JP2020050655A - Composition for improving gastrointestinal tract disorder - Google Patents

Abstract

To provide a gastrointestinal tract disorder improver that can be taken conveniently.SOLUTION: The present invention provides an oral composition for improving gastrointestinal tract disorder, containing at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a lipid-soluble antioxidant as an active ingredient.SELECTED DRAWING: None

Description

  The present invention relates to a composition for improving gastrointestinal disorders. In particular, the present invention relates to oral compositions that improve gastrointestinal disorders.

  The gastrointestinal tract has not only digestion and absorption of ingested food but also a barrier function for preventing foreign substances from entering the body. It is known that a decrease in the barrier function leads to invasion of intestinal bacteria into the body, causing inflammation and causing not only upset of the digestive tract but also general deterioration of physical condition. In severe cases, bacteria can migrate to the organs and cause multiple organ failure. Such a decrease in the gastrointestinal tract barrier function is caused by intense exercise (Non-Patent Document 1). Although the decrease in gastrointestinal tract function during exercise resembles Crohn's disease, ulcerative colitis and stress-related diseases, the detailed mechanism is still largely unknown. At present, it is thought that during exercise, the barrier function decreases due to exercise-specific physiological phenomena such as blood collecting in muscles and the heart, reducing blood supply to the digestive tract, and increasing body temperature. Maintaining the gastrointestinal barrier function is important for the athlete, because the deterioration of the barrier function leads to a decrease in the condition and performance of the athlete.

  Bovine colostrum, glutamine and arginine have been reported to improve exercise-induced impaired gastrointestinal barrier function. It has been reported that in bovine colostrum, intestinal stress tolerance is increased by growth factors such as TGF-1 contained therein (Patent Document 1). Colostrum from cows is valuable and lacks versatility. In addition, it has been reported that ingestion of amino acids such as glutamine and arginine for one week alleviates exercise-induced decrease in gastrointestinal barrier function (Non-Patent Documents 2 and 3).

JP 2002-513544 A

Wijck et al. (2011) Plos One 6 (7) e22366 Zuhl et al. (2014) J. Appl. Physiol. 116, 183-191 Costa et al. (2014) J Nutr. 144, 218-223

  In Non-Patent Documents 2 and 3, glutamine and arginine need to be taken for a long period of time, and the use during exercise is complicated. Further, glutamine has low stability in an aqueous solution and its use is limited. An object of the present invention is to provide an improving agent for gastrointestinal disorders that can exert an improvement effect equal to or more than that of the conventional art on gastrointestinal disorders including gastrointestinal barrier function deterioration and can be easily taken. It is in.

  The present inventors have conducted intensive studies to solve the above-mentioned object, and as a result, amino acids such as histidine, serine, and branched-chain amino acids (leucine, isoleucine, and valine) and fat-soluble antioxidants are useful as materials for improving gastrointestinal disorders. This led to the completion of the present invention.

That is, the present invention is as follows.
(1) An oral composition for improving gastrointestinal disorders containing at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient (hereinafter referred to as “the present invention”). Inventive composition ").
(2) The composition according to (1), comprising serine as an active ingredient.
(3) The composition according to (1) or (2), wherein the gastrointestinal tract disorder is at least one selected from gastrointestinal barrier function deterioration, gastrointestinal inflammation, and gastrointestinal upset.
(4) The composition according to any one of (1) to (3), wherein the digestive tract disorder is exercise-induced.
(5) The composition according to any one of (2) to (4), wherein the content of serine is 10 mg to 10 g per unit dosage of human.
(6) The composition according to any one of (2) to (5), further comprising at least one selected from the group consisting of histidine, arginine, and a fat-soluble antioxidant.
(7) The composition according to any one of (2) to (6), wherein the content of serine is 50% by weight or more based on all amino acids in the composition.
(8) containing as an active ingredient at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant;
The composition according to (1), wherein the gastrointestinal tract disorder is exercise-induced gastrointestinal barrier function deterioration.
(9) containing as an active ingredient at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine;
The composition according to (1), wherein the gastrointestinal tract disorder is exercise-induced gastrointestinal barrier function deterioration.
(10) The composition according to (8) or (9), comprising valine, leucine and isoleucine as active ingredients.
(11) The composition according to (9), comprising serine and histidine as active ingredients.
(12) The composition according to (8) or (9), comprising histidine, valine, leucine and isoleucine as active ingredients.
(13) The composition according to (10) or (12), wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5 to 2.5: 0.8 to 1.7.
(14) The composition according to any one of (8) to (13), further comprising arginine and / or serine.
(15) The composition according to (9), comprising serine, valine, leucine and isoleucine as active ingredients.
(16) The composition according to (9), comprising histidine, serine, valine, leucine and isoleucine as active ingredients.
(17) The composition according to any one of (8) to (16), wherein the content of the active ingredient is 0.1 to 100 g per unit intake of human.
(18) The composition according to any one of (8) to (17), which is taken at least once before the start of exercise.
(19) The composition according to any one of (8) to (17), which is taken during or immediately after the exercise.
(20) The composition according to any one of (8) to (17), which is taken at least once before the start of exercise and at least once during exercise or immediately after the end of exercise.
(21) A food or medicine containing the composition according to any one of (1) to (20).
(22) The composition according to any one of (1) to (20), and a description stating that the composition can or should be used for improving gastrointestinal disorders. Including, commercial packages.
(23) A composition containing as an active ingredient at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant is orally administered to a subject in need thereof at least once. A method for improving gastrointestinal disorders, comprising:
(24) The method according to (23), wherein the composition contains serine as an active ingredient.
(25) The method according to (23) or (24), wherein the gastrointestinal tract disorder is at least one selected from gastrointestinal tract barrier function deterioration, gastrointestinal inflammation and gastrointestinal upset.
(26) The method according to any one of (23) to (25), wherein the digestive tract disorder is exercise-induced.
(27) The method according to any one of (24) to (26), wherein the composition contains serine in an amount of 10 mg to 10 g per unit dose of human.
(28) The method according to any one of (24) to (27), wherein the composition further comprises at least one selected from the group consisting of histidine, arginine, and a fat-soluble antioxidant.
(29) The method according to any one of (24) to (28), wherein the content of serine in the composition is 50% by weight or more based on all amino acids in the composition.
(30) the composition contains at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient;
The method according to (23), wherein the gastrointestinal tract disorder is exercise-induced decrease in gastrointestinal tract barrier function.
(31) the composition contains at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine as an active ingredient;
The method according to (23), wherein the gastrointestinal tract disorder is exercise-induced decrease in gastrointestinal tract barrier function.
(32) The method according to (30) or (31), wherein the composition contains valine, leucine and isoleucine as active ingredients.
(33) The method according to (31), wherein the composition contains serine and histidine as active ingredients.
(34) The method according to (30) or (31), wherein the composition contains histidine, valine, leucine and isoleucine as active ingredients.
(35) The method according to (32) or (34), wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5 to 2.5: 0.8 to 1.7.
(36) The method according to any one of (30) to (35), wherein the composition further contains arginine and / or serine.
(37) The method according to (31), wherein the composition contains serine, valine, leucine and isoleucine as active ingredients.
(38) The method according to (31), wherein the composition contains histidine, serine, valine, leucine and isoleucine as active ingredients.
(39) The method according to any one of (30) to (38), wherein the composition contains 0.1 to 100 g of the active ingredient per unit dose of human.
(40) The method according to any one of (30) to (39), wherein the composition is taken at least once before starting exercise.
(41) The method according to any one of (30) to (39), wherein the composition is taken during or immediately after exercise.
(42) The method according to any one of (30) to (39), wherein the composition is taken at least once before the start of exercise and at least once during or immediately after the end of exercise.

The composition of the present invention is suitably used for improving gastrointestinal disorders. In particular, the compositions of the present invention are effectively used to improve exercise-induced gastrointestinal disorders.
In one aspect, the composition of the present invention is suitably used for maintaining the condition of an athlete during training. In particular, the compositions of the present invention are effectively used to ameliorate exercise-induced loss of gastrointestinal barrier function.
Further, the composition of the present invention is extremely advantageous because it has high safety and has almost no side effects.

It is a schematic diagram which shows a fall of a digestive tract barrier function. LPS: Lipopolysaccharide. The outline of the experimental method such as Example 1 is shown. It is a schematic diagram of the evaluation method of Example 1 and the like. Fig. 4 shows the effects of amino acids and carbohydrates on exercise-induced reduction in gastrointestinal barrier function. Each sample was administered at 1 g / kg body weight (10 ml / kg body weight) 30 minutes before exercise (Mean ± SE, n = 11-51). Sed: non-exercise group, Exercise: exercise group, Water: water, Gln: L-glutamine, ArgHCL: L-arginine hydrochloride, HisHCL: L-histidine hydrochloride, CHO: maltodextrin. FIG. 4 shows the effect of branched-chain amino acids on exercise-induced reduction in gastrointestinal barrier function. Sed: non-exercise group, Ex: exercise group, CMC-Na: 0.5% carboxymethylcellulose solution, BCAA: branched-chain amino acid, L-leucine: L-isoleucine: L-valine = 2: 1: 1. The effect of α-lipoic acid and chlorogenic acid on exercise-induced reduction of gastrointestinal barrier function is shown. Sedentary: non-exercise group, CMC-Na: 0.5% carboxymethylcellulose solution, α-lipoic acid: α-lipoic acid, chlorogenic acid: chlorogenic acid. 3 shows the combined effect of histidine and other amino acids on exercise-induced gastrointestinal barrier function reduction. Sedentary: non-exercise group, Water: water, 0.5 g / kg His: aqueous solution of L-histidine hydrochloride, 0.25 g / kg Arg + 0.25 g / kg His: aqueous solution of L-arginine hydrochloride and L-histidine hydrochloride, 0.25 g / kg His + 0.25 g / kg Ser: aqueous solution of L-serine and L-histidine hydrochloride. Fig. 4 shows the effect of serine on exercise-induced reduction in gastrointestinal barrier function. Water: water, Ser: L-serine, Gly: glycine. The effect of serine on exercise-induced reduction in gastrointestinal barrier function (measurement result of FD4 concentration in blood) is shown. Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. 2 shows the effect of serine on exercise-induced decrease in gastrointestinal barrier function (measurement result of endotoxin concentration in blood). Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. 3 shows the effect of serine on gastrointestinal inflammation (measurement result of IL-6 concentration in blood). Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. 3 shows the effect of serine on gastrointestinal inflammation (measurement result of SAA2 concentration in blood). Sed: non-exercise group, Water: water, Ser: L-serine aqueous solution. The effect of serine on gastrointestinal inflammation (measurement of IL-6 gene expression level in jejunum) is shown. Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. The effect of serine on intestinal inflammation (measurement of IL-6 gene expression level in ileum) is shown. Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. 3 shows the combined effect of serine and other amino acids on exercise-induced reduction in gastrointestinal barrier function (measurement result of FD4 concentration in blood). Sedentary: non-exercising group, Water: water, Ser: aqueous solution of L-serine, Ser + His: aqueous solution of L-serine and L-histidine hydrochloride, Ser + Arg: aqueous solution of L-serine and L-arginine hydrochloride. The effect of the combined use of serine and other amino acids on the exercise-induced decrease in gastrointestinal barrier function (measurement result of IL-6 concentration in blood) is shown. Sedentary: non-exercising group, Water: water, Ser: aqueous solution of L-serine, Ser + His: aqueous solution of L-serine and L-histidine hydrochloride, Ser + Arg: aqueous solution of L-serine and L-arginine hydrochloride. FIG. 9 shows the combined effect of histidine and a fat-soluble antioxidant on exercise-induced decrease in gastrointestinal barrier function (Mean ± SEM, n = 3-6). Sedentary: non-exercising group, Ex-Water: water, Ex-His 0.5 g / kg: L-histidine hydrochloride aqueous solution, Ex-chlorogenic acid: chlorogenic acid aqueous solution, Ex-His + chlorogenic acid: L-histidine hydrochloride and chlorogenic acid Aqueous solution.

  In the present invention, “digestive tract disorder” refers to damage and decreased function of tissues in the digestive tract (pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine), and symptoms caused by them. For example, gastrointestinal barrier function is reduced, gastrointestinal inflammation, gastrointestinal upset and the like.

  Transport pathways of substances through gastrointestinal epithelial cells are roughly classified into intracellular (transcellular) and intercellular (paracellular) pathways. The intracellular pathway contributes to nutrient absorption through transporters and channels on the cell membrane. On the other hand, in the intercellular pathway, selective permeability is controlled by adhesion molecules between adjacent cells, which helps in the absorption of minerals such as calcium, as well as intestinal bacteria and dietary antigens present in large quantities in the lumen. On the other hand, it shows a barrier function that does not allow it to enter the body. The adhesive molecular structure responsible for this selective permeability is a tight junction. Tight junctions are large protein complexes located near the brush border membrane on the epithelial cell-side basal membrane, and are composed of transmembrane proteins such as occludin and claudin and intracellular lining proteins such as zonula occludens.

  In the present invention, "reduced gastrointestinal barrier function" means that the barrier between epithelial cells in the gastrointestinal tract is broken, and the permeability of the gastrointestinal tract is increased, and foreign substances, intestinal bacteria or toxins produced by intestinal bacteria are increased. Refers to a state in which such substances easily enter the body through the digestive tract. It is considered that the decrease in the gastrointestinal tract barrier function is caused by, for example, a decrease in blood supply to the gastrointestinal tract during exercise. Further, it is considered that the decrease in the gastrointestinal barrier function is caused by, for example, an increase in body temperature. FIG. 1 shows a schematic diagram of the decrease in the gastrointestinal barrier function.

  Deterioration of the gastrointestinal barrier function and its improvement are determined by the fact that when the gastrointestinal barrier function is maintained normally, transfer from the gastrointestinal tract to the body is suppressed, but when the gastrointestinal barrier function is reduced. Confirmation by orally administering a labeled compound having a molecular weight (for example, about 4,000 molecular weight) enough to penetrate the digestive tract into the blood and measuring the amount (concentration) of the labeled compound in the blood. can do. In the case of humans, it can be confirmed by measuring the amount of permeation of non-metabolizable sugar molecules such as mannitol, rhamnose and lactulose through the intestinal mucosa.

  In the present invention, “inflammation of the digestive tract” includes any inflammation that is observed in the digestive tract, regardless of the cause or the like. The inflammation may be acute or chronic. Moreover, it may be accompanied by one or more of inflammatory symptoms such as redness, pain, fever, and swelling, or may be free from these inflammatory symptoms.

  In the present invention, "gastrointestinal upset" is a general term for pathological symptoms that occur in the gastrointestinal tract and pathological symptoms that occur due to gastrointestinal dysfunction, for example, stomach pain, nausea, diarrhea, etc. No.

  In the present invention, “exercise-induced gastrointestinal disorders” refers to gastrointestinal disorders that develop with exercise (particularly intense exercise). Here, “vigorous exercise” refers to, for example, long-time exercise, daily exercise, exercise of relatively high intensity, exercise in a severe environment such as high temperature, or the like. As a method for determining whether or not a gastrointestinal disorder is exercise-induced, for example, a significant increase in TNF-α cannot be confirmed, but when a gastrointestinal disorder is occurring, the gastrointestinal disorder is exercise-induced. It can be determined that there is. Whether the gastrointestinal tract disorder is exercise-induced or not is determined not only by TNF-α but also by, for example, increase in body temperature, blood shortage, occurrence of inflammation (in particular, inflammation in which TNF-α is not significantly increased). It may be determined.

In the present invention, “exercise-induced decrease in gastrointestinal barrier function” refers to a decrease in gastrointestinal barrier function that occurs with exercise (particularly intense exercise).
Exercise-induced depression of gastrointestinal barrier function is thought to be mainly caused by increased body temperature and decreased blood flow due to exercise. On the other hand, stress-induced bowel disease and inflammatory bowel disease are caused by inflammation, and it is considered that these are different from exercise-induced decrease in gastrointestinal barrier function in the mechanism and condition.

  In the present invention, “exercise-induced gastrointestinal inflammation” refers to gastrointestinal inflammation that occurs with exercise (particularly intense exercise). Further, “exercise-induced gastrointestinal upset” refers to gastrointestinal upset that occurs with exercise (particularly intense exercise).

In the present invention, “improvement” is intended to include “prevention or treatment”. For example, taking the example of “exercise-induced barrier function decline”, which is a type of gastrointestinal disorder, as an example, “improvement” of exercise-induced barrier function decline refers to exercise-induced gastrointestinal barrier function during exercise. Significantly reduces exercise-induced nausea and digestive decline during or after exercise associated with exercise-induced reduction in gastrointestinal barrier function, and significantly reduces post-exercise appetite decline Means preventing intestinal bacteria and toxins derived from bacteria from entering the body to alleviate physical deterioration.
In the present invention, "prevention" of gastrointestinal inflammation or gastrointestinal upset means preventing or delaying the onset of gastrointestinal inflammation or gastrointestinal upset. Alleviating the symptoms of inflammation or gastrointestinal upset, or preventing or delaying the progress (deterioration) of the symptoms.

Serine, histidine, valine, leucine, and isoleucine, which are amino acids contained as an active ingredient in the composition of the present invention, can be used in any of L-form, D-form, and DL-form, respectively. , L-form and DL-form, and more preferably L-form.
The amino acid can be used not only in a free form but also in a salt form. Examples of the salt form include an acid addition salt and a salt with a base, and it is preferable to select a pharmacologically acceptable salt.
Examples of the salt of serine include a salt with an inorganic base, a salt with an inorganic acid, and a salt with an organic acid. Examples of the salt with an inorganic base include a salt with an alkali metal such as sodium, potassium, and lithium, a salt with an alkaline earth metal such as calcium and magnesium, and an ammonium salt. Examples of the salt with an inorganic acid include salts with hydrohalic acid (such as hydrochloric acid, hydrobromic acid, and hydroiodic acid), sulfuric acid, nitric acid, and phosphoric acid. Examples of the salt with an organic acid include salts with formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, glutamic acid, aspartic acid, and the like.
Examples of the histidine salt include a salt with an inorganic base, a salt with an inorganic acid, and a salt with an organic acid. Examples of the salt with an inorganic base include a salt with an alkali metal such as sodium, potassium, and lithium, a salt with an alkaline earth metal such as calcium and magnesium, and an ammonium salt. Examples of the salt with an inorganic acid include salts with hydrohalic acid (such as hydrochloric acid, hydrobromic acid, and hydroiodic acid), sulfuric acid, nitric acid, and phosphoric acid. Examples of the salt with an organic acid include salts with formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, and the like.
Examples of the acid which forms a pharmacologically acceptable salt by adding to each of the branched-chain amino acids of isoleucine, leucine and valine include, for example, inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and phosphoric acid; acetic acid, lactic acid and citric acid Organic acids such as acid, tartaric acid, maleic acid, fumaric acid, monomethyl sulfate and the like can be mentioned.
Examples of pharmacologically acceptable bases of isoleucine, leucine and valine branched-chain amino acids include, for example, hydroxides or carbonates of metals such as sodium, potassium and calcium, and inorganic bases such as ammonia; ethylenediamine, propylenediamine, ethanol Organic bases such as amine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine are exemplified.

  The fat-soluble antioxidant contained as an active ingredient in the composition of the present invention is not particularly limited as long as it has an action capable of improving gastrointestinal disorders, for example, chlorogenic acid compound, α-lipoic acid compound, vitamin E, astaxanthin and the like, and preferably a chlorogenic acid compound and an α-lipoic acid compound.

  The chlorogenic acid compound used in the present invention includes 5-caffeoylquinic acid (chlorogenic acid) in which caffeic acid is ester-bonded to the 5-position hydroxyl group of quinic acid, and derivatives thereof. Examples of the derivative include 4-caffeoylquinic acid (cryptochlorogenic acid) in which caffeic acid is ester-bonded to the 4-hydroxyl group of quinic acid, and 3-caffeic acid in which caffeic acid is ester-bonded to the 3-hydroxyl group of quinic acid. Oil quinic acid (neochlorogenic acid), dicaffeoylquinic acid (isochlorogenic acid) in which caffeic acid is ester-bonded to any two of the 3-, 4- and 5-hydroxyl groups of quinic acid, and quinic acid Ferulyl quinic acid in which ferulic acid is ester-bonded to any one of the 3-, 4- and 5-position hydroxyl groups, and caffeic acid in two of the 3-, 4- and 5-position hydroxyl groups of quinic acid And ferulic acid quinic acid in which ferulic acid is ester-bonded. Further, these physiologically acceptable salts (eg, alkali metal salts, alkaline earth metal salts, etc.), esters, and amides may be used. The chlorogenic acid compound used in the present invention may be any one of these compounds or a mixture of two or more compounds. The chlorogenic acid compound used in the present invention is preferably chlorogenic acid.

  The α-lipoic acid compound used in the present invention includes α-lipoic acid (thioctic acid (1,2-dithiolan-3-pentanoic acid)) and its derivatives. Examples of the derivative include dihydrolipoic acid (6,8-dimercaptooctanoic acid). Further, these physiologically acceptable salts (eg, alkali metal salts, alkaline earth metal salts, etc.), esters, and amides may be used. The α-lipoic acid compound used in the present invention may be any one of these compounds or a mixture of two or more compounds. The α-lipoic acid compound used in the present invention is preferably α-lipoic acid.

  As the fat-soluble antioxidant (for example, chlorogenic acid compound, α-lipoic acid compound, etc.), those extracted from nature may be used, or those chemically synthesized industrially may be used. A commercially available product may be used, which is preferred because it is simple.

  The composition of the present invention contains at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine, and a fat-soluble antioxidant (eg, chlorogenic acid compound, α-lipoic acid compound, etc.) as an active ingredient. Is what you do. The composition of the present invention may contain, as an active ingredient, a combination of two or more selected from the group consisting of serine, histidine, valine, leucine, isoleucine, and a fat-soluble antioxidant. The composition of the present invention may contain, as an active ingredient, at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine, and the group consisting of serine, histidine, valine, leucine and isoleucine. It may contain two or more selected combinations as active ingredients.

  The composition of the present invention may contain serine as an essential active ingredient. In this case, the composition of the present invention may further contain at least one selected from the group consisting of histidine, arginine and a fat-soluble antioxidant as an active ingredient.

  The composition of the present invention may contain at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an essential active ingredient. In this case, the composition of the present invention may further contain arginine and / or serine as an active ingredient.

Arginine which can be contained as an active ingredient in the composition of the present invention can be any of L-form, D-form and DL-form, but is preferably L-form and DL-form, and more preferably. Is an L-form.
Examples of arginine salts include salts with inorganic bases, salts with inorganic acids, and salts with organic acids. Examples of the salt with an inorganic base include a salt with an alkali metal such as sodium, potassium, and lithium, a salt with an alkaline earth metal such as calcium and magnesium, and an ammonium salt. Examples of the salt with an inorganic acid include salts with hydrohalic acid (such as hydrochloric acid, hydrobromic acid, and hydroiodic acid), sulfuric acid, nitric acid, and phosphoric acid. Examples of the salt with an organic acid include salts with formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, and the like.

  The composition of the present invention may contain serine as an essential component and at least one amino acid selected from the group consisting of histidine, valine, leucine and isoleucine as an active ingredient.

Preferred combinations of active ingredients (amino acids, fat-soluble antioxidants) include
Serine and histidine; serine and arginine; or two amino acids, histidine and arginine;
Histidine and a chlorogenic acid compound (preferably chlorogenic acid);
Three amino acids valine, leucine and isoleucine;
Serine, valine, leucine and isoleucine; or four amino acids of histidine, valine, leucine and isoleucine;
The five amino acids histidine, serine, valine, leucine and isoleucine are mentioned.

The content of the active ingredient (amino acid, fat-soluble antioxidant) in the composition of the present invention is determined based on the effect of improving human digestive tract disorders (eg, exercise-induced decrease in gastrointestinal barrier function). When applied to a single dose, the amount is preferably 0.1 g or more, more preferably 0.5 g or more, particularly preferably 1 g or more per unit dose. From the viewpoint of ease of ingestion in actual ingestion, the content is preferably 100 g or less, more preferably 10 g or less. In the present invention, when the amino acid forms a salt, the content of the amino acid is calculated after converting the salt to a free form.
The content of the active ingredient is, for example, when the composition contains only one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient, It refers to the content of the one component per unit intake. When the composition contains two or more combinations selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient in the composition, the combination per one unit dose Means the total amount of Here, the “single intake unit amount” is an amount that is taken or administered at one time.

  When the composition of the present invention contains serine as an active ingredient, the content of serine is preferably 10 mg or more per unit dose when applied to humans, from the viewpoint of improving digestive tract disorders, It is more preferably at least 50 mg, particularly preferably at least 100 mg. In addition, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.

  When the composition of the present invention contains serine as an active ingredient, the content of serine is preferably at least 10% by weight, more preferably at least 20% by weight, based on all amino acids in the composition of the present invention. And particularly preferably at least 50% by weight. In this case, the content of serine is preferably 100% by weight or less, more preferably 95% by weight or less, and particularly preferably 90% by weight or less, based on all amino acids in the composition of the present invention. .

  When the composition of the present invention contains histidine as an active ingredient, the content of histidine is preferably 10 mg or more per unit dose when applied to humans, from the viewpoint of improving the digestive tract disorder, It is more preferably at least 50 mg, particularly preferably at least 100 mg. In addition, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.

  When the composition of the present invention contains histidine as an active ingredient, the content of histidine is preferably at least 10% by weight, more preferably at least 20% by weight, based on all amino acids in the composition of the present invention. And particularly preferably at least 50% by weight. In this case, the content of histidine is preferably 100% by weight or less, more preferably 95% by weight or less, and particularly preferably 90% by weight or less, based on all amino acids in the composition of the present invention. .

  The composition of the present invention may contain, as an active ingredient, a mixture of three kinds of branched-chain amino acids of isoleucine, leucine and valine (in the present invention, it may be abbreviated as BCAA). The mixing ratio of these three amino acids is usually in a weight ratio of isoleucine: leucine: valine = 1: 1.5 to 2.5: 0.8 to 1.7, particularly preferably 1: 1.5. 1.9-2.2: The range is 1.1-1.3.

  When the composition of the present invention contains BCAA as an active ingredient, the content of BCAA is preferably 10 mg or more per unit dose when applied to humans, from the viewpoint of the effect of improving gastrointestinal disorders, It is more preferably at least 50 mg, particularly preferably at least 100 mg. In addition, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.

  When the composition of the present invention contains BCAA as an active ingredient, the content of BCAA is preferably at least 50% by weight, more preferably at least 60% by weight, based on all amino acids in the composition of the present invention. And particularly preferably at least 70% by weight. In this case, the content of BCAA is preferably 100% by weight or less, more preferably 95% by weight or less, and particularly preferably 90% by weight or less, based on all amino acids in the composition of the present invention. .

  When the composition of the present invention contains a chlorogenic acid compound as an active ingredient, the content of the chlorogenic acid compound is preferably 1 mg per ingestion unit dose when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders. It is more preferably at least 5 mg, particularly preferably at least 50 mg. In addition, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.

  When the composition of the present invention contains an α-lipoic acid compound as an active ingredient, the content of the α-lipoic acid compound is, from the viewpoint of the effect of improving gastrointestinal disorders, when applied to humans, per unit dose. , Preferably 10 mg or more, more preferably 50 mg or more, particularly preferably 100 mg or more. In addition, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 10 g or less, more preferably 5 g or less.

  When the composition of the present invention contains histidine and serine, or histidine and BCAA, the ratio of serine or BCAA to histidine, respectively, is usually in the range of histidine: serine or BCAA = 1: 0.1 to 5 by weight. It is. When containing serine and BCAAs, the ratio of BCAA to serine is usually in the range of serine: BCAA = 1: 0.1-5.

  When the composition of the present invention contains histidine, serine and BCAA, the compounding ratio of the amino acids is usually in the range of histidine: serine: BCAA = 1: 0.1-5: 0.1-5 by weight. It is.

  When the composition of the present invention contains serine and arginine, the ratio of serine to arginine is usually in the range of serine: arginine = 1: 0.1 to 10, preferably 1: 1, by weight. It is in the range of 0.2 to 5.

  When the composition of the present invention contains histidine and arginine, the ratio between histidine and arginine is usually in the range of histidine: arginine = 1: 0.1 to 10 by weight, preferably 1: 0.1. It is in the range of 0.2 to 5.

  When the composition of the present invention contains histidine and a fat-soluble antioxidant (for example, a chlorogenic acid compound or the like), the ratio of histidine to the fat-soluble antioxidant is usually by weight, and usually histidine: fat-soluble antioxidant. Oxidizing agent = 1: 0.001-5, preferably 1: 0.01-2.

  The composition of the present invention can be used in combination with a therapeutic agent for gastrointestinal ulcer (hereinafter, sometimes referred to as a concomitant drug). The concomitant drug is not particularly limited as long as it is a therapeutic drug usually used in the treatment of gastrointestinal diseases, and specific examples include rebamipide.

  The composition of the present invention can be used in combination with good bacteria such as lactic acid bacteria and bifidobacteria. Specific examples include VSL # 3 (registered trademark).

  The composition of the present invention can be used in combination with glutamine or arginine.

  The composition of the present invention is applied to mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.). When applied to mammals other than humans, the intake of the composition of the present invention may be appropriately set according to the weight or size of the animal.

  The composition of the present invention is generally used orally, but can be administered via an enteral route such as enteral tube administration or infusion depending on the condition of the subject. Dosage forms for oral use include granules, fine granules, powders, coated tablets, tablets, powders, (micro) capsules, chewables, syrups, juices, solutions, suspensions, and emulsions. And the like.

  Preparation into these dosage forms is carried out by formulating them in a conventional manner. Various pharmacologically acceptable substances for pharmaceutical preparations can be blended as required for the preparation. The substance for preparation can be appropriately selected depending on the dosage form of the preparation. For example, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, glidants, lubricants, flavoring agents , A flavoring agent, a sweetening agent, a solubilizing agent and the like. Further, specific examples of substances for preparation include magnesium carbonate, titanium dioxide, lactose, mannitol and other saccharides, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterile water and monohydric or polyhydric alcohols such as glycerol.

  The intake or dosage of the composition of the present invention varies depending on the condition, age, body weight or dosage form of the subject, the method of ingestion or the method of administration, and the like, but histidine is 0.005 g / kg body weight to 5 g / day per adult per day. kg body weight, serine 0.005 g / kg body weight to 5 g / kg body weight, isoleucine 0.005 g / kg body weight to 5 g / kg body weight, leucine 0.01 g / kg body weight to 10 g / kg body weight, valine 0.005 g / kg body weight to 5 g / kg body weight, fat-soluble antioxidant (eg, chlorogenic acid compound, α-lipoic acid compound, etc.) 0.001 g / kg body weight to 1 g / kg body weight are used as a guide. In the case of general adults, preferably, histidine 0.01 g / kg body weight to 1 g / kg body weight, serine 0.01 g / kg body weight to 1 g / kg body weight, isoleucine 0.01 g / kg body weight to 1 g / day kg body weight, leucine 0.02 g / kg body weight to 2 g / kg body weight, valine 0.01 g / kg body weight to 1 g / kg body weight, fat-soluble antioxidant 0.001 g / kg body weight to 0.05 g / kg body weight, more preferably Histidine 0.02 g / kg body weight to 0.2 g / kg body weight, serine 0.02 g / kg body weight to 0.2 g / kg body weight, isoleucine 0.02 g / kg body weight to 0.2 g / kg body weight, leucine 0. 04 g / kg body weight to 0.4 g / kg body weight, valine 0.02 g / kg body weight to 0.2 g / kg body weight, fat-soluble antioxidant (for example, chlorogenic acid compound, α-lipoic acid compound ) And 0.003 g / kg body weight ~0.01g / kg body weight, preferably 0.01 g / kg body weight to 2 g / kg body weight about per day as the total amount of the active ingredient. When the composition of the present invention contains arginine, the daily intake or dose of arginine is usually 0.005 g / kg body weight to 5 g / kg body weight, preferably 0.01 g / kg body weight to 1 g / day. kg body weight. The above-mentioned daily dose can be taken or administered at once or in several portions. The composition of the present invention may be taken or administered before, after, or during exercise. The time of ingestion or administration of the composition of the present invention is preferably before, during or immediately after exercise. Immediately after the exercise ends within one hour after the exercise ends. The number of times of ingestion or administration is at least once. More preferably, it is taken or administered at least once before the start of exercise and at least once during or immediately after the end of exercise. Although the period of ingestion or administration is not particularly limited, the composition of the present invention can exert its effects significantly by a single administration before exercise.

  The composition of the present invention contains, as active ingredients, two or more selected from the group consisting of serine, histidine, valine, leucine, isoleucine, and a fat-soluble antioxidant (eg, chlorogenic acid compound, α-lipoic acid compound, etc.). When these active ingredients are used, each of these active ingredients may be contained alone or in any combination in the preparation, or all may be contained in one preparation. The timing of administration of each may be simultaneous or different. When there is a drug to be used in combination, the timing of administration is appropriately determined depending on the type and effect. That is, the composition of the present invention may be a preparation containing at least two kinds of active ingredients at the same time, or may be a combination preparation which is separately prepared and used in combination. In particular, an embodiment in which all the active ingredients are contained in the same preparation is preferable because it can be easily administered.

  In the present invention, the “weight ratio” indicates the ratio of the weight of each component in the preparation. For example, when at least two kinds of active ingredients are included in one preparation, the ratio is the content of each. When each of the active ingredients is contained alone or in any combination in a plurality of preparations, Is the weight ratio of each active ingredient included in each formulation.

  In the present invention, the actual dose ratio is a ratio of a single dose or a daily dose of each active ingredient per subject. For example, when at least two kinds of active ingredients are contained in one formulation and administered to a subject, the weight ratio corresponds to the dose ratio. When each active ingredient is administered alone or in any combination in a plurality of preparations, the ratio of the total amount of each active ingredient in each preparation once or daily administered corresponds to the weight ratio.

Further, the composition of the present invention can be used by adding it to various foods. When added to food, there is no restriction other than the addition of the composition of the present invention, and any food can be used as long as it is a general meal form. For example, drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor. Specifically, for example, it can be added to juice, milk, confectionery, jelly, yogurt, candy and the like for eating and drinking.
Further, the food to which such a composition of the present invention is added can be provided as a health functional food or a dietary supplement. The health functional food includes a food for specified health use and a nutritional functional food. The specific health food is a food that can indicate that a specific health purpose, such as improvement of gastrointestinal disorders, can be expected. Nutritionally functional foods are foods that can display the function of the nutritional component when the amount of the nutritional component included in the daily intake reference amount conforms to the standard standards of the upper and lower limits set by the country. . Dietary supplements include so-called dietary or health supplements. In the present invention, the food for specified health use is provided with a label indicating that the food is used for a purpose such as gastrointestinal tract disorder, and further, a document stating that the food is used for such a purpose (so-called indication of effect), etc. , Etc. as a package.

  Further, the composition of the present invention can be used by adding it to a thick liquid food or a food supplement. When added to a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like together with other components. The food supplement in the present invention refers to those taken for the purpose of supplementing nutrition other than those taken as food, and includes nutrition supplements, supplements, and the like.

  In addition, the “concentrated liquid diet” is adjusted to a concentration of about 1 kcal / ml, and the qualitative composition of each nutrient is sufficiently taken into consideration so that even a long-term ingestion does not cause a significant excess or deficiency of the nutrient, one day Is a comprehensive nutritional food (liquid food) designed based on the nutritional requirements of

  The composition of the present invention can be in unit package form. In the present invention, the “unit packaging form” refers to a form in which one unit or two or more units are contained in one package with a specific amount (for example, a single intake unit amount) as one unit. The unit packaging form in which the unit dose is taken as one unit is referred to as “unit packaging form per unit dose”. The packaging used in the unit packaging form can be appropriately selected depending on the form of the composition, and examples thereof include a paper container, a plastic container, an aluminum can, a steel can, a glass bottle, a plastic bottle, and a PTP sheet.

  In the present invention, gastrointestinal disorders (for example, exercise-induced gastrointestinal barrier function) containing at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine, and a fat-soluble antioxidant as an active ingredient. Oral compositions for ameliorating reduction, etc.) can or can be used to ameliorate gastrointestinal disorders (eg, exercise-induced gastrointestinal barrier function loss, etc.). Also included are commercial packages containing the written material.

The composition of the present invention can improve gastrointestinal disorders by at least one oral administration to a subject in need thereof. In particular, the compositions of the present invention can effectively ameliorate exercise-induced gastrointestinal disorders.
Further, the composition of the present invention is orally administered to a subject in need thereof at least once, whereby the gastrointestinal tract barrier function is reduced, gastrointestinal tract (preferably, small intestine (duodenum, jejunum, ileum)) inflammation, and May improve gastrointestinal upset. In particular, the compositions of the present invention can effectively ameliorate exercise-induced impaired gastrointestinal barrier function, exercise-induced gastrointestinal inflammation, and exercise-induced gastrointestinal upset.
When the composition of the present invention contains serine as an active ingredient, it is particularly suitably used for improving gastrointestinal disorders (preferably, exercise-induced gastrointestinal disorders). When the composition of the present invention contains, as an active ingredient, at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant, the gastrointestinal barrier function is reduced (preferably, exercise-induced It is particularly preferably used for improving gastrointestinal barrier function lowering).

The present invention comprises orally administering the composition of the present invention to a subject in need thereof at least once, for example, gastrointestinal disorders (eg, reduced gastrointestinal barrier function, gastrointestinal inflammation and gastrointestinal upset). It also provides a way to improve.
The present invention also provides a method for ameliorating exercise-induced gastrointestinal disorders, comprising orally administering the composition of the present invention to a subject in need thereof at least once.
These methods may exclude medical practice. Here, the “medical practice” refers to an act of treating, operating, or diagnosing a human being performed by a doctor or dentist or under the supervision of a doctor or dentist.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited to these examples.

Example 1 Effect of Histidine to Improve Exercise-Induced Gastrointestinal Barrier Function Degradation Macromolecular substances that are not usually absorbed from the gastrointestinal tract penetrate the intestinal tract and enter the blood when the gastrointestinal barrier function is reduced. It is known that this will happen (Fig. 1). Therefore, the effect of improving the exercise-induced decrease in gastrointestinal barrier function of amino acids was examined in the following test.
Seven-week-old male CD2F1 mice (Charles River Japan Co., Ltd.) were administered with aqueous solutions of various amino acids or their salts at a dose of 1 g / kg body weight, and 30 minutes later, they were allowed to run in a rotating car for 4 hours (speed 10. 5 m / min). After running, FITC-dextran (average molecular weight: 4000; FD4, Sigma-Aldrich Japan) was orally administered at a dose of 500 mg / kg body weight, and blood was collected after 1 hour (FIG. 2). Cani et al. , Gut 2009, 58 (8): 1091-1103, by calculating the concentration of FD4 leaked from the gastrointestinal tract into the blood by measuring the fluorescence intensity in the blood, the gastrointestinal tract permeability of FD4 is calculated. Was evaluated (FIG. 3). Specifically, blood was collected from mice under isoflurane anesthesia. Blood was centrifuged to obtain plasma. Thereafter, the plasma was diluted 2-fold with a phosphate buffer, and the fluorescence intensity was measured under the conditions of an excitation wavelength of 485 nm and a detection wavelength of 535 nm (measurement device SPECTRA MAX GEMINI EM Molecular Device Japan).
FIG. 4 shows the results. The FD4 concentration in the blood was higher in the group (Water) that was exercised for 4 hours with water than in the animals in the non-exercise group (Sed). From these results, it was confirmed that the gastrointestinal barrier function was lowered by running for 4 hours, and that a large amount of high molecular weight substances flowed into the blood. In the group (CHO) to which the carbohydrate maltodextrin was administered at a dose of 1 g / kg body weight, it was found that the FD4 concentration in the blood did not decrease, so that ingestion of carbohydrate did not improve the gastrointestinal barrier function. On the other hand, the FD4 concentration was reduced in the L-histidine hydrochloride administration group (HisHCL), indicating that histidine suppressed exercise-induced decrease in gastrointestinal barrier function. The effect was higher than the L-glutamine administration group (Gln) and the L-arginine hydrochloride administration group (ArgHCL).

Example 2 Effect of BCAA on Improvement of Exercise-Induced Gastrointestinal Barrier Function Decrease In the same manner as in Example 1, the effect of various amino acids on exercise-induced reduction of gastrointestinal barrier function was examined.
A branched chain amino acid (L-leucine, L-isoleucine, L-valine = 2: 1: 1) in which 0.5% carboxymethylcellulose (CMC-Na) is dispersed as a solvent is administered at 1 g / kg body weight to exercise. In the group (BCAA, Ex), the FD4 concentration in the blood was significantly reduced as compared with the group (CMC-Na, Ex) in which only the solvent was administered and exercised (FIG. 5). From these results, it was confirmed that BCAA has an effect of improving exercise-induced gastrointestinal barrier function.

Example 3 Effect of improving the exercise-induced decrease in gastrointestinal barrier function of α-lipoic acid and chlorogenic acid Except for shortening the nails of mice to prevent injuries in which toenails peel off during running In the same manner as in Example 1, the effects of α-lipoic acid and chlorogenic acid on exercise-induced reduction in gastrointestinal barrier function were examined.
Α-lipoic acid dispersed in 0.5% carboxymethyl cellulose (CMC-Na) as a solvent was administered at 80 mg / kg body weight to exercise (α-lipoic acid), and 0.5% carboxymethyl cellulose (CMC-Na). -Na) was administered at a dose of 50 mg / kg body weight with chlorogenic acid dispersed therein as a solvent and exercised (chlorogenic acid) as compared to a group administered only with a solvent and exercised (CMC-Na). The increase in blood FD4 concentration was suppressed (FIG. 6). From these results, it was confirmed that α-lipoic acid and chlorogenic acid each have an effect of alleviating exercise-induced decrease in gastrointestinal barrier function.

Example 4 Effect of using histidine in combination with another amino acid In the same manner as in Example 3, the effect of using L-histidine in combination with another amino acid was examined.
A group exercised by administering an aqueous solution of L-serine (dose: 0.25 g / kg body weight) and L-histidine hydrochloride (dose: 0.25 g / kg body weight) (0.25 g / kg His + 0.25 g / kg) Ser) and a group (0.25 g) exercised by administering an aqueous solution of L-arginine hydrochloride (dose: 0.25 g / kg body weight) and L-histidine hydrochloride (dose: 0.25 g / kg body weight). / Kg Arg + 0.25 g / kg His), compared with the group (0.5 g / kg His) exercised with an aqueous solution of L-histidine hydrochloride (dose: 0.5 g / kg body weight). The increase in FD4 concentration was suppressed (FIG. 7). These results revealed that the effect of reducing exercise-induced gastrointestinal barrier function reduction was greater when serine or arginine was used in combination than when histidine was administered alone.

Example 5 Effect of Serine on Improvement of Exercise-Induced Gastrointestinal Barrier Function Decrease In the same manner as in Example 1, the effect of L-serine and glycine on exercise-induced reduction of gastrointestinal barrier function was examined. As a result, the blood FD4 concentration was significantly reduced in the group exercised by administering L-serine at 1 g / kg body weight, as compared with the group exercised by administering water. On the other hand, in the group in which glycine was administered at 1 g / kg body weight and exercised, no decrease in blood FD4 concentration was observed (FIG. 8). From these results, it was confirmed that serine had an effect of alleviating exercise-induced decrease in gastrointestinal barrier function.

Example 6 Effect of Serine to Improve Gastrointestinal Barrier Function Deterioration Water or an L-serine aqueous solution (dose: 1 g / kg body weight) was administered to 7-week-old male CD2F1 mice (Charles River Japan). After 30 minutes, the vehicle was driven for 4 hours in a rotating vehicle (speed: 10.5 m / min). After running, FITC-dextran (average molecular weight: 4000; FD4, Sigma-Aldrich Japan) was orally administered at a dose of 500 mg / kg body weight, and blood was collected after 1 hour (FIG. 2). In addition, the group which did not run after water administration (Sed) was fasted and water-fast as in the running group. Cani et al. , Gut 2009, 58 (8): 1091-1103, by calculating the concentration of FD4 leaked from the gastrointestinal tract into the blood by measuring the fluorescence intensity in the blood, the gastrointestinal tract permeability of FD4 is calculated. Was evaluated (FIG. 3). The specific measuring method is the same as in the first embodiment. The endotoxin concentration in plasma was measured using Toxinometer (registered trademark) ET-6000 (Wako Pure Chemical Industries, Ltd.).
FIG. 9 shows the evaluation results of gastrointestinal permeability of FD4. The FD4 concentration in the blood was higher in the group (Water) that was exercised for 4 hours by administering water than in the non-exercise group (Sedentary). From these results, it was confirmed that the gastrointestinal barrier function was reduced by exercise for 4 hours, and a large amount of FD4, a high molecular weight substance, flowed into the blood. On the other hand, in the group (Ser 1.0 g / kg) in which the L-serine aqueous solution was administered and exercised for 4 hours, the concentration of FD4 in the blood was decreased, so that L-serine was not induced by exercise-induced digestion. It was found that the decrease in vascular barrier function was suppressed.
FIG. 10 shows the measurement results of the endotoxin concentration in plasma. As shown in FIG. 10, the blood concentration of endotoxin, which is one of the toxins, was increased in the group (Water) that was exercised for 4 hours by administering water, but was administered with the L-serine aqueous solution. No increase was observed in the group (Ser 1.0 g / kg) that was exercised for 4 hours.
From the above results, it has been clarified that serine improves the deterioration of the gastrointestinal barrier function.

Example 7 Inhibitory Effect of Serine on Gastrointestinal Inflammation As in Example 6, 7-week-old male CD2F1 mice (Charles River Japan Co., Ltd.) were given water or L-serine aqueous solution (dose: 1 g / kg body weight). ) Was administered, and 30 minutes later, the vehicle was run in a rotating car for 4 hours (speed: 10.5 m / min). After running, plasma was collected, and the interleukin 6 (IL-6) concentration and serum amyloid A (SAA2) concentration in the blood were measured using the Mouse IL-6 ELISA Ready-SET-Go! (EBioscience) and MOUSE SERUM AMYLOID A ELISA TEST KIT (Life Diagnostics). IL-6 and SAA2 are indicators of inflammation, respectively. In addition, the small intestine was collected from the mouse after running, and the expression level of the IL-6 gene in the small intestine (jejunum, ileum) was measured by a real-time PCR method (GAPDH gene was used as housekeeping).
11 and 12 show the measurement results of IL-6 concentration and SAA2 concentration in blood. In the group administered with water and exercised for 4 hours (Water), IL-6 concentration and SAA2 concentration in the blood were increased as compared with animals in the non-exercise group (“Sedentary” or “Sed”). (FIGS. 11 and 12). From the results, it was found that inflammation was induced by exercise for 4 hours. In the group ("Ser 1.0 g / kg" or "Ser") to which the L-serine aqueous solution was administered and exercised for 4 hours, the blood IL-6 concentration and the SAA2 concentration were decreased.
FIG. 13 shows the measurement results of the IL-6 gene expression level in the jejunum, and FIG. 14 shows the measurement results of the IL-6 gene expression level in the ileum. The IL-6 gene expression level was increased in both the jejunum and ileum in the group to which water was administered and exercised for 4 hours (Water) as compared to the animals in the non-exercise group (Sedentary). From this result, it was found that inflammation was induced in the small intestine by exercise for 4 hours. In the group (Ser 1.0 g / kg) in which the L-serine aqueous solution was administered and exercised for 4 hours, the expression level of the IL-6 gene was decreased in both the jejunum and the ileum.
From the above results, it became clear that serine has an effect of suppressing inflammation of the digestive tract.

Example 8 Effect of Combination of Serine and Other Amino Acids A 7-week-old male CD2F1 mouse (Charles River Japan) was treated with water, an aqueous L-serine solution (dose: 0.5 g / kg body weight), L-serine ( Dose: 0.25 g / kg body weight) and an aqueous solution of L-histidine hydrochloride (dose: 0.25 g / kg body weight), or L-serine (dose: 0.25 g / kg body weight) and L-arginine hydrochloride ( Aqueous solution (dose: 0.25 g / kg body weight) was administered, and 30 minutes later, the vehicle was run in a rotating car for 4 hours (speed: 10.5 m / min).
After running, FD4 was orally administered at a dose of 500 mg / kg body weight, and blood was collected after one hour. Cani et al. , Gut 2009, 58 (8): 1091-1103, by calculating the concentration of FD4 leaked from the gastrointestinal tract into the blood by measuring the fluorescence intensity in the blood, the gastrointestinal tract permeability of FD4 is calculated. Was evaluated. The specific measuring method is the same as in the first embodiment.
After running, plasma was collected and the concentration of IL-6 in the blood was measured using the Mouse IL-6 ELISA Ready-SET-Go! (EBioscience).
FIG. 15 shows the evaluation results of the gastrointestinal tract permeability of FD4, and FIG. 16 shows the measurement results of the IL-6 concentration in blood. From these results, it is clear that the effect of improving the decrease in gastrointestinal barrier function and the effect of suppressing gastrointestinal inflammation are higher when histidine or arginine is used in combination than when serine is administered alone. It became.

Example 9 Combined effect of L-histidine and fat-soluble antioxidant In the same manner as in Example 8, the effect of combined use of L-histidine and a fat-soluble antioxidant (chlorogenic acid) was examined.
The group (Ex-His + chlorogenic acid), which was administered with an aqueous solution of L-histidine hydrochloride (dose: 0.5 g / kg body weight) and chlorogenic acid (dose: 50 mg / kg body weight), was treated with L-histidine hydrochloride (dose: 0.5 mg / kg body weight). A group (Ex-His 0.5 g / kg) exercised by administering an aqueous solution and a group exercised by administering an aqueous solution of chlorogenic acid (dose: 50 mg / kg body weight). Compared with Ex-chlorogenic acid), an increase in blood FD4 concentration was suppressed (FIG. 17). From these results, it was clarified that the effect of alleviating exercise-induced decrease in gastrointestinal barrier function was higher when histidine and a fat-soluble antioxidant were used together than when they were both used alone. .

The composition of the present invention is suitably used for improving gastrointestinal disorders. In particular, the compositions of the present invention are effectively used to improve exercise-induced gastrointestinal disorders.
In one aspect, the composition of the present invention is suitably used for maintaining the condition of an athlete during training. In particular, it has been suggested that the gastrointestinal barrier function is reduced during high-intensity and long-term exercise in a hot environment, and it can be used as a composition for protecting athletes' health during daily practice and games.

  This application is based on a patent application No. 2014-093417 filed in Japan (filing date: April 30, 2014), the contents of which are incorporated in full herein.

Claims (10)

  Exercise-induced, containing as active ingredients at least one selected from the group consisting of (i) histidine, (ii) valine, leucine and isoleucine, (iii) a chlorogenic acid compound, and (iv) an α-lipoic acid compound. Oral composition for ameliorating gastrointestinal barrier function lowering in rats.   2. The composition according to claim 1, comprising valine, leucine and isoleucine as active ingredients.   The composition according to claim 1, comprising at least one selected from the group consisting of histidine, a chlorogenic acid compound and an α-lipoic acid compound as an active ingredient.   2. The composition according to claim 1, comprising histidine, valine, leucine and isoleucine as active ingredients.   The composition according to claim 1, further comprising arginine.   The composition according to any one of claims 1 to 5, wherein the content of the active ingredient is 0.1 to 100 g per unit intake of human.   The composition according to any one of claims 1 to 6, which is taken at least once before starting exercise.   The composition according to any one of claims 1 to 6, which is taken during or immediately after exercise.   The composition according to any one of claims 1 to 6, which is ingested at least once before the start of exercise, and at least once during or immediately after the end of exercise.   A food containing the composition according to claim 1.