JP6693413B2 - Composition for improving digestive tract disorders - Google Patents

Description

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

  The digestive tract not only digests and absorbs ingested food, but also has a barrier function to prevent 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, causes inflammation, and causes not only a disorder of the digestive tract but also a general deterioration of physical condition. In severe cases, bacteria may migrate to the organs, resulting in multiple organ failure. Such a decrease in the barrier function of the digestive tract is caused by vigorous exercise (Non-Patent Document 1). The decline in gastrointestinal function during exercise has some similarities to Crohn's disease, ulcerative colitis, and stress-related diseases, but the detailed mechanism remains unclear. At present, it is considered that during exercise, blood collects in muscles and hearts, the supply of blood to the digestive tract is reduced, and physiological functions peculiar to exercise such as an increase in body temperature reduce the barrier function. Maintaining the gastrointestinal barrier function is important for athletes because this decrease in barrier function leads to deterioration in athletes' condition and performance.

  Bovine colostrum, glutamine, and arginine have been reported to improve exercise-induced gastrointestinal barrier impairment. In bovine colostrum, it has been reported that growth tolerance factors such as TGF-1 contained therein increase the stress tolerance of the intestinal tract (Patent Document 1). Cow's colostrum is precious and lacks versatility. In addition, it has been reported that ingestion of amino acids such as glutamine and arginine for one week alleviates the exercise-induced decrease in gastrointestinal barrier function (Non-patent Documents 2 and 3).

Japanese Patent Publication No. 2002-513544

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

  Non-Patent Documents 2 and 3 require long-term intake of glutamine and arginine, which is cumbersome to use during exercise. Further, glutamine has low stability in an aqueous solution and its use is limited. An object of the present invention is to provide an ameliorating agent for gastrointestinal tract disorders, which can exert an improvement effect equal to or higher than that of the prior art against gastrointestinal tract disorders including deterioration of digestive tract barrier function, and which can be easily taken. It is in.

  As a result of intensive studies to solve the above-mentioned object, the present inventors have found that histidine, serine, branched chain amino acids (leucine, isoleucine, valine), amino acids and fat-soluble antioxidants are useful materials for improving gastrointestinal disorders. This has 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 book" Also referred to as "the composition of the invention").
(2) The composition according to (1), which contains serine as an active ingredient.
(3) The composition according to (1) or (2), wherein the gastrointestinal tract disorder is at least one selected from reduced gastrointestinal barrier function, 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 intake amount of human.
(6) The composition according to any one of (2) to (5), further containing 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) contains at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient,
The composition according to (1), wherein the digestive tract disorder is exercise-induced decrease in digestive tract barrier function.
(9) contains at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine as an active ingredient,
The composition according to (1), wherein the digestive tract disorder is exercise-induced decrease in digestive tract barrier function.
(10) The composition according to (8) or (9), which contains valine, leucine and isoleucine as active ingredients.
(11) The composition according to (9), which contains serine and histidine as active ingredients.
(12) The composition according to (8) or (9), which contains 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), which further contains arginine and / or serine.
(15) The composition according to (9), which contains serine, valine, leucine and isoleucine as active ingredients.
(16) The composition according to (9), which contains 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 amount of human.
(18) The composition according to any one of (8) to (17), which is ingested at least once before the start of exercise.
(19) The composition according to any one of (8) to (17), which is taken during exercise or immediately after the end of exercise.
(20) The composition according to any one of (8) to (17), which is ingested at least once before the start of exercise and at least once during or immediately after the end of exercise.
(21) A food or drug containing the composition according to any one of (1) to (20).
(22) The composition according to any one of (1) to (20), and the statement that the composition can be or should be used for improving gastrointestinal disorders. Including commercial packages.
(23) A composition containing at least one selected from the group consisting of serine, histidine, valine, leucine, isoleucine and a fat-soluble antioxidant as an active ingredient is orally administered to a subject in need thereof at least once. A method for improving gastrointestinal disorders, including:
(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 digestive tract disorder is at least one selected from reduced digestive tract barrier function, digestive tract 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 intake amount of human.
(28) The method according to any one of (24) to (27), wherein the composition further contains 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 digestive tract disorder is exercise-induced decrease in digestive 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 digestive tract disorder is exercise-induced decrease in digestive 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 the active ingredient in an amount of 0.1 to 100 g per unit dose of human intake.
(40) The method according to any one of (30) to (39), wherein the composition is ingested at least once before the start of exercise.
(41) The method according to any one of (30) to (39), wherein the composition is ingested during exercise or immediately after the end of 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 the exercise or immediately after the end of the exercise.

The composition of the present invention is preferably used for improving gastrointestinal disorders. In particular, the composition of the present invention is effectively used for ameliorating exercise-induced gastrointestinal disorders.
As one aspect, the composition of the present invention is suitably used for maintaining the condition of an athlete during training. Among other things, 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 highly advantageous because it is highly safe and has few side effects.

It is a schematic diagram which shows a fall of a digestive tract barrier function. LPS: lipopolysaccharide. An outline of the experimental method of Example 1 and the like is shown. It is a schematic diagram of an evaluation method such as Example 1. We show the effects of amino acids and carbohydrates on exercise-induced decline 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. The effect of the branched chain amino acid on the exercise-induced deterioration of the gastrointestinal barrier function is shown. 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. 2 shows the effects of α-lipoic acid and chlorogenic acid on exercise-induced deterioration of gastrointestinal barrier function. Sedentary: non-exercise group, CMC-Na: 0.5% carboxymethylcellulose solution, α-lipoic acid: α-lipoic acid, chlorogenic acid: chlorogenic acid. Fig. 7 shows the effect of combined use of histidine and other amino acids on exercise-induced decline in gastrointestinal barrier function. Sedentary: non-exercise group, Water: water, 0.5 g / kg His: L-histidine hydrochloride aqueous solution, 0.25 g / kg Arg + 0.25 g / kg His: L-arginine hydrochloride and L-histidine hydrochloride aqueous solution, 0.25 g / kg His + 0.25 g / kg Ser: an aqueous solution of L-serine and L-histidine hydrochloride. The effect of serine on exercise-induced reduction in gastrointestinal barrier function is shown. Water: water, Ser: L-serine, Gly: glycine. The effect of serine on the exercise-induced decrease in digestive tract 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. Fig. 3 shows the effect of serine on exercise-induced decline in gastrointestinal barrier function (measurement result of blood endotoxin concentration). Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. The effect of serine on the inflammation of the digestive tract (measurement result of IL-6 concentration in blood) is shown. Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. The effect of serine on inflammation of the digestive tract (measurement result of SAA2 concentration in blood) is shown. Sed: non-exercise group, Water: water, Ser: L-serine aqueous solution. The effect of serine on inflammation of the digestive tract (result of 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 the inflammation of the digestive tract (result of measurement of IL-6 gene expression level in the ileum) is shown. Sedentary: non-exercise group, Water: water, Ser 1.0 g / kg: L-serine aqueous solution. Fig. 7 shows the effect of combined use of serine and other amino acids on exercise-induced decline in digestive tract barrier function (measurement result of FD4 concentration in blood). Sedentary: Non-exercise group, Water: Water, Ser: L-serine aqueous solution, Ser + His: L-serine and L-histidine hydrochloride aqueous solution, Ser + Arg: L-serine and L-arginine hydrochloride aqueous solution. Fig. 7 shows the effect of combined use of serine and other amino acids on exercise-induced decline in gastrointestinal barrier function (measurement result of IL-6 concentration in blood). Sedentary: Non-exercise group, Water: Water, Ser: L-serine aqueous solution, Ser + His: L-serine and L-histidine hydrochloride aqueous solution, Ser + Arg: L-serine and L-arginine hydrochloride aqueous solution. Fig. 7 shows the combined effect of histidine and a fat-soluble antioxidant on exercise-induced decline in gastrointestinal barrier function (Mean ± SEM, n = 3-6). Sedentary: non-exercise 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 tissue damage and functional decline in the digestive tract (pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine), and symptoms caused by them. , For example, a decrease in digestive tract barrier function, digestive tract inflammation, and gastrointestinal upset.

  The transport routes of substances through the gastrointestinal epithelial cells are roughly divided into intracellular (paracellular) and intercellular (paracellular) routes. The intracellular pathway contributes to the absorption of nutrients via 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 absorption of minerals such as calcium, and intestinal bacteria and diet-derived antigens present in large amounts in the lumen. On the other hand, it shows a barrier function that prevents entry into the body. Tight junction is the adhesive molecular structure responsible for this selective permeability. Tight junctions are giant protein complexes that are localized near the brush border membrane of the epithelial cell basolateral membrane, and consist of transmembrane proteins such as occludin and claudin and intracellular lining proteins such as zonula occludens.

  In the present invention, “diminished digestive tract barrier function” means that the barrier between the epithelial cells of the digestive tract is broken, and the permeability of the digestive tract is enhanced to cause foreign substances, enterobacteria or toxins produced by enterobacteria. It is a state in which the body easily enters the body through the digestive tract. It is considered that the decrease in the digestive tract barrier function is caused by, for example, a decrease in blood supply to the digestive tract during exercise. In addition, it is considered that the decrease in the gastrointestinal barrier function is also caused by, for example, an increase in body temperature. FIG. 1 shows a schematic diagram of a decrease in gastrointestinal barrier function.

  The decrease and improvement of the gastrointestinal barrier function means that if the gastrointestinal barrier function is maintained normally, the migration from the gastrointestinal tract to the body is suppressed, but if the gastrointestinal barrier function is decreased, Confirmed by orally administering to the animal a labeled compound having a molecular weight (for example, a molecular weight of about 4000) of such a level that it penetrates the digestive tract and enters the blood, and measures the amount (concentration) of the labeled compound in blood. can do. In the case of human, it can be confirmed by measuring the amount of non-metabolizable sugar molecules such as mannitol, rhamnose and lactulose that permeate the intestinal mucosa.

  In the present invention, “inflammation of the digestive tract” includes any inflammation observed in the digestive tract regardless of the cause or the like. The inflammation may be acute or chronic. Further, it may be accompanied by one or more inflammatory symptoms such as redness, pain, fever and swelling, or may not be accompanied by 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 a decline in gastrointestinal function, for example, stomach pain, nausea, diarrhea, etc. Can be mentioned.

  In the present invention, “exercise-induced gastrointestinal tract disorder” refers to gastrointestinal tract disorder that occurs with exercise (particularly, intense exercise). Here, the “intense exercise” means, for example, long-term exercise, daily exercise, relatively high-intensity exercise, or exercise in a harsh environment such as under high temperature. As a method for determining whether or not the digestive tract disorder is exercise-induced, for example, a significant increase in TNF-α cannot be confirmed, but when the digestive tract disorder occurs, the digestive tract disorder is exercise-induced. It can be determined that there is. Whether or not the digestive tract disorder is exercise-induced can be determined not only from TNF-α but also from, for example, an increase in body temperature, blood deficiency, inflammation (in particular, an inflammation in which TNF-α is not significantly increased). You may decide.

In the present invention, “exercise-induced decrease in digestive tract barrier function” refers to a decrease in digestive tract barrier function that occurs with exercise (particularly intense exercise).
The main cause of "exercise-induced decrease in gastrointestinal barrier function" is increased body temperature and decreased blood flow due to exercise. On the other hand, stress-induced intestinal diseases and inflammatory bowel diseases are caused by inflammation, and it is considered that these are different in mechanism and state from exercise-induced decrease in digestive tract barrier function.

  In the present invention, “exercise-induced inflammation of the digestive tract” refers to inflammation of the digestive tract that occurs with exercise (particularly intense exercise). The term “exercise-induced gastrointestinal upset” refers to a gastrointestinal upset that occurs with exercise (particularly, intense exercise).

In the present invention, “improvement” is meant to include “prevention or treatment”. For example, the exercise-induced decline in barrier function, which is a type of gastrointestinal disorder, will be described as an example of "improvement" of exercise-induced decline in barrier function. Significantly suppresses decrease in nausea, suppresses nausea and decreased digestive ability during or after exercise associated with exercise-induced decrease in gastrointestinal barrier function, and significantly suppresses post-exercise loss of appetite That means to prevent intestinal bacteria and toxins derived from bacteria from entering the body and alleviate the deterioration of physical condition.
In the present invention, "prevention" of gastrointestinal inflammation or gastrointestinal upset means preventing or delaying development of gastrointestinal inflammation or gastrointestinal upset, and "treatment" means gastrointestinal upset. It means reducing the symptoms of inflammation or gastrointestinal upset, or preventing or delaying the progress (exacerbation) of the symptoms.

Amino acids contained as an active ingredient in the composition of the present invention, serine, histidine, valine, leucine and isoleucine can be used in any of L-form, D-form and DL-form, respectively, but preferably , L-form and DL-form, and more preferably L-form.
Further, the amino acid can be used not only in the free form but also in the form of a salt. Examples of the salt form include acid addition salts and salts with bases, and it is preferable to select a pharmacologically acceptable salt.
Examples of serine salts include salts with inorganic bases, salts with inorganic acids, salts with organic acids, and the like. Examples of the salt with an inorganic base include salts with alkali metals such as sodium, potassium and lithium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts and the like. Examples of the salt with an inorganic acid include salts with hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of salts with organic acids 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 histidine salts include salts with inorganic bases, salts with inorganic acids, salts with organic acids, and the like. Examples of the salt with an inorganic base include salts with alkali metals such as sodium, potassium and lithium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts and the like. Examples of the salt with an inorganic acid include salts with hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like. 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 that forms a pharmacologically acceptable salt by adding to 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 acids, tartaric acid, maleic acid, fumaric acid, monomethylsulfate and the like can be mentioned.
Examples of pharmacologically acceptable bases of isoleucine, leucine and valine branched chain amino acids include, for example, metal hydroxides or carbonates such as sodium, potassium and calcium, or inorganic bases such as ammonia; ethylenediamine, propylenediamine, ethanol. Examples thereof include organic bases such as amines, monoalkylethanolamines, dialkylethanolamines, diethanolamines and triethanolamines.

  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 compounds, α-lipoic acid compounds, vitamins. E, astaxanthin and the like can be mentioned, with preference given to chlorogenic acid compounds and α-lipoic acid compounds.

  The chlorogenic acid compound used in the present invention includes 5-caffeoylquinic acid (chlorogenic acid) in which caffeic acid is ester-bonded to the hydroxyl group at the 5-position of quinic acid and derivatives thereof. Examples of the derivative include 4-caffeoylquinoic acid (cryptchlorogenic acid) in which caffeic acid is ester-bonded to the 4-position hydroxyl group of quinic acid, and 3-cafe-caffeic acid is ester-bonded to the 3-position hydroxyl group of quinic acid. Oil quinic acid (neochlorogenic acid), quinic acid decaffeoyl quinic acid (isochlorogenic acid), in which caffeic acid is ester-bonded to any two of the 3-, 4- and 5-position hydroxyl groups, Ferrylquinic acid in which ferulic acid is ester-bonded to any one of 3-, 4-, and 5-position hydroxyl groups, and caffeic acid in any two of 3-, 4-, and 5-position hydroxyl groups of quinic acid And ferulic caffeoylquinic acid in which ferulic acid is ester-bonded to each other. In addition, 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 may be 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-dithiolane-3-pentanoic acid)) and its derivatives. Examples of the derivative include dihydrolipoic acid (6,8-dimercaptooctanoic acid) and the like. In addition, 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 (eg, 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, and it is preferable 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. To 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 at least one selected from the group consisting of serine, histidine, valine, leucine and isoleucine as an active ingredient, and a group consisting of serine, histidine, valine, leucine and isoleucine. A combination of two or more selected from the above may be contained as an active ingredient.

  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 used in any of L-form, D-form and DL-form, but is preferably L-form and DL-form, and further preferably Is an L-body.
Examples of the arginine salt include a salt with an inorganic base, a salt with an inorganic acid, a salt with an organic acid, and the like. Examples of the salt with an inorganic base include salts with alkali metals such as sodium, potassium and lithium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts and the like. Examples of the salt with an inorganic acid include salts with hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like. 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 ingredient and at least one amino acid selected from the group consisting of histidine, valine, leucine and isoleucine as an active ingredient.

As a preferred combination of active ingredients (amino acid, fat-soluble antioxidant),
Serine and histidine; serine and arginine; or two amino acids, histidine and arginine;
Histidine and chlorogenic acid compounds (preferably chlorogenic acid);
Three amino acids, valine, leucine and isoleucine;
Serine, valine, leucine and isoleucine; or four amino acids, histidine, valine, leucine and isoleucine;
There are five amino acids: histidine, serine, valine, leucine and isoleucine.

The content of the active ingredient (amino acid, fat-soluble antioxidant) of the composition of the present invention is determined from the viewpoint of improving effects on digestive tract disorders (eg, exercise-induced decrease in digestive tract barrier function). When applied to, it is preferably 0.1 g or more, more preferably 0.5 g or more, and particularly preferably 1 g or more, per unit intake amount. From the viewpoint of ease of ingestion in actual ingestion, the above 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 into a free form.
The content of the active ingredient, for example, when the composition contains only one selected from the group consisting of serine, histidine, valine, leucine, isoleucine, and a fat-soluble antioxidant, 1 The content of the one component per unit intake amount. When two or more combinations selected from the group consisting of serine, histidine, valine, leucine, isoleucine and fat-soluble antioxidants are contained in the composition as active ingredients, the combination per unit dose is the above-mentioned combination. The total amount of Here, the "single intake unit dose" is an amount that is ingested 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 taken when applied to humans, from the viewpoint of the effect of improving gastrointestinal disorders, The amount is more preferably 50 mg or more, and particularly preferably 100 mg or more. From the viewpoint of ease of ingestion in actual ingestion, the above 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 10% by weight or more, more preferably 20% by weight or more, based on all amino acids in the composition of the present invention. And particularly preferably 50% by weight or more. 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 intake amount when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders, The amount is more preferably 50 mg or more, and particularly preferably 100 mg or more. From the viewpoint of ease of ingestion in actual ingestion, the above 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 10% by weight or more, more preferably 20% by weight or more, based on the total amino acids in the composition of the present invention. And particularly preferably 50% by weight or more. 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 the total amino acids in the composition of the present invention. ..

  The composition of the present invention may contain a mixture of three types of branched chain amino acids of isoleucine, leucine and valine (which may be abbreviated as BCAA in the present invention) as an active ingredient. The mixing ratio of these three kinds of amino acids is usually in the range of isoleucine: leucine: valine = 1: 1.5 to 2.5: 0.8 to 1.7, and particularly preferably 1 :. The range is 1.9 to 2.2: 1.1 to 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 ingestion unit amount when applied to humans, from the viewpoint of the effect of improving gastrointestinal disorders, The amount is more preferably 50 mg or more, and particularly preferably 100 mg or more. From the viewpoint of ease of ingestion in actual ingestion, the above 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 50% by weight or more, more preferably 60% by weight or more, based on all amino acids in the composition of the present invention. And particularly preferably 70% by weight or more. 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 the 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 ingested unit amount when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders. It is above, more preferably 5 mg or more, and particularly preferably 50 mg or more. From the viewpoint of ease of ingestion in actual ingestion, the above 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 per unit ingestion amount when applied to humans from the viewpoint of the effect of improving gastrointestinal disorders. , Preferably 10 mg or more, more preferably 50 mg or more, particularly preferably 100 mg or more. From the viewpoint of ease of ingestion in actual ingestion, the above 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 is usually in the range of histidine: serine or BCAA = 1: 0.1-5 by weight ratio, respectively. Is. When containing serine and BCAA, the ratio of BCAA to serine is usually in the range serine: BCAA = 1: 0.1-5.

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

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

  When the composition of the present invention contains histidine and arginine, the weight ratio of histidine to arginine is usually in the range of histidine: arginine = 1: 0.1 to 10, preferably 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, etc.), the ratio of histidine to the fat-soluble antioxidant is, by weight ratio, usually histidine: fat-soluble antioxidant. The oxidizing agent is in the range of 1: 0.001 to 5, preferably in the range of 1: 0.01 to 2.

  The composition of the present invention can also be used in combination with a therapeutic agent for gastrointestinal ulcer (hereinafter, also 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 digestive system diseases, and specific examples thereof include rebamipide and the like.

  The composition of the present invention can also be used in combination with beneficial 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 can be applied to mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.). When applied to mammals other than humans, the intake amount 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 usually used orally, but can be administered by an administration route such as enteral tube administration or infusion according to the symptoms of the subject. When used orally, the dosage forms include granules, fine granules, powders, coated tablets, tablets, powders, (micro) capsules, chewable tablets, syrups, juices, solutions, suspensions, and emulsions. Etc.

  Preparation into these dosage forms is carried out by formulating into a conventional method. Various pharmacologically acceptable substances for formulation can be blended as required for the formulation. The substance for formulation can be appropriately selected depending on the dosage form of the formulation, for example, excipient, diluent, additive, disintegrant, binder, coating agent, lubricant, glidant, lubricant, flavoring agent. , Flavoring agents, sweetening agents, solubilizing agents, and the like. Furthermore, specific examples of the substances for formulation include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents, For example, sterile water and monohydric or polyhydric alcohols such as glycerol can be mentioned.

  Although the intake or dose of the composition of the present invention varies depending on the symptoms, age, weight or dosage form of the subject, ingestion method or administration method, etc., histidine 0.005 g / kg body weight to 5 g / day per adult. 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 As a standard, 5 g / kg body weight and 0.001 g / kg body weight to 1 g / kg body weight of a fat-soluble antioxidant (eg, chlorogenic acid compound, α-lipoic acid compound, etc.) are used. In the case of a general adult, 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 for an adult. 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, and more preferably Is 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 (eg, 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 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 for an adult. It is kg body weight. The above daily dose can be ingested or administered at once or in several divided doses. The composition of the present invention may be ingested or administered before exercise, after exercise, or during exercise. The timing of ingestion or administration of the composition of the present invention is preferably before the start of exercise, during exercise, or immediately after the end of exercise. Immediately after the end of exercise means within 1 hour after the end of exercise. The number of times of ingestion or administration is at least once. It is more preferable to ingest or administer at least once before the exercise and at least once during or immediately after the exercise. The period of ingestion or administration is not particularly limited, but the composition of the present invention can exert its effect significantly by single administration before exercise.

  The composition of the present invention contains, as an active ingredient, 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.). In such cases, these active ingredients may be contained in the preparation either individually or in any combination, or all of them may be contained in one preparation. The timing of administration of each may be the same or different. When there is a concomitant drug, the timing of administration should be 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 in which each of them is separately prepared and used in combination. In particular, an embodiment in which all active ingredients are contained in the same preparation is preferable because it can be easily administered.

  In the present invention, the “weight ratio” refers to the weight ratio of each component in the preparation. For example, when at least two kinds of active ingredients are included in one preparation, it is the ratio of individual contents, and when each of the active ingredients is included in multiple preparations alone or in any combination. Is the weight ratio of each active ingredient included in each formulation.

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

Furthermore, the composition of the present invention can be used by adding it to various foods. When it is added to foods, there is no limitation other than adding the composition of the present invention, and any ordinary diet form may be used. For example, a suitable flavor may be added to give a drink, for example, a soft drink or a powdered drink. Specifically, for example, it can be added to juice, milk, confectionery, jelly, yogurt, candy and the like to be eaten and drinked.
It is also possible to provide a food to which such a composition of the present invention is added as a food with health claims or a dietary supplement. The food with health claims also includes foods for specified health uses and foods with nutritional claims. The food for specified health use is a food that can indicate that a specific health purpose, such as improvement of digestive tract disorders, can be expected. In addition, a nutritionally functional food is a food that can display the function of the nutritional component when the amount of the nutritional component contained in the daily intake standard amount conforms to the standard criteria of the upper and lower limits set by the country. .. Dietary supplements include so-called nutritional supplements or health supplements. In the present invention, the food for specified health uses a food with a label indicating that it is used for gastrointestinal disorders, and further, a document stating that it is used for such a purpose (so-called efficacy statement), etc. Foods that include as a package are also included.

  Furthermore, the composition of the present invention can be used by adding it to a concentrated liquid food or a food supplement. When it is added to a food supplement, it can be prepared together with other components in the form of tablets, capsules, powders, granules, suspensions, chewable preparations, syrups and the like. The food supplement in the present invention refers to those ingested for the purpose of supplementing nutrition in addition to those ingested as a food, and includes nutritional supplements and supplements.

  In addition, "concentrated liquid food" is adjusted to a concentration of about 1 kcal / ml, and the qualitative composition of each nutrient is carefully considered so that no significant nutrient excess or deficiency will occur even after long-term single intake. It is a comprehensive nutrition food (liquid food) designed based on the nutritional requirement of.

  The composition of the present invention can be in unit packaging 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, for example, 1 The unit packaging form in which the unit dose is one unit is referred to as "unit packaging form per unit dose". The packaging used in the unit packaging form may be appropriately selected depending on the form of the composition and the like, and examples thereof include a paper container, a plastic container, an aluminum can, a steel can, a glass bottle, a PET bottle, a PTP sheet and the like.

  In the present invention, a digestive tract disorder (eg, 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 composition for improving gastrointestinal tract disorders, etc., can be or should be used for improving gastrointestinal disorders (eg, exercise-induced gastrointestinal barrier function deterioration). Also included are commercial packages containing the written material.

The composition of the present invention can improve gastrointestinal disorders by orally administering to a subject in need thereof at least once. In particular, the composition of the present invention can effectively ameliorate exercise-induced gastrointestinal disorders.
In addition, the composition of the present invention, by orally administering at least once to a subject in need thereof, reduces the digestive tract barrier function, digestive tract (preferably small intestine (duodenum, jejunum, ileum)) inflammation, and Can improve gastrointestinal upset. Among other things, the composition of the present invention can effectively ameliorate exercise-induced 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 preferably 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, a decrease in digestive tract barrier function (preferably exercise-induced It is particularly preferably used for improving the digestive tract barrier function deterioration).

The present invention includes gastrointestinal disorders (eg, gastrointestinal barrier function deterioration, gastrointestinal irritation, gastrointestinal upset, etc.), which comprises orally administering the composition of the present invention to a subject in need thereof at least once. The improvement method of is also provided.
The present invention also provides a method for improving exercise-induced gastrointestinal tract disorder, which comprises orally administering the composition of the present invention to a subject in need thereof at least once.
These methods may exclude medical intervention. Here, the "medical act" refers to an act of treating, operating or diagnosing a human being performed by a doctor or a dentist or under the supervision of a doctor or a 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 on Improving Exercise-Induced Reduction of Gastrointestinal Barrier Function A polymeric substance that is not normally absorbed from the digestive tract permeates the intestine and enters the blood when the gastrointestinal barrier function is reduced. It is known to go on (Fig. 1). Therefore, the effect of improving the exercise-induced decrease in digestive tract barrier function of amino acids was examined in the following tests.
A 7-week-old male CD2F1 mouse (Charles River Japan Co., Ltd.) was administered with an aqueous solution of various amino acids or a salt thereof at a dose of 1 g / kg body weight, and 30 minutes after that, the vehicle was run for 4 hours in a rotating car (speed 10. 5 m / min). After the 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 1 hour later (FIG. 2). Cani et al. , Gut 2009, 58 (8): 1091-1103, the FD4 concentration leaked from the gastrointestinal tract into the blood was calculated by measuring the fluorescence intensity in the blood to determine the gastrointestinal permeability of FD4. Was evaluated (FIG. 3). Specifically, blood was collected from a mouse under isoflurane anesthesia. Blood was centrifuged to obtain plasma. After that, 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 (measuring instrument SPECTRA MAX GEMINI EM Molecular Device Japan).
The results are shown in FIG. In the group (Water) in which water was administered and exercise was performed for 4 hours, the FD4 concentration in blood was increased as compared with the animals in the non-exercise group (Sed). From this result, it was confirmed that the gastrointestinal barrier function was deteriorated by running for 4 hours, and a large amount of high-molecular weight substances flowed into the blood. In the group (CHO) in which the carbohydrate maltodextrin was administered at a dose of 1 g / kg body weight, it was found that ingestion of carbohydrate did not improve the gastrointestinal barrier function since the FD4 concentration in blood was not decreased. On the other hand, since the FD4 concentration was decreased in the L-histidine hydrochloride-administered group (HisHCL), it was found that histidine suppressed exercise-induced decrease in digestive tract 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 improving exercise-induced decrease in digestive tract barrier function The effects of various amino acids on exercise-induced decrease in digestive tract barrier function were examined in the same manner as in Example 1.
Branched chain amino acids (L-leucine, L-isoleucine, L-valine = 2: 1: 1) dispersed with 0.5% carboxymethylcellulose (CMC-Na) as a solvent were administered at 1 g / kg body weight and exercised. In the group (BCAA, Ex), the FD4 concentration in blood was significantly decreased as compared with the group (CMC-Na, Ex) in which only the solvent was administered and exercised (FIG. 5). From this result, it was confirmed that BCAA has the effect of improving exercise-induced gastrointestinal barrier function.

Example 3 Effect of a-lipoic acid and chlorogenic acid on improving exercise-induced decline in gastrointestinal barrier function Except that the nail of a mouse was cut short in order to prevent an injury in which the toenail is peeled off during running In the same manner as in 1, the effect of α-lipoic acid and chlorogenic acid on the exercise-induced decrease in gastrointestinal barrier function was examined.
A group (α-lipoic acid) in which α-lipoic acid dispersed in 0.5% carboxymethylcellulose (CMC-Na) as a solvent was administered at 80 mg / kg body weight, and 0.5% carboxymethylcellulose (CMC) In a group (chlorogenic acid) in which chlorogenic acid dispersed in a solvent of -Na) was administered at 50 mg / kg body weight and exercised (CMC-Na), compared with a group in which only solvent was administered 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 a relaxing effect on exercise-induced reduction in gastrointestinal barrier function.

Example 4 Combined effect of histidine and other amino acids In the same manner as in Example 3, the combined effect of L-histidine and other amino acids was examined.
L-serine (dose: 0.25 g / kg body weight) and L-histidine hydrochloride (dose: 0.25 g / kg body weight) aqueous solution administered to exercise group (0.25 g / kg His + 0.25 g / kg) Ser) and a group (0.25 g) that was 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) that was exercised by administering an aqueous solution of L-histidine hydrochloride (dose: 0.5 g / kg body weight) in blood. The increase in FD4 concentration was suppressed (Fig. 7). From these results, it was clarified that the effect of alleviating the exercise-induced deterioration of the gastrointestinal barrier function was higher 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 Deterioration In the same manner as in Example 1, the effect of L-serine and glycine on the exercise-induced decrease of gastrointestinal barrier function was examined. As a result, in the group in which L-serine was administered at 1 g / kg body weight and exercised, the blood FD4 concentration was significantly reduced compared to the group in which water was administered and exercised. On the other hand, a decrease in blood FD4 concentration was not seen in the group in which glycine was administered at a dose of 1 g / kg body weight and exercised (FIG. 8). From these results, it was confirmed that serine has an effect of alleviating exercise-induced deterioration of digestive tract barrier function.

Example 6 Effect of Serine on Improving Digestive Tract Barrier Function Decrease 7-week-old male CD2F1 mice (Charles River Japan Co., Ltd.) were administered water or an L-serine aqueous solution (dose: 1 g / kg body weight), and After 30 minutes, the vehicle was 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 1 hour later (FIG. 2). The group that did not run after water administration (Sed) was fasted and water-free as in the running group. Cani et al. , Gut 2009, 58 (8): 1091-1103, the FD4 concentration leaked from the gastrointestinal tract into the blood was calculated by measuring the fluorescence intensity in the blood to determine the gastrointestinal permeability of FD4. Was evaluated (FIG. 3). The specific measuring method is the same as that of the first embodiment. Moreover, the endotoxin concentration in plasma was measured using a Toxinometer (registered trademark) ET-6000 (Wako Pure Chemical Industries, Ltd.).
FIG. 9 shows the results of evaluation of gastrointestinal permeability of FD4. In the group (Water) in which water was administered and exercise was performed for 4 hours, the FD4 concentration in blood was higher than that in the non-exercise group (Sedentary). From this result, it was confirmed that the digestive tract barrier function was lowered by the exercise for 4 hours, and a large amount of FD4, which was 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 FD4 concentration in blood was decreased, and therefore L-serine was induced by exercise. It was found that the reduction of the tube barrier function was suppressed.
Moreover, the measurement result of the endotoxin concentration in plasma is shown in FIG. As shown in FIG. 10, the blood concentration of endotoxin, which is one of the toxins, was increased in the group (Water) in which water was administered and exercise was performed for 4 hours, but L-serine aqueous solution was administered. No increase was observed in the group (Ser 1.0 g / kg) that had been exercised for 4 hours.
From the above results, it was clarified that serine improves the deterioration of digestive tract barrier function.

Example 7 Effect of Serine on Inhibition of Gastrointestinal Inflammation In the same manner as in Example 6, 7-week-old male CD2F1 mice (Charles River Japan Co., Ltd.) were treated with water or an aqueous L-serine solution (dose: 1 g / kg body weight). ) Was administered, and 30 minutes after that, 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 the serum amyloid A (SAA2) concentration in the blood were calculated as 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 mice after running, and the expression level of IL-6 gene in the small intestine (jejunum, ileum) was measured by the 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 in which water was administered and exercise was performed for 4 hours (Water), the IL-6 concentration in blood and the SAA2 concentration were increased as compared with the animals in the non-exercise group (“Sedentary” or “Sed”). (FIGS. 11 and 12). From this result, it was found that inflammation was caused by 4 hours of exercise. In the group in which the L-serine aqueous solution was administered and exercised for 4 hours (“Ser 1.0 g / kg” or “Ser”), the IL-6 concentration and SAA2 concentration in blood 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. In the group (Water) in which water was administered and exercise was performed for 4 hours, the IL-6 gene expression level was increased in both jejunum and ileum, as compared with the animals in the non-exercise group (Sedentary). From this result, it was revealed that the 4-hour exercise causes inflammation in the small intestine. In the group in which the L-serine aqueous solution was administered and exercised for 4 hours (Ser 1.0 g / kg), the IL-6 gene expression level was decreased in both jejunum and ileum.
From the above results, it became clear that serine has an effect of suppressing inflammation of the digestive tract.

Example 8 Combined effect of serine and other amino acids 7-week-old male CD2F1 mice (Charles River Japan, Inc.) were treated with water, L-serine aqueous solution (dose: 0.5 g / kg body weight), L-serine ( Dose: 0.25 g / kg body weight) and L-histidine hydrochloride (dose: 0.25 g / kg body weight) in water, or L-serine (dose: 0.25 g / kg body weight) and L-arginine hydrochloride ( An aqueous solution (dosage: 0.25 g / kg body weight) was administered, and 30 minutes after that, the vehicle was run in a rotating car for 4 hours (speed 10.5 m / min).
After the running, FD4 was orally administered at a dose of 500 mg / kg body weight, and blood was collected 1 hour later. Cani et al. , Gut 2009, 58 (8): 1091-1103, the FD4 concentration leaked from the gastrointestinal tract into the blood was calculated by measuring the fluorescence intensity in the blood to determine the gastrointestinal permeability of FD4. Was evaluated. The specific measuring method is the same as that of the first embodiment.
In addition, plasma was collected after the end of running, and the IL-6 concentration in blood was determined by Mouse IL-6 ELISA Ready-SET-Go! (EBioscience).
FIG. 15 shows the evaluation results of FD4 gastrointestinal permeability, and FIG. 16 shows the measurement results of IL-6 concentration in blood. From these results, it is clear that the effect of improving the deterioration of the gastrointestinal barrier function and the effect of suppressing inflammation of the gastrointestinal tract are higher when the histidine or arginine is used in combination than when serine is administered alone. Became.

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

The composition of the present invention is preferably used for improving gastrointestinal disorders. In particular, the composition of the present invention is effectively used for ameliorating exercise-induced gastrointestinal disorders.
As 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 digestive tract barrier function deteriorates during high-intensity, long-time exercise in a hot environment, and it can be used as a composition that protects the health of athletes during daily practice and competition.

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

Claims (14)

  An oral composition for improving exercise-induced gastrointestinal disorders, which comprises serine as an active ingredient.   The composition according to claim 1, further comprising at least one selected from the group consisting of histidine, valine, leucine, isoleucine and a fat-soluble antioxidant.   The exercise-induced gastrointestinal tract disorder is at least one selected from exercise-induced gastrointestinal barrier function deterioration, exercise-induced gastrointestinal inflammation and exercise-induced gastrointestinal upset. Composition.   The composition according to any one of claims 1 to 3, wherein the content of serine is 10 mg to 10 g per unit intake amount of human.   The composition according to any one of claims 1 to 4, further comprising at least one selected from the group consisting of histidine, arginine and a fat-soluble antioxidant.   The composition according to any one of claims 1 to 5, wherein the content of serine is 50% by weight or more based on all amino acids in the composition.   The composition according to any one of claims 1 to 6, which contains serine and histidine as active ingredients.   The composition according to any one of claims 1 to 7, which contains serine, valine, leucine and isoleucine as active ingredients.   The composition according to any one of claims 1 to 8, which contains histidine, serine, valine, leucine and isoleucine as active ingredients.   The composition according to any one of claims 1 to 9, wherein the content of the active ingredient is 0.1 to 100 g per unit dose of human ingestion.   The composition according to any one of claims 1 to 10, which is ingested at least once before the start of exercise.   The composition according to any one of claims 1 to 10, which is ingested during exercise or immediately after the end of exercise.   The composition according to any one of claims 1 to 10, which is ingested at least once before the start of exercise and at least once during the exercise or immediately after the end of the exercise. A food for improving exercise-induced gastrointestinal tract disorder, which comprises the composition according to any one of claims 1 to 13.