components thereof present in the intestinal tract are transferred into the living body through the intercellular spaces, and the cells of the immune system are stimulated, whereby the release of proinflammatory cytokines is promoted, and inflammation is induced. It is thought that the result induces various pathological conditions resulting from chronic inflammation: the intestinal tract is an inflammatory bowel disease, the liver is a non-alcoholic fatty liver disease (NAFLD), the blood vessels are symptoms caused by arteriosclerosis, and the systemic is diabetes, lipid metabolism disorder, autoimmune disease, and the like. Furthermore, it is envisaged that undigested material may induce allergy by invasion from the intestinal tract.

As described above, a decrease in intestinal barrier function may be a cause of various diseases. From this viewpoint, attempts have been made to search for substances that improve the barrier function of the intestinal tract. Epithelial cell growth factor (EGF) is known to promote maturation of intestinal epithelial cells and to improve barrier function. However, since EGF, which is a cytokine, is present only in a trace amount in the body, it is not preferable in terms of economy or safety when used as a material for improving the intestinal barrier function. Non-patent document 1 describes that flavonoids such as quercetin promote the formation of tight junctions and the like and prevent chronic inflammation.

Non-patent document

Non-kyo literature 1: suzuki T.et al, The Journal of Nutritional biochemistry.2011May, Vol.22(5), p.404-408

Disclosure of Invention

The purpose of the present invention is to provide a novel composition for improving intestinal barrier function, which can be used for improving intestinal barrier function.

The present inventors have made intensive studies to solve the above problems, and have made an attempt to solve the above problems by adding a proinflammatory cytokine to an intestinal tract permeation model using human intestinal cell culture strain Caco-2 to create a state in which the intestinal barrier function can be disrupted in humans, and finding a substance that can improve the state. As a result, it was found that the ursane-type triterpene and its derivative are useful for improving the intestinal barrier function.

Namely, the present invention relates to the following composition for improving intestinal barrier function and the like.

[1] A composition for improving the barrier function of the intestinal tract, which comprises at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof as an active ingredient.

[2] The composition for improving the barrier function of the intestinal tract according to [1], wherein the compound is at least 1 compound selected from the group consisting of acetylursolic acid, ursolic acid glycoside and salts thereof.

[3] The composition for improving the barrier function of the intestinal tract according to the above [1] or [2], wherein the compound is acetylursolic acid and/or a salt thereof.

[4] The composition for improving the barrier function of the intestinal tract according to [2] or [3], wherein the acetylursolic acid is 3-acetylursolic acid.

[5] The composition for improving the intestinal barrier function according to any one of [1] to [4], which is a composition for oral administration.

[6] The composition for improving the barrier function of the intestinal tract according to [5], wherein the composition for oral administration is a food, drink, drug or quasi-drug.

[7] The composition for improving intestinal barrier function according to any one of [1] to [6], which is used for intestinal regulation.

[8] The composition for improving the intestinal barrier function according to any one of [1] to [7], which is characterized by being labeled to have an intestinal regulatory effect.

[9] Use of at least 1 compound selected from ursane-type triterpenes, derivatives and salts thereof for improving the intestinal barrier function.

The present invention provides a novel composition for improving intestinal barrier function, which can improve intestinal barrier function. According to the invention, the intestinal barrier function can be improved. The present invention can contribute to the prevention or amelioration of a condition or disease associated with an abnormality of intestinal barrier function by improving intestinal barrier function.

Detailed Description

The present invention will be described in detail below. The following embodiments are illustrative of the present invention and do not limit the present invention to these embodiments. The present invention can be implemented in any manner as long as it does not depart from the gist of the invention.

The composition for improving the barrier function of the intestinal tract of the present invention contains at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof as an active ingredient.

In the present specification, at least 1 compound selected from ursane-type triterpenes, derivatives thereof, and salts thereof is also referred to as a compound as an active ingredient of the present invention. In the present invention, 1 or 2 or more of the above-mentioned compounds can be used as an active ingredient.

Examples of the ursane-type triterpene include ursolic acid, corosolic acid, and 2A, 19A-dihydroxyursolic acid. Examples of derivatives of an ursane-type triterpene include ursane-type triterpene glycosides and ursane-type triterpenes having an acetyl group.

The ursane-type triterpene glycoside is a glycoside with ursane-type triterpene as aglycone. For example, ursolic acid glycoside is a glycoside having ursolic acid as a ligand.

Examples of the ursane-type triterpene having an acetyl group include acetylursolic acid, acetylcorosolic acid, and acetyl 2A, 19A-dihydroxyursolic acid. The ursane-type triterpene or a derivative thereof in the present invention is preferably acetylursolic acid, ursolic acid glycoside. The sugar constituting the ursane-type triterpene glycoside is preferably monosaccharide, disaccharide or the like. Examples of the monosaccharide include glucose, galactose, rhamnose, fructose, mannose, and arabinose. Examples of the disaccharide include maltose, sucrose, lactose and the like.

The salt of the ursane-type triterpene and its derivative is not particularly limited, and those which can be orally ingested are preferable. Examples of such salts include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium; ammonium salts, and the like.

The compound as an active ingredient of the present invention is preferably at least 1 compound selected from acetyl ursolic acid, ursolic acid glycoside, and salts thereof. Among them, from the viewpoint of having a high effect of improving the intestinal barrier function, it is more preferable to contain acetylursolic acid and/or its salt as an active ingredient.

As the acetyl ursolic acid, 3-acetyl ursolic acid in which an acetyl group is bonded to a hydroxyl group at the 3-position of ursolic acid is preferable. The composition for improving intestinal barrier function of the present invention more preferably contains 3-acetylursolic acid and/or its salt as an active ingredient.

The 3-acetyl ursolic acid is a compound shown as the following formula (1).

[ chemical formula 1]

The ursane-type triterpene, the derivative thereof, and the salt thereof contained in the composition for improving intestinal barrier function of the present invention are not particularly limited depending on the origin and production method thereof. For example, plant sources extracted from plants may be used, and those obtained by synthesis may also be used. Further, commercially available products can be used. For example, the source of the acetyl ursolic acid, ursolic acid glycoside and their salts from the plant is preferably at least 1 kind of plant selected from the group consisting of Aronia genus of rosaceae, Rubus genus of rosaceae family (Rubus), Chaenomeles genus of rosaceae family (Chaenomeles), apple genus of rosaceae family (Malus), pear genus of rosaceae family (Pyrus), bearberry genus of ericaceae family (artosphylos), blueberry genus of rhododendron family (Vaccinium), Syzygium genus of myrtaceae family (Syzygium), swirtium genus of gentianaceae family (Swertia), mussakura genus of theaceae family (ternesia), Ilex genus of wintergreen family (Ilex), Ficus genus of moraceae family (Ficus), oleaceae genus of oleaceae family (olena), and Eucommia genus Eucommia of eucommea family (Eucommia).

In the present invention, the source of 3-acetylursolic acid and its salt is preferably at least 1 plant selected from the group consisting of plants of Aronia genus of rosaceae family, Rubus genus (Rubus) of rosaceae family, Chaenomeles genus (Chaenomeles genus) of rosaceae family, coriander genus (ternstraemia) of theaceae family, Ilex genus (Ilex) of wintergreen family, Ficus genus (Ficus) of moraceae family, and Eucommia genus (Eucommia) of Eucommia family.

Further, when the source of the 3-acetylursolic acid and the salt thereof is a plant of the genus Aronia of the family rosaceae, the plant of the genus Aronia of the family rosaceae is preferably at least 1 selected from the group consisting of bitter red fruit (Aronia arbor), black chokeberry (Aronia melanocarpa) and Aronia x prunifolia.

In addition, Aronia melanocarpa (Aronia melanocarpa) is also called as cherries (Chokeberry) or cherries (Black cherries). In the case of extraction from plants, for example, a raw material containing the compound of the present invention as an active ingredient is extracted with aqueous ethanol, and the extract is concentrated and then column-purified to obtain the compound of the present invention as an active ingredient.

The compound as an active ingredient of the present invention is a component contained in the above-mentioned plant, and has little side effect and high safety even when taken for a long period of time. The present invention provides a composition for improving intestinal barrier function, which contains a substance having little side effect and high safety as an active ingredient even when taken for a long period of time.

In the present invention, the intestinal barrier function means a function of preventing the invasion (permeation) of foreign substances (for example, toxins such as endotoxin, inflammatory substances, undigested substances, and the like) from the outside (inside) of intestinal epithelial cells to the inside of the body. The intestinal tract includes the large and small intestines. A state in which the entry of a foreign substance into the body from outside the intestinal epithelial cells is promoted as compared with a normal state is referred to as a state in which the permeability of a foreign substance in the intestinal epithelial cells is increased (enhanced). The inhibition of the increase in the permeability of foreign substances in intestinal epithelial cells and the reduction in the permeability of foreign substances in intestinal epithelial cells are intended to improve the intestinal barrier function. In the present invention, the intestinal barrier function is improved to include the effect of suppressing the decrease in the intestinal barrier function and improving the decreased intestinal barrier function. For example, intestinal barrier function can be improved by normalizing or strengthening the tight junctions that hold intestinal epithelial cells to each other. In one embodiment, the composition for improving intestinal barrier function of the present invention can be used for improving intestinal barrier function by normalizing or strengthening tight junctions in intestinal epithelial cells.

The effect of improving the barrier function of the intestinal tract can be exhibited by, for example, increasing the resistance value of intestinal epithelial cells (trans-epithelial membrane resistance value (TEER)), or suppressing the decrease in TEER. The substance for increasing or inhibiting the decrease of TEER has the effect of normalizing or strengthening the tight junction in the intestinal epithelial cells. The effect of improving the intestinal barrier function can also be expressed by reducing the amount of a substance that permeates from the intestinal side of the intestinal epithelial cells to the inside of the body.

The person skilled in the art can select a specific evaluation method of the effect of improving the intestinal barrier function according to the purpose. For example, as shown in examples described later, a method of measuring TEER using an intestinal passage model of human intestinal epithelial cells (Caco-2 cells) can be used. Specifically, when a substance to be tested is added to a Caco-2 monolayer culture cell in a state where it is possible to destroy the intestinal barrier function in humans by adding proinflammatory cytokines (TNF α, IL-1 β, IFN γ, etc.), and the decrease in TEER is suppressed as compared with the case where the substance is not added, it can be evaluated that the substance to be tested has an effect of improving the intestinal barrier function.

As shown in the examples, acetyl ursolic acid and ursolic acid have excellent effects of improving intestinal barrier function by inhibiting the decrease of TEER caused by the addition of proinflammatory cytokines in an intestinal permeation model using Caco-2 cells. Furthermore, as shown in the examples, acetyl ursolic acid exhibits a superior intestinal barrier function improving effect compared to ursolic acid having no acetyl group.

The composition for improving the intestinal barrier function of the present invention comprises at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof as an active ingredient, and thereby exerts an effect of improving the intestinal barrier function. Therefore, the composition for improving intestinal barrier function of the present invention is useful for preventing or improving a condition or disease in which improvement of intestinal barrier function is effective, for example, a condition or disease associated with intestinal barrier dysfunction. An intestinal barrier dysfunction includes a decrease in intestinal barrier function. The condition or disease associated with intestinal barrier dysfunction includes conditions or diseases caused by or accompanied by intestinal barrier dysfunction. Examples of such conditions or diseases associated with the dysfunction of the intestinal barrier include inflammatory bowel diseases, irritable bowel syndrome, systemic autoimmune diseases (rheumatoid arthritis, lupus erythematosus, etc.), allergies (food allergy, pollinosis, etc.), lifestyle diseases (obesity, type 1 or type 2 diabetes, hypertension, hyperlipidemia, nonalcoholic fatty Liver disease (NAFLD), arteriosclerosis, etc.) (e.g., camileri et al, Am J Physiol gateway lever physical 303: G775-G785,2012; Mu et al, front. immunological., vol.8, Article 598,2017; Bischoff et al, bmcgastrointermology 201414: 189).

As more specific examples of the state or disease associated with the dysfunction of the intestinal barrier, there are symptoms such as diarrhea, constipation, and a feeling of lack of appetite (sensation of fullness, purring, and abdominal pain) in the stomach (abdomen). The composition for improving intestinal barrier function of the present invention has an effect of improving the state of the intestinal tract by improving the intestinal barrier function. Accordingly, the composition for improving intestinal barrier function of the present invention can regulate the condition of the intestine by improving intestinal barrier function, and is useful for preventing or improving intestinal symptoms as described above. In one mode, the composition for improving intestinal barrier function of the present invention can be used for intestinal regulation (for example, for preventing or improving diarrhea, constipation, abdominal discomfort, etc.). In addition, intestinal barrier dysfunction is also associated with lifestyle diseases and the like (e.g., Bischoff et al, BMC Gastroenterology 201414: 189, supra). Improving intestinal barrier function, and preventing or improving habit diseases. Examples of the symptoms of lifestyle-related diseases include abnormal glucose metabolism, abnormal lipid metabolism, increased body fat, increased visceral fat, increased abdominal fat, and high blood pressure. Accordingly, the composition for improving intestinal barrier function of the present invention can also contribute to improvement of carbohydrate metabolism, improvement of lipid metabolism, reduction or increase in fat such as body fat, visceral fat, and abdominal fat, improvement of high blood pressure, and the like by improving intestinal barrier function.

In the present specification, the term "prevention of a condition or disease" means to improve resistance of a subject to a condition or disease, to delay or prevent onset of a condition or disease, or the like. In addition, in the present specification, the term "improvement of a condition or disease" means to recover a subject from a condition or disease, to alleviate symptoms of a condition or disease, or to delay or prevent the progression of a condition or disease. The recovering comprises at least partially recovering.

The composition of the present invention is suitable for either therapeutic use (medical use) or non-therapeutic use (non-medical use).

The composition for improving the intestinal barrier function of the present invention can be provided in the form of, for example, foods, drinks, pharmaceuticals, quasi drugs, feeds, and the like, but is not limited thereto. The composition for improving the intestinal barrier function of the present invention may be a food, drink, drug, quasi drug, feed, or the like, or may be a preparation or material such as an additive used for these products. The composition for improving intestinal barrier function of the present invention may be provided in the form of a pharmaceutical preparation, for example, but is not limited to this form. The agent may also be provided directly as a composition or as a composition containing the agent. In one mode, the composition for improving intestinal barrier function of the present invention may also be referred to as an intestinal barrier function-improving agent.

In one mode, the intestinal barrier function improving composition of the present invention is preferably an orally administrable composition. According to the present invention, an oral composition having an excellent effect of improving the intestinal barrier function can be provided. The composition for oral administration includes foods and drinks, pharmaceuticals, and quasi drugs, and preferably foods and drinks.

The composition for improving intestinal barrier function of the present invention may contain 1 or 2 or more components (other components) other than the above-mentioned compound as the active ingredient of the present invention, as long as the effect of the present invention is not impaired.

In one embodiment, the other components may include, for example, lactic acid bacteria, bifidobacteria, dietary fibers, polysaccharides, and the like. The lactic acid bacteria and bifidobacteria are preferably orally ingestible bacteria.

The dietary fiber can be water-insoluble dietary fiber or water-soluble dietary fiber. Examples of the water-insoluble dietary fiber include cellulose, lignin, hemicellulose, wheat bran, apple fiber, sweet potato fiber, and chitin. The water-soluble dietary fiber is roughly classified into a high-viscosity material and a low-viscosity material, and examples of the high-viscosity material include pectin, konjac mannan, alginic acid, sodium alginate, guar gum, and agar. Among dietary fibers generally known in japan, a low-viscosity water-soluble dietary fiber refers to a dietary fiber material containing 50 wt% or more of dietary fiber, which is dissolved in water at normal temperature to form a low-viscosity solution, and which exhibits a viscosity of 20mPa · s or less in an approximately 5 wt% aqueous solution. Examples of the low viscosity material of the water-soluble dietary fiber include indigestible dextrin, polydextrose, guar gum degradation product, and Litesse (polydextrose). In addition, dietary fiber materials satisfying the conditions of low viscosity and water solubility can be included. The dietary fiber can be used in 1 kind, or more than 2 kinds.

Examples of the polysaccharides include oligosaccharides such as galactooligosaccharide, xylooligosaccharide, mannooligosaccharide, agarooligosaccharide, fructooligosaccharide, isomaltooligosaccharide, and raffinose. These may be used in 1 kind, or 2 or more kinds.

The composition for improving the barrier function of the intestinal tract of the present invention may contain any additive and any component other than the above. These additives and components can be selected depending on the form of the composition for improving intestinal barrier function, and generally, additives and components that can be used in foods, drinks, pharmaceuticals, quasi drugs, feeds, and the like can be used. Examples of the oral administration agent include various additives acceptable in foods, drinks or pharmaceutical products, for example, excipients, lubricants, stabilizers, dispersants, binders, diluents, flavoring agents, sweeteners, flavoring agents, colorants, and the like. For example, when the composition for improving the intestinal barrier function of the present invention is prepared as a composition for oral administration, the composition may further contain, in addition to the above, components that can be taken orally, such as vitamins, vitamin-like substances, proteins, amino acids, oils and fats, organic acids, carbohydrates, plant-derived materials, animal-derived materials, microorganisms, additives for foods and drinks, and additives for pharmaceuticals, as appropriate, within a range that does not impair the effects of the present invention.

In addition to the above, ingredients such as materials used in foods, drinks, pharmaceuticals, quasi drugs, feeds, and the like may be appropriately blended according to the use.

The form of the composition for improving intestinal barrier function of the present invention is not particularly limited as long as it has the effect of the present invention.

In one embodiment, when the composition for improving the intestinal barrier function of the present invention is prepared into a food or beverage, a component usable in a food or beverage (for example, a food or beverage material, an additive used as needed, or the like) may be blended with the compound as an active ingredient of the present invention to prepare various foods or beverages (food or beverage composition). The food or drink is not particularly limited, and examples thereof include general foods or drinks, health foods, functional foods, foods for specified health use, foods for patients, food additives, and raw materials thereof. The form of the food or drink is not particularly limited, and the food or drink can be made into oral solid preparations such as tablets, coated tablets, fine granules, powders, pills, capsules (including soft capsules and hard capsules), dry syrups, and chewable agents; various forms of liquid preparations for oral administration such as liquid preparations for oral administration and syrups.

In one embodiment, when the composition for improving intestinal barrier function of the present invention is prepared into a pharmaceutical product or a quasi-drug, the pharmaceutical product (pharmaceutical composition) or the quasi-drug (quasi-drug composition) in various dosage forms can be prepared by blending an additive such as a pharmaceutically acceptable excipient with the compound as an active ingredient of the present invention. The administration form of the pharmaceutical or quasi-pharmaceutical is preferably oral administration. The pharmaceutical preparation or quasi-pharmaceutical preparation may be in a form suitable for administration. Examples of the dosage form of the pharmaceutical product for oral administration or the quasi-pharmaceutical product for external use include solid preparations for oral administration such as tablets, coated tablets, fine granules, powders, pills, capsules (including soft capsules and hard capsules), dry syrups, and chewable preparations; oral liquid preparation such as oral liquid and syrup.

In the case of tablets, pills and granules, the tablets may be prepared into dosage forms to which conventional coatings are applied, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets and the like, or may be prepared into multi-layer tablets such as double tablets, as required.

The method for producing the composition for improving intestinal barrier function of the present invention into foods, drinks, pharmaceuticals, quasi drugs, feeds, and the like is not particularly limited, and the composition can be produced by a general method using the compound as the active ingredient of the present invention. The present invention also includes the use of at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof for the manufacture of a composition for improving intestinal barrier function.

The composition for improving intestinal barrier function of the present invention may be used in 1 or 2 or more types, for example, in packages, containers, instructions, etc., the types of active ingredients, the effects described above, and the methods of use (for example, methods of ingestion and administration). The composition for improving intestinal barrier function of the present invention may be accompanied by a substance having an effect of improving intestinal barrier function or an effect based on the effect of improving intestinal barrier function. Such a marker may be accompanied by a marker having a function of regulating the intestinal tract.

The intestinal tract regulating action is not particularly limited as long as it is an intestinal tract regulating action based on improvement of the intestinal barrier function. Examples of the indication of the effect of regulating the intestinal tract include "for a person who suffers from slight constipation or diarrhea", "for a person who is in a state of being minded with a belly", "for a person who is likely to feel a lack of a sensation in the belly", "for improving defecation", "for improving a state of defecation", "for improving the number of times of defecation", "for improving a defecation amount", "for making the belly smooth", "for regulating the state of the belly", "for regulating the state of the intestines", "for improving a lack of sensation in the belly", "for reducing the generation of gas", "for reducing the bloating in the belly", and "for reducing the sensation of purring and purring in the belly". In the composition for improving intestinal barrier function of the present invention, 1 or 2 or more of these markers may be attached.

The content of the compound as the active ingredient in the composition for improving intestinal barrier function of the present invention can be appropriately set according to the form of the composition and the like. In one embodiment, when the composition for improving the intestinal barrier function is formulated into an orally administrable composition such as a food, drink, medicine, quasi drug or the like, the total content of the ursane-type triterpene, its derivative or a salt thereof is preferably 0.0001% by weight or more, more preferably 0.01% by weight or more, further preferably 80% by weight or less, more preferably 20% by weight or less in the composition. In one embodiment, the total content of the ursane-type triterpene, the derivative thereof, and the salt thereof in the composition for improving intestinal barrier function is preferably 0.0001 to 80% by weight, more preferably 0.01 to 20% by weight.

The content of the ursane-type triterpene, its derivative and its salt can be measured by a known method, and for example, HPLC method and the like can be used.

The composition for improving intestinal barrier function of the present invention can be ingested or administered by an appropriate method according to the form thereof. The composition for improving intestinal barrier function of the present invention is preferably administered orally or ingested orally.

The amount of the composition for improving intestinal barrier function of the present invention to be taken (may be referred to as an administration amount) is not particularly limited, and may be appropriately set according to the administration form, administration method, and the like, as long as the effect of improving intestinal barrier function is obtained. In one embodiment, the amount of the composition for improving intestinal barrier function to be taken in a human (adult) is 0.01 to 5000mg, preferably 0.1 to 3000mg, more preferably 1 to 1500mg, and still more preferably 1 to 1000mg per 1 day, based on the total amount of ursane-type triterpene, its derivative, and its salt to be taken in the oral administration or ingestion. The above amount is preferably administered or ingested orally, for example, 1 time or 2 to 3 times per day. In one embodiment, when the composition for improving intestinal barrier function is ingested for the purpose of obtaining an effect of improving intestinal barrier function in a human (adult) as a subject, it is preferable that the composition for improving intestinal barrier function is ingested or administered orally to the subject in such a manner that the total intake amount of the ursane-type triterpene, the derivative thereof, and the salt thereof falls within the above range. The above intake amount may be 1 day per 60kg body weight. In one embodiment, the composition for improving intestinal barrier function of the present invention may be a composition for oral administration, which is administered to an adult human to ingest or administer the compound as the active ingredient of the present invention in an amount of 1 day per 60kg body weight.

In one embodiment, the composition for improving intestinal barrier function of the present invention preferably contains an effective amount of the active ingredient of the present invention in an amount that can achieve the desired effect of the present invention, in other words, in consideration of the administration form, administration method, and the like. In one embodiment, for example, when the composition for improving the intestinal barrier function is an oral composition such as a food or drink or an oral pharmaceutical preparation, the total content of the ursane-type triterpene, the derivative thereof, or the salt thereof may be 0.01 to 5000mg, preferably 0.1 to 3000mg, more preferably 1 to 1500mg, and still more preferably 1 to 1000mg per 1 day in the amount of the composition to be taken by 1 adult per 1 day.

The compound as the active ingredient of the present invention is expected to have an improved effect of improving the intestinal barrier function by continuous ingestion (administration). In a preferred embodiment, the composition for improving intestinal barrier function of the present invention is a composition to be continuously ingested. In one embodiment of the present invention, the composition for improving intestinal barrier function is preferably ingested continuously for 1 week or more.

The subject to which the composition for improving intestinal barrier function of the present invention is administered or ingested (hereinafter also simply referred to as the administration subject) is preferably a human or an animal other than a human, more preferably a human or a non-human mammal, and still more preferably a human. In addition, the administration subject in the present invention is preferably a subject who needs or desires improvement of the intestinal barrier function. Examples of suitable subjects include subjects with decreased intestinal barrier function, subjects desiring to prevent or ameliorate the above-mentioned conditions or diseases associated with intestinal barrier dysfunction, subjects desiring to prevent or ameliorate the conditions or diseases, and the like.

The present invention also includes the following intestinal barrier function improving methods and the like.

A method for improving the barrier function of the intestinal tract, characterized by administering to a subject at least 1 compound selected from the group consisting of ursane-type triterpenes, derivatives thereof and salts thereof.

Use of at least 1 compound selected from ursane-type triterpenes, derivatives and salts thereof for improving the intestinal barrier function.

The methods and uses described above may be therapeutic methods and uses, or may be non-therapeutic methods and uses. The term "non-therapeutic" is a concept that does not include medical practice, i.e., surgery, treatment, or diagnosis. The active ingredient compound of the present invention can be administered to (or taken into) a subject for improving the intestinal barrier function of the subject. In one mode, the above-mentioned compound as an active ingredient of the present invention is preferably used for improving the intestinal barrier function by normalizing or strengthening the tight junction of the intestinal epithelial cells.

The amount of at least 1 compound selected from ursane-type triterpenes, derivatives thereof and salts thereof to be administered is not particularly limited as long as it is an amount that can obtain an effect of improving intestinal barrier function, i.e., an effective amount, and for example, the above amount is preferably administered. The route of administration is preferably oral administration. The above compounds may be administered directly or in combination with a pharmaceutically acceptable carrier. For example, the composition for improving intestinal barrier function of the present invention described above may be administered. The compounds, subjects (administration subjects), administration methods, administration amounts, and preferred embodiments thereof as the active ingredient of the present invention are the same as those in the composition for improving intestinal barrier function described above. In one embodiment, for example, when orally administered to a human (adult), the total amount of the ursane-type triterpene, the derivative thereof, or the salt thereof to be administered may be 0.01 to 5000mg, preferably 0.1 to 3000mg, more preferably 1 to 1500mg, and still more preferably 1 to 1000mg per 1 day. In the above method and application, it is preferable to continuously administer the compound as the active ingredient of the present invention for 1 week or more.

Examples

The following shows embodiments that more particularly illustrate the invention. The present invention is not limited to these examples.

< example 1 >

Comparative evaluation of the improvement of intestinal barrier function was performed.

(evaluation method of improving intestinal Barrier function)

Caco-2 cells were cultured at 37 ℃ for 3 weeks using DMEM (Darbeck modified eagle's medium) with a transfer plate (Transwell) (Millicell Co., Ltd.). The medium was removed from the culture plate in which Caco-2 cells were cultured, and the wells were washed 3 times each with serum-free DMEM and filled with the medium. Then, trans-epithelial electrical resistance (TEER) of Caco-2 monolayer cells was measured by Millicell-ERS (Millipore Co., Ltd.), and cells judged to form sufficient tight junctions (TEER ≧ 1000. omega. cm) were selected²) For subsequent screening. Next, the test solution (culture medium) on both the mucosal side and the basement membrane side was added with TNF α (40ng/mL), IL-1 β (20ng/mL) and IFN γ (10ng/mL) to the sample for 48 hours. The sample was dissolved in dimethyl sulfoxide (DMSO) and then added to the test solution. At this time, the microwells to which proinflammatory cytokines (TNF α, IL-1 β, and IFN γ) were not added and the samples were set to normal. In addition, microwells to which proinflammatory cytokines were added but to which no sample was added were set as controls. TEER was again assayed after culture to assess whether the samples inhibited the decrease in TEER caused by pro-inflammatory cytokines.

The TEER reduction inhibition (%) of the sample was determined from the TEER values of the microwell, normal and control to which the sample was added by the following formula.

(calculation formula of TEER reduction inhibition Rate)

TEER reduction inhibition (%) was 100 × ((TEER of microwell to which sample was added) - (TEER of control))/((normal TEER) - (TEER of control))

In this evaluation system, the higher the TEER reduction inhibition rate (%), the stronger the intestinal barrier function improving effect.

As the sample, commercially available standard products of 3-acetylursolic acid (manufactured by Ark Pharm), 3-acetyloleanolic acid (manufactured by Ark Pharm), ursolic acid (manufactured by United States pharmaceutical Convention), and oleanolic acid (manufactured by ChromaDex) were used. Each sample was added so that the concentration of the sample in the test solution became 5. mu.g/mL. Furthermore, quercetin was evaluated as a positive control. The quercetin was obtained using a commercially available standard (manufactured by Funakoshi Co., Ltd.). Quercetin was added to the test solution so as to reach 9. mu.g/mL.

The results are shown in Table 1. 3-acetyl ursolic acid and ursolic acid have intestinal tract barrier function improving effect. It is clear that 3-acetyl ursolic acid has a higher effect of improving the barrier function of the intestinal tract than ursolic acid without acetyl group. 3-acetylursolic acid has the same degree of intestinal barrier function improvement effect as quercetin at a lower concentration than that of quercetin known as an intestinal barrier protective agent.

[ Table 1]

Sample(s)	Concentration (μ g/mL)	TEER reduction inhibition ratio (%)
			3-acetyl ursolic acid	5	24
Ursolic acid	5	18
			3-acetyl oleanolic acid	5	-13
Oleanolic acid	5	-23
			Quercetin	9	25

Industrial applicability

The composition for improving the barrier function of the intestinal tract of the present invention is useful in the fields of foods and beverages, medicines, and the like.