TW202102210A - Composition for intestinal barrier function improvement - Google Patents

Abstract

The purpose of the present invention is to provide a novel composition for intestinal barrier function improvement that is capable of improving intestinal barrier function. This invention relates to a composition for intestinal barrier function improvement containing, as an active ingredient, at least one compound selected from the group consisting of a ursane-type triterpene, a derivative thereof, and salts thereof.

Description

Composition for improving intestinal barrier function

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

In recent years, awareness about intestinal health has gradually increased, and many intestinal-related functional foods have been sold. As the function of the intestine, it is mainly the absorption function of nutrients and the barrier function (intestinal barrier function) to prevent the intrusion (penetration) of harmful substances. Among these, it has been clearly known that the intestinal barrier function is deeply related to chronic inflammatory diseases that increase with age.

Under the intestinal epithelial cells, there are many immune system cells such as macrophages, dendritic cells, T cells, and B cells. In general, intestinal epithelial cell lines are firmly connected to each other through structures called tight junctions, and are tightly controlled in such a way that high molecular weight substances do not penetrate the intercellular spaces. In addition, in the intestinal epithelial cells, there are also transporters for expelling hydrophobic foreign bodies from the cells. These tight junction structures or transporters are responsible for the intestinal barrier function to prevent the invasion of foreign bodies. However, if the intestinal barrier is damaged due to aging, incontinence of life, stress and other reasons, and the penetration of the intestine is increased, the bacteria in the intestine or high molecular substances such as bacterial components are present in the intestine. It migrates into the organism through the intercellular space, stimulates immune system cells, etc., promotes the release of inflammatory cytokines, and induces inflammation. As a result, it is generally believed to induce inflammatory bowel disease in the intestines, non-alcoholic fatty liver disease (NAFLD) in the liver, symptoms caused by arteriosclerosis in the blood vessels, and diabetes and lipids in the systemic Metabolic abnormalities, autoimmune diseases, etc. are caused by various pathologies of chronic inflammation. In addition, it has been assumed that undigested substances induce allergies by invading from the intestine.

As mentioned above, the reduction of intestinal barrier function may be the cause of various diseases. From this point of view, we are trying to explore substances that can improve the barrier function of the intestinal tract. It is known that epithelial growth factor (EGF) promotes the maturation of intestinal epithelial cells and improves the barrier function. However, since EGF, which is a cytokine, is only present in a small amount in the body, it is not good in terms of economic efficiency or safety when it is used as a material for improving the barrier function of the intestine. In Non-Patent Document 1, it has been described that flavonoids such as quercetin promote the formation of tight junctions and the like to prevent chronic inflammation. [Prior Technical Literature] [Non-Patent Literature]

[Non-Patent Document 1] Suzuki T. et al, The Journal of Nutritional Biochemistry. 2011 May, Vol.22(5), p.401-408

[The problem to be solved by the invention]

The object of the present invention is to provide a novel composition for improving the intestinal barrier function, etc., which can improve the intestinal barrier function. [Means to solve the problem]

In order to solve the above-mentioned problems, the inventors have devoted themselves to research and have tried to add inflammatory cytokines to the intestinal penetration model using the human intestinal cell culture strain Caco-2 to create an intestinal barrier function in humans. In the state of being flawed, the above-mentioned problems can be solved by finding substances that can improve the state. As a result, it has been found that ursane type triterpenes and their derivatives are useful for improving intestinal barrier function.

That is, the present invention relates to the following composition for improving intestinal barrier function, etc. [1] A composition for improving intestinal barrier function, which contains at least one compound selected from the group consisting of arbutane-type triterpenes, derivatives thereof, and salts thereof as an active ingredient. [2] The composition for improving intestinal barrier function as described in [1] above, wherein the compound is selected from the group consisting of acetylursolic acid, ursolic acid, ursolic acid glycosides, and salts thereof At least one compound of the group consisting of. [3] The composition for improving intestinal barrier function as described in [1] or [2], wherein the compound is acetylursolic acid and/or its salt. [4] The composition for improving the intestinal barrier function as described in [2] or [3], wherein the acetylursolic acid is 3-acetylursolic acid. [5] The composition for improving intestinal barrier function as described in any one of [1] to [4] above, which is an oral composition. [6] The composition for improving intestinal barrier function as described in [5] above, wherein the composition for oral administration is a food or beverage, a pharmaceutical, or a quasi-drug. [7] The composition for improving intestinal barrier function as described in any one of [1] to [6] above, which is used for intestinal regulation. [8] The composition for improving the intestinal barrier function as described in any one of [1] to [7] above, which has an indication that it has an intestinal regulation effect. [9] The use of at least one compound selected from the group consisting of arbutane-type triterpenes, their derivatives and salts thereof, which is used to improve the barrier function of the intestines. [Effects of the invention]

According to the present invention, it is possible to provide a novel composition for improving the intestinal barrier function, etc., which can improve the intestinal barrier function. According to the present invention, the intestinal barrier function can be improved. The present invention can also help prevent or improve the state or disease related to the abnormality of the intestinal barrier function by improving the intestinal barrier function.

Hereinafter, the present invention will be described in detail. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention to only this embodiment. The present invention can be implemented in various forms without departing from its gist.

The composition for improving intestinal barrier function of the present invention contains at least one compound selected from the group consisting of arbutane-type triterpenes, derivatives thereof, and salts thereof as an active ingredient. In this specification, at least one compound selected from the group consisting of arbutane-type triterpenes, derivatives thereof, and salts thereof is also referred to as the compound of the active ingredient in the present invention. In the present invention, one or two or more of the above-mentioned compounds can be used as an active ingredient.

Examples of arbutane-type triterpenes include ursolic acid, corosolic acid, and tormic acid. Examples of derivatives of arbutane-type triterpenes include arbutane-type triterpene glycosides and arbutane-type triterpenes having an acetyl group. Arbutane-type triterpene glycosides are glycosides that use arbutane-type triterpenes as aglycone. For example, ursolic acid glycosides are glycosides that use ursolic acid as the aglycone. Examples of arbutane-type triterpenes having an acetyl group include acetyl ursolic acid, acetyl corosolic acid, and acetyl trihydroxyursonic acid. As arbutane-type triterpenes or derivatives thereof in the present invention, acetylursolic acid, ursolic acid, and ursolic acid glycosides are preferred. As the sugar constituting the arbutane-type triterpene glycoside, monosaccharides, disaccharides, and the like are preferred. Examples of monosaccharides include glucose, galactose, rhamnose, fructose, mannose, arabinose, and the like. Examples of disaccharides include maltose, sucrose, lactose, and the like.

The salt of arbutane-type triterpenes and derivatives thereof is not particularly limited, but those that can be taken orally are preferred. Examples of such a salt 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 effective ingredient in the present invention is preferably at least one compound selected from the group consisting of acetylursolic acid, ursolic acid, ursolic acid glycosides and these salts. Among them, from the viewpoint of a higher effect of improving the intestinal barrier function, it is more preferable to include acetylursolic acid and/or its salt as an active ingredient.

The acetylursolic acid is preferably 3-acetylursolic acid obtained by bonding an acetyl group to the hydroxyl group at the 3-position of ursolic acid. The composition for improving intestinal barrier function of the present invention preferably contains 3-acetylursolic acid and/or its salt as an active ingredient.

The so-called 3-acetylursolic acid is a compound represented by the following formula (1).

The arbutane-type triterpenes, their derivatives, and these salts contained in the composition for improving intestinal barrier function of the present invention are not particularly limited by their source or production method. For example, a plant-derived product extracted from a plant can be used, or a product obtained by synthesis can also be used. In addition, commercially available products can also be used. For example, the source of acetyl ursolic acid, ursolic acid, ursolic acid glycosides and these salts derived from plants is preferably selected from the group consisting of Aronia and Rubus of Rosaceae. Genus (Rubus), Rosaceae Chaenomeles (Chaenomeles), Rosaceae Malus (Malus), Rosaceae Pyrus (Pyrus), Rhododendron (Arctostaphylos), Rhododendron (Vaccinium) Myrtle family Syzygium (Syzygium), Gentianaceae as medicine genus (Swertia), Five row wood family Ternstroemia (Ternstroemia), Holly family Ilex (Ilex), Moraceae Ficus (Ficus), Smelt At least one plant in the group consisting of Olea and Eucommia.

In addition, in the present invention, the source of 3-acetylursolic acid and its salt is preferably selected from the group consisting of Aronia, Rubus, and Papaya and Begonia of Rosaceae. At least one plant in the group consisting of Chaenomeles, Ternstroemia, Ilex, Ficus, and Eucommia.

Furthermore, in the case where the source of 3-acetylursolic acid and its salt is a plant of the genus Aronia, the plant of the genus Rosaceae is preferably selected from Aronia. At least one species of the group consisting of Aronia arbutifolia, Aronia melanocarpa and Aronia x prunifolia. In addition, Aronia melanocarpa is also called chokeberry or black chokeberry as an alias. In the case of extraction from plants, for example, the raw material of the compound containing the active ingredient of the present invention can be extracted with aqueous ethanol, the extract is concentrated, and then subjected to column purification to obtain the active ingredient of the present invention. Compound.

The compound of the active ingredient in the present invention is the ingredient contained in the above-mentioned plant, and even if it is taken for a long time, it has fewer side effects and higher safety. According to the present invention, it is possible to provide a composition for improving the intestinal barrier function that contains, as an active ingredient, a substance that has fewer side effects and is highly safe even if it is taken for a long period of time.

In the present invention, the so-called intestinal barrier function refers to preventing the intrusion (penetration) of foreign bodies (such as toxins such as endotoxin, inflammatory substances, undigested substances, etc.) from outside the intestinal epithelial cells (in the intestine) to the body ) Function. The intestine includes the large intestine and the small intestine. Compared with the normal state, the state in which the intrusion of foreign bodies from outside the intestinal epithelial cells into the body is promoted is called a state in which the penetration of foreign bodies in the intestinal epithelial cells is increased (increased). The so-called improvement of the intestinal barrier function means to inhibit the increase in the penetration of foreign bodies in the intestinal epithelial cells, and to reduce the penetration of foreign bodies in the intestinal epithelial cells. In addition, in the present invention, improving the intestinal barrier function is used to include the meaning of inhibiting the decrease in the intestinal barrier function and improving the reduced intestinal barrier function. For example, by normalizing or strengthening the tight junctions that connect intestinal epithelial cells to each other, the intestinal barrier function is improved. In one aspect, the composition for improving intestinal barrier function of the present invention can be used to improve the intestinal barrier function by normalizing or strengthening tight junctions in intestinal epithelial cells.

The effect of improving the barrier function of the intestine can be demonstrated by, for example, increasing the resistance value (transepithelial electric resistance (TEER)) of intestinal epithelial cells, or suppressing the decrease of TEER. The substances that increase or inhibit the decrease of TEER mentioned above have the effect of normalizing or strengthening tight junctions in intestinal epithelial cells. In addition, the effect of improving intestinal barrier function can also be demonstrated by the decrease in the amount of substances penetrating from the intestinal side of the intestinal epithelial cells to the inside of the body. Those who are familiar with this technique can choose a specific evaluation method for improving the effect of intestinal barrier function according to the purpose. For example, as shown in the following examples, a method for measuring TEER using an intestinal penetration model using human intestinal epithelial cells (Caco-2 cells) can be used. Specifically, the addition of inflammatory cytokines (TNFα, IL-1β, IFNγ, etc.) to Caco-2 monolayer cultured cells creates a state in which the intestinal barrier function can be flawed in humans. Compared with the case where the test substance is not added, the decrease in TEER is suppressed, and it can be evaluated that the test substance has the effect of improving the intestinal barrier function. As shown in the examples, in the intestinal penetration model using Caco-2, acetylursolic acid and ursolic acid have been shown to inhibit the decrease of TEER caused by the addition of inflammatory cytokines, and have excellent Improved effect of intestinal barrier function. In addition, as shown in the examples, acetyl ursolic acid exhibits a better effect of improving the intestinal barrier function than ursolic acid without acetyl ursolic acid.

The composition for improving the intestinal barrier function of the present invention exerts the intestine by containing at least one compound selected from the group consisting of arbutane-type triterpenes, derivatives thereof, and salts thereof as an effective ingredient. Improve the effect of barrier function. Therefore, the composition for improving the intestinal barrier function of the present invention is useful for preventing or improving the intestinal barrier function. The improvement of the intestinal barrier function is effective for preventing or improving the state or disease, for example, the state related to the abnormality of the intestinal barrier function. Or illness. The abnormality of the intestinal barrier function includes a decrease in the intestinal barrier function. As the state or disease related to the abnormality of the intestinal barrier function, a state or disease caused by the abnormality of the intestinal barrier function, or a state or disease accompanied by an abnormality of the intestinal barrier function can be cited. Examples of conditions or diseases related to the abnormality of the intestinal barrier function include inflammatory bowel disease, irritable bowel syndrome, systemic autoimmune diseases (rheumatoid arthritis, lupus erythematosus, etc.), allergies ( Food allergies, hay fever, etc.), lifestyle diseases (obesity, type 1 or type 2 diabetes, hypertension, hyperlipidemia, non-alcoholic fatty liver disease (NAFLD), arteriosclerosis, etc.), etc. (e.g. Camilleri et al ., Am J Physiol Gastrointest Liver Physiol 303: G775-G785, 2012; Mu et al., Front. Immunol., Vol. 8, Article 598, 2017; Bischoff et al., BMC Gastroenterology 2014 14:189).

Examples of more specific symptoms of the state or disease related to the abnormality of the intestinal barrier function include diarrhea, constipation, and discomfort in the stomach (abdomen) (satisfaction, rolling, abdominal pain, etc.). The composition for improving the intestinal barrier function of the present invention has the effect of improving the state of the intestines by improving the intestinal barrier function. Therefore, the composition for improving the intestinal barrier function of the present invention can adjust the condition of the intestines by improving the intestinal barrier function, and is useful for preventing or improving the above-mentioned intestinal symptoms. In one aspect, 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, the abnormality of intestinal barrier function is also related to lifestyle-related diseases (for example, Bischoff et al., BMC Gastroenterology 2014 14:189). Improving the intestinal barrier function is also effective in preventing or improving lifestyle diseases. The symptoms of lifestyle-related diseases include abnormal glucose metabolism, abnormal lipid metabolism, increase in body fat, increase in visceral fat, increase in abdominal fat, and higher blood pressure. Therefore, the composition for improving the intestinal barrier function of the present invention can also contribute to the improvement of glucose metabolism, the improvement of lipid metabolism, the reduction of body fat, visceral fat, abdominal fat, etc., by improving the intestinal barrier function. Increase inhibition, improvement of higher blood pressure, etc.

When referring to "prevention of a state or disease" in this specification, it means to increase the subject's resistance to the state or disease, and to delay or prevent the onset of the state or disease. In addition, when referring to "improvement of a state or disease" in this specification, it means to restore the subject from the state or disease, alleviate the symptoms of the state or disease, and delay or prevent the progress of the state or disease. Recovery includes at least partial recovery.

The composition of the present invention can be applied to any of 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, food, drink, medicine, quasi-drug, feed, etc., but is not limited to these. The composition for improving the intestinal barrier function of the present invention may itself be a food, drink, medicine, quasi-drug, feed, etc., or it may be a preparation or material such as an additive used in the same. As an example, the composition for improving the intestinal barrier function of the present invention can be provided in the form of a dosage form, but is not limited to this form. The agent can also be provided as a composition as it is, or in the form of a composition containing the agent. In one aspect, 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 aspect, the composition for improving intestinal barrier function of the present invention is preferably an oral composition. According to the present invention, an oral composition having an excellent intestinal barrier function improvement effect can be provided. Examples of the oral composition include food and drink, pharmaceuticals, and quasi-drugs, and food and drink are preferred.

The composition for improving the intestinal barrier function of the present invention may contain one or more components (other components) other than the above-mentioned active ingredients of the present invention, provided that the effect of the present invention is not impaired. In one aspect, for example, lactic acid bacteria, bifidobacteria, dietary fiber, polysaccharides, etc. may be contained as other components. Lactic acid bacteria and bifidobacteria are preferably orally ingestible bacteria.

The above-mentioned dietary fiber may be any of water-insoluble dietary fiber and water-soluble dietary fiber. Examples of water-insoluble dietary fibers include cellulose, lignin, hemicellulose, wheat bran, apple fiber, sweet potato fiber, chitin, and the like. Water-soluble dietary fibers are roughly classified into high-viscosity substances and low-viscosity substances. Examples of high-viscosity substances include pectin, konjac polymannose, alginic acid, sodium alginate, guar gum, and agar. Among the dietary fibers generally known in Japan, the so-called low-viscosity water-soluble dietary fiber refers to a low-viscosity solution that contains more than 50% by weight of dietary fiber and is dissolved in water at room temperature. It is a dietary fiber material that shows a solution with a viscosity of 20mPa·s or less. Examples of the low-viscosity substance of water-soluble dietary fiber include indigestible dextrin, polydextrose, guar gum decomposition product, Litesse (polydextrose), and the like. In addition, dietary fiber materials that meet the requirements of low viscosity and water solubility are included. One type of dietary fiber can be used, or two or more types can be used.

Examples of the above-mentioned polysaccharides include oligosaccharides such as galactooligosaccharides, xylo-oligosaccharides, mannose-oligosaccharides, agar-oligosaccharides, fructooligosaccharides, isomalt-oligosaccharides, and raffinose. One type of these may be used, or two or more types may be used.

The composition system for improving the intestinal barrier function of the present invention may contain any additives and components in addition to the above. These additives and components can be selected in accordance with the form of the composition for improving the intestinal barrier function, etc. Generally, those that can be used in foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. can be used. For example, as the oral administration agent, various additives in foods and beverages or pharmaceutically acceptable, such as excipients, lubricants, stabilizers, dispersants, binders, diluents, flavors, sweeteners, Flavoring agent, coloring agent, etc. For example, when the composition for improving the intestinal barrier function of the present invention is made into an oral composition, in addition to the above, vitamins, vitamin-like substances, and proteins may be suitably contained within the range that does not impair the effects of the present invention. , Amino acids, oils, fats, organic acids, carbohydrates, plant-derived raw materials, animal-derived raw materials, microorganisms, food additives, pharmaceutical additives, and other ingredients that can be ingested orally. In addition to the above, ingredients used in foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. can also be appropriately blended in accordance with the application.

The form of the composition for improving the intestinal barrier function of the present invention is proposed before it has the effect of the present invention, and is not particularly limited. In one aspect, when the composition for improving the intestinal barrier function of the present invention is made into a food or drink, the compound of the active ingredient of the present invention may be blended with ingredients that can be used in the food (for example, Food and beverage materials, additives used as needed, etc.), and made into a variety of food and beverage products (food and beverage composition). Food and beverage products are not particularly limited, and examples thereof include general food and beverage products, health foods, functional foods, foods for specific health care, foods for patients, food additives, and other raw materials. The form of the food and drink is also not particularly limited, and it can also be made into lozenges, coated lozenges, fine granules, granules, powders, pills, capsules (including soft capsules and hard capsules), dry syrups, and chewable tablets. Oral solid preparations such as pharmaceuticals; oral liquid preparations, syrups, and other oral liquid preparations.

In one aspect, when the composition for improving the intestinal barrier function of the present invention is made into a pharmaceutical or a quasi-drug, the compound of the active ingredient of the present invention may be blended with pharmaceutically acceptable Additives such as excipients to produce various dosage forms of pharmaceuticals (medicinal composition) or quasi-drugs (quasi-drug composition). The form of administration of pharmaceuticals or quasi-drugs is preferably oral administration. The dosage form of the pharmaceutical or quasi-drug may be made into a dosage form suitable for administration. Examples of dosage forms of oral pharmaceuticals or quasi-drugs include tablets, coated tablets, fine granules, granules, powders, pills, capsules (including soft capsules and hard capsules), and dry syrups. Oral solid preparations such as tablets, chewable lozenges; oral liquid preparations such as oral liquid preparations and syrups.

In the case of tablets, pills and granules, they can also be made into dosage forms that are applied with customary skins as needed, such as dragees, gelatin encapsulants, enteric encapsulants, film coatings, etc. In addition, lozenges can also be used Multi-layer ingots such as double ingots are made.

When the composition for improving the intestinal barrier function of the present invention is made into food and beverages, pharmaceuticals, quasi-drugs, feeds, etc., the production method is not particularly limited, and the compound of the active ingredient of the present invention can be used. It is manufactured by a general method. The present invention also includes the use of at least one compound selected from the group consisting of arbutane-type triterpenes, derivatives thereof, and salts thereof, which are used to manufacture a composition for improving intestinal barrier function.

In the composition for improving the intestinal barrier function of the present invention, the use, the type of active ingredient, the above-mentioned effect, the method of use (for example, the method of ingestion, the method of administration), etc. may also be indicated in the package, container, or manual. Or more than 2 kinds. The composition for improving the intestinal barrier function of the present invention may also be accompanied by a mark having the purpose of improving the intestinal barrier function or based on the effect of improving the intestinal barrier function. For example, a label with the purpose of regulating the bowel may be attached as such a label. The intestinal regulation effect is not particularly limited as long as the intestinal regulation effect is based on the improvement of the intestinal barrier function. As an example of the indications with the purpose of regulating the intestines, "for those with constipation or diarrhea", "for those who are concerned about the condition of the stomach", "for those who easily feel the discomfort of the stomach", and "improve Laxative", "Improve the state of stool", "Improve the frequency of bowel movements", "Improve the amount of bowel movement", "Relieve the stomach", "Adjust the condition of the stomach", "Adjust the condition of the intestines", "Improve the discomfort of the stomach ", "Relieve the production of gas", "Relieve the bloating of the stomach", "Relieve the feeling of rolling in the stomach", etc. In the composition for improving intestinal barrier function of the present invention, one or more of such labels may be attached.

The content of the compound of the active ingredient in the composition for improving the intestinal barrier function of the present invention can be appropriately set according to the form of the composition and the like. In one aspect, when the composition for improving the intestinal barrier function is made into an oral composition such as food and drink, medicine, and quasi-drug, arbutane-type triterpenes, their derivatives, and the like The total content of the salt in the composition is preferably 0.0001% by weight or more, more preferably 0.01% by weight or more, in addition, preferably 80% by weight or less, and more preferably 20% by weight or less. In one aspect, the total content of arbutane-type triterpenes, their derivatives and their salts in the composition for improving the barrier function of the intestine is preferably 0.0001 to 80% by weight, more preferably 0.01 to 20%. weight%. The content of arbutane-type triterpenes, derivatives thereof, and salts thereof can be measured in accordance with a known method, for example, an HPLC method or the like can be used.

The composition for improving the intestinal barrier function of the present invention can be ingested or administered in an appropriate method according to its form. The composition for improving intestinal barrier function of the present invention is preferably administered orally or ingested. The intake of the composition for improving the intestinal barrier function of the present invention (also referred to as the dosage) is not particularly limited, as long as it is an amount that can obtain the effect of improving the intestinal barrier function, as long as it corresponds to the dosage form and dosage. It can be set appropriately according to the method and so on. As one aspect, in the case of humans (adults) as subjects for oral administration or ingestion, the intake of the composition for improving the intestinal barrier function is arbutane-type triterpenes, their derivatives, and the like The total intake of the salt can be 0.01-5000 mg per day, preferably 0.1-3000 mg, more preferably 1-1500 mg, and still more preferably 1-1000 mg. Preferably, the above-mentioned amount is orally administered or ingested, for example, once a day or divided into 2 to 3 times. In one aspect, when a composition for improving the intestinal barrier function is taken in a human (adult) for the purpose of obtaining the effect of improving the intestinal barrier function, arbutane-type triterpenes and derivatives thereof may be used And the total intake of these salts is in the above-mentioned range, so that the subject can orally ingest or administer a composition for improving the intestinal barrier function. The above intake may be the intake per 60 kg of body weight per day. In one aspect, the composition for improving the intestinal barrier function of the present invention can be used for oral administration of the compound of the active ingredient of the present invention in the above-mentioned amount per 60 kg body weight of an adult. Use the composition.

In one aspect, the composition for improving the intestinal barrier function of the present invention preferably contains an amount that can obtain the desired effect of the present invention in consideration of its administration form, administration method, etc., that is, an effective amount of the present invention Among the active ingredients of the compound. As one aspect, for example, when the composition for improving the intestinal barrier function is an oral composition such as a food or drink, an oral medicine, etc., the daily intake of the composition per adult is the bear The total content of fructan-type triterpenes, their derivatives and their salts can be 0.01-5000mg per day, preferably 0.1-3000mg, more preferably 1-1500mg, still more preferably 1-1000mg .

By continuously ingesting (administering) the compound of the active ingredient of the present invention, the improvement effect of the intestinal barrier function can be expected to be improved. In a preferred aspect, the composition for improving intestinal barrier function of the present invention is continuously taken. In one embodiment of the present invention, it is preferable to continuously ingest the composition for improving intestinal barrier function for more than 1 week.

The subject to which the composition for improving intestinal barrier function of the present invention is administered or ingested (hereinafter, also referred to only as the subject of administration) is preferably humans, animals other than humans, more preferably humans, non-human mammals, and even more preferably For humans. In addition, as the subject of administration in the present invention, those who need or wish to improve the intestinal barrier function are preferred. For example, a target whose intestinal barrier function is reduced, a target who wishes to prevent or ameliorate the above-mentioned state or disease related to the abnormality of the intestinal barrier function, and a target who needs to prevent or ameliorate the state or disease are suitable targets.

The present invention also includes the following methods for improving the barrier function of the intestinal tract. A method for improving the barrier function of the intestines, which comprises administering to a subject at least one compound selected from the group consisting of arbutane-type triterpenes, their derivatives, and these salts. A use of at least one compound selected from the group consisting of arbutane-type triterpenes, their derivatives and these salts, which is used to improve the intestinal barrier function. The above methods and uses can be therapeutic methods and uses, or non-therapeutic methods and uses. The so-called "non-treatment" does not include medical behavior, that is, the concept of surgery, treatment or diagnosis. In order to improve the intestinal barrier function of the subject, the compound of the active ingredient in the present invention can be administered to the subject (or ingested) for use. In one aspect, the above-mentioned compound of the active ingredient of the present invention is suitably used to improve the intestinal barrier function by normalizing or strengthening tight junctions in intestinal epithelial cells.

The dosage of at least one compound selected from the group consisting of arbutane-type triterpenes, their derivatives, and these salts is an amount that can improve the intestinal barrier function, that is, the effective amount is However, it is not particularly limited. For example, it is preferable to administer the above-mentioned amount. The method of administration is preferably oral administration. The above-mentioned compounds can be administered as they are, or a composition containing them can be administered. For example, the composition for improving intestinal barrier function of the present invention described above can be administered. In the present invention, the compound, object (administration object), administration method, administration amount, and preferable aspects of the active ingredient in the present invention are the same as those in the composition for improving intestinal barrier function described above. In one aspect, for example, in the case of oral administration of humans (adults) as subjects, the total dosage of arbutane-type triterpenes, their derivatives, and these salts can be administered per 1 day. It is 0.01 to 5000 mg, preferably 0.1 to 3000 mg, more preferably 1 to 1500 mg, still more preferably 1 to 1000 mg. In the above methods and uses, it is preferable to continuously administer the compound of the active ingredient of the present invention for more than 1 week. [Example]

Hereinafter, examples for explaining the present invention more specifically are shown. In addition, the present invention is not limited to these embodiments.

<Example 1> A comparative evaluation to improve the intestinal barrier function was performed. (Method for evaluating the effect of improving intestinal barrier function) Using DMEM (Dulbecco's Modified Eagle Medium), Caco-2 cells were cultured at 37°C for 3 weeks in Transwell (manufactured by Millicell). The culture medium was removed from the cultured Caco-2 cell dish, the wells were washed 3 times with serum-free DMEM, and the wells were filled with the culture medium. Then, the transepithelial resistance (TEER) of Caco-2 monolayer cells was measured by Millicell-ERS (manufactured by Millipore), and cells judged to form sufficient tight junctions (TEER≧1000Ω·cm ² ) were selected for subsequent use Of screening. Next, the sample and TNFα (40ng/mL), IL-1β (20ng/mL) and IFNγ (10ng/mL) described later were added to the test solution (medium) on both the mucosal side and the basement membrane side, and cultured for 48 hours. In addition, the sample was dissolved in dimethyl sulfoxide (DMSO) and then added to the test solution. At this time, set the wells without adding inflammatory cytokines (TNFα, IL-1β and IFNγ) and samples as normal. In addition, a well with inflammatory cytokines and no sample added was set as a control. After incubation, TEER was measured again to evaluate whether the sample inhibited the decrease (decrease) of TEER caused by inflammatory cytokines.

From the TEER values of the wells of the added sample, the normal and the control, the TEER reduction inhibition rate (%) induced by the sample is calculated by the following formula. (Calculation formula for TEER reduction inhibition rate) TEER reduction inhibition rate (%)=100×((TEER of the well to which the sample has been added)-(TEER of the control))/((normal TEER)-(TEER of the control)) In this evaluation system, the higher the TEER reduction inhibition rate (%), the higher the improvement effect of intestinal barrier function.

As samples, 3-acetyl ursolic acid (manufactured by Ark Pharm), 3-acetyl oleanolic acid (manufactured by Ark Pharm), ursolic acid (manufactured by United States Pharmacopeial Convention), and oleanolic acid (manufactured by Ark Pharm) were used. A commercially available standard product of fruit acid (manufactured by ChromaDex). Add each sample so that the concentration of the sample in the test solution becomes 5 μg/mL. In addition, quercetin was evaluated as a positive control. For the quercetin system, a commercially available standard product (manufactured by Funakoshi Co., Ltd.) was used. Quercetin is added to the test solution so that it becomes 9 μg/mL.

The results are shown in Table 1. 3-Acetylursolic acid and ursolic acid have an effect of improving intestinal barrier function. It has been found that 3-acetyl ursolic acid has a higher intestinal barrier function improvement effect than that of ursolic acid which does not have acetyl ursolic acid. 3-Acetylursolic acid, at a lower concentration than quercetin, which is known as an intestinal barrier protective agent, has the same degree of improving intestinal barrier function as quercetin.

[產業上之可利用性]

[Industrial availability]

The composition for improving the intestinal barrier function of the present invention is actually useful in the field of food and drink, the field of medicine, and the like.

Claims (9)

A composition for improving the barrier function of the intestine, which contains at least one compound selected from the group consisting of ursane type (ursane type) triterpenes, their derivatives and these salts as active ingredients. Such as the composition for improving intestinal barrier function of claim 1, wherein the aforementioned compound is at least one selected from the group consisting of acetylursolic acid, ursolic acid, ursolic acid glycosides and these salts Compound. The composition for improving intestinal barrier function of claim 1 or 2, wherein the aforementioned compound is acetylursolic acid and/or its salt. According to claim 2 or 3, the composition for improving intestinal barrier function, wherein the aforementioned acetylursolic acid is 3-acetylursolic acid. The composition for improving intestinal barrier function according to any one of claims 1 to 4 is an oral composition. The composition for improving intestinal barrier function according to claim 5, wherein the aforementioned oral composition is a food, drink, medicine, or quasi-medicine. For example, the composition for improving intestinal barrier function according to any one of claims 1 to 6, which is used for intestinal regulation. For example, the composition for improving the intestinal barrier function of any one of claims 1 to 7, which is accompanied by a label with the purpose of regulating the intestine. A use of at least one compound selected from the group consisting of arbutane-type triterpenes, their derivatives and these salts, which is used to improve the intestinal barrier function.