JP2016172722A - Nutritional composition beneficial to small intestine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compositions useful for the maintenance and improvement of intestinal function.SOLUTION: The invention provides a composition containing milk proteins selected from casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin, lactoferrin, and the like, and fermented milk-derived proteins derived from fresh cheese and the like, as protein, oil and fats as a lipid, and isomaltulose as a carbohydrate; and having a promoting effect of villus growth of the small intestine.SELECTED DRAWING: None

Description

  The present invention relates to a composition useful for improving intestinal tract function, comprising a hydrolyzate of milk protein, fermented milk-derived protein, lipid, and carbohydrate.

Increasing incidence of lifestyle-related diseases in recent years has an important relationship with dietary habits. In order to maintain and promote health, it is important to take necessary nutrients, and it is desirable to maintain normal intestinal function in order to efficiently digest and absorb the nutrients. However, in reality, intestinal dysfunction such as constipation and diarrhea caused by disordered lifestyles, irregular eating habits, mental disorders such as fear, sadness, and fear are caused. Furthermore, the persistence of these abnormal intestinal tracts causes diseases such as intestinal diseases and cancer. So far, bifidobacteria exhibiting an effect of improving intestinal tract function, yogurt using lactic acid bacteria (probiotics) such as Lactobacillus, and fermented beverages have been widely used as foods. In addition, oligosaccharides that help the growth of useful microorganisms in the intestinal tract and foods having an intestinal function such as dietary fiber are also widely used. Although such foods are known to have the effect of regulating the intestinal environment alone, it is unlikely that they have a function of promoting growth and repair of the small intestinal mucosa, and development of such foods is desired. .
From a clinical point of view, intestinal resection, irradiation, intestinal ischemia and trauma, Crohn's disease, ulcerative colitis, etc. are considered as pathological conditions in which the functional surface area of the small intestine decreases. For such pathological conditions, treatment for repairing the damaged small intestinal mucosa and enhancing the compensation function is necessary. Specific nutrients such as glutamine, n-3 polyunsaturated fatty acids and zinc have been found to be important. In addition, in order to promote metabolism / endocrine adaptation ability as an intestinal metabolic response ability and to promote proliferation / repair ability of the intestinal mucosa, it is essential to supply and administer nutrients through the intestinal lumen, and physiological such as bile and pancreatic juice secretion It is premised on the passage of intestinal contents. Nutrition can be replenished with central venous nutrition, high-calorie infusion, complete venous nutrition, or the like, but atrophy of the small intestinal mucosa often occurs, leading to a decrease in intestinal tract function. Therefore, the development of drugs and foods that are good for the intestinal tract has been desired. A variety of enteral nutritional foods have been developed, and foods containing dietary fiber that have an intestinal regulating action have been developed, but so far the growth of the small intestinal villi, the increase in the thickness of the intrinsic muscle layer, etc. Drugs and comprehensive nutritional foods useful for maintaining and improving intestinal function have not been developed.

WO 2004/047556 JP2004-99563

  An object of the present invention is to provide a composition useful for maintaining and improving intestinal tract function. Alternatively, the present invention provides a composition for promoting villi growth in the small intestine, a composition for increasing the intrinsic muscle layer thickness of the small intestine, a composition for improving intestinal function, and preventing tissue damage in the small intestine. An object of the present invention is to provide a composition for the above or an anti-inflammatory composition.

Using the mouse ConA-induced hepatitis model, the present inventors prepared and examined tissue samples for cytokine production and small intestinal disorders in the small intestine and spleen for the nutritional composition intake group and the general liquid food intake group of the present invention. did. In addition to the production of TNF-α and IL-6 as cytokines, the production of MCP-1 which is a chemokine was examined. As a result, in the nutritional composition intake group of the present invention, in addition to suppressing the increase in cytokine production in the liver and plasma, the effect of suppressing the increase in MCP-1 and IL-6 production in the small intestine and spleen was confirmed. Furthermore, it was revealed that tissue damage of the small intestine was reduced (Examples 1 and 2).
From this result, it was inferred that taking the nutritional composition of the present invention caused some change in the intestinal tract, and the small intestine weight and large intestine weight of normal mice after 2 weeks of intake were measured. In addition, small intestine tissue specimens were prepared and evaluated. As a result, a significant increase in the weight of the small intestine and the weight of the large intestine was shown. In addition, as a result of evaluating the small intestine tissue, there was no difference in the number of villi, but the average length of villi and the thickness of the intrinsic muscle layer were significantly higher than the control group. From these results, it was shown that they have a protective action against disorders of the small intestine and a growth promoting action of the small intestinal mucosa epithelium and muscle layer (Example 3).
Furthermore, the present inventors have used a rat indomethacin-induced small intestinal injury model, and the urinary excretion rate of phenolsulfonephthalein as an index of intestinal permeability for the nutritional composition intake group and the general liquid food group of the present invention. I investigated. We also examined bacterial translocation to the liver and mesenteric lymph nodes (also called Bacterial Translocation) and general blood tests. As a result, in the nutritional composition intake group of the present invention, it was shown that the increase in permeability of the mesentery was suppressed, and that bacterial translocation to the liver and mesenteric lymph nodes was suppressed. . Furthermore, the results of general blood tests showed that the nutritional composition intake group suppressed the increase in the number of neutrophils and monocytes in the blood associated with small intestinal disorders caused by indomethacin administration. From the above results, the intake of the nutritional composition has the effect of protecting the intestinal tract and suppressing the small intestine damage to drugs such as non-steroidal anti-inflammatory drugs, and is also induced by bacterial translocation caused by the intestinal damage It was effective in preventing infectious diseases such as sepsis and pneumonia, and was shown to have an effect of maintaining the immune system normally (Example 4).

  In addition, the present inventors examined which components are involved in the hepatic inhibitory action, protective action against small intestinal disorders and maintenance of intestinal tract function of the obtained nutritional composition using a mouse ConA-induced hepatitis model. As a result, it was shown that whey protein hydrolyzate, isomaltulose and quark are involved in maintaining intestinal function (Example 5). In addition, it was shown that whey protein hydrolyzate and quark are mainly involved in the hepatitis inhibitory action (Example 6).

This application provides the following invention based on this knowledge.
[1] A composition for promoting villous growth in the small intestine, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, fats and oils as lipids, and isomaltulose as a carbohydrate.
[2] Group of milk protein consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to [1], which is more selected.
[3] The composition according to [1] or [2], wherein the protein derived from fermented milk is derived from fresh cheese.
[4] A composition for increasing the thickness of the intrinsic muscle layer of the small intestine, comprising a milk protein hydrolyzate and a protein derived from fermented milk as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate.
[5] Group of milk protein consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to [4], which is selected from the above.
[6] The composition according to [4] or [5], wherein the protein derived from fermented milk is derived from fresh cheese.
[7] A composition for improving intestinal tract function, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, fats and oils as lipids, and isomaltulose as a carbohydrate.
[8] The milk protein is a group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin. [7] The composition according to [7].
[9] The composition according to [7] or [8], wherein the protein derived from fermented milk is derived from fresh cheese.
[10] A composition for preventing tissue damage in the small intestine, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, fats and oils as lipids, and isomaltulose as a carbohydrate.
[11] The group wherein the milk protein is casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin [10] The composition according to [10].
[12] The composition according to [10] or [11], wherein the fermented milk-derived protein is derived from fresh cheese.
[13] An anti-inflammatory composition comprising a milk protein hydrolyzate and fermented milk-derived protein as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate.
[14] The group wherein the milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin [13] The composition according to [13].
[15] The composition according to [13] or [14], wherein the protein derived from fermented milk is derived from fresh cheese.
[16] A method for promoting small intestinal villus growth, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, a fat and oil as a lipid, and isomaltulose as a carbohydrate.
[17] Increasing the thickness of the intrinsic muscle layer of the small intestine, comprising the step of administering a hydrolyzate of milk protein and protein derived from fermented milk as protein, fat and oil as lipid, and isomaltulose as carbohydrate How to make.
[18] A method for improving intestinal tract function, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, an oil or fat as a lipid, and isomaltulose as a carbohydrate.
[19] A method for preventing tissue damage in the small intestine, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, a fat and oil as a lipid, and isomaltulose as a carbohydrate.
[20] A method for suppressing inflammation, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, a fat or oil as a lipid, and isomaltulose as a carbohydrate.
[21] Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a sugar in the manufacture of a composition for promoting villi growth in the small intestine .
[22] In the manufacture of a composition for increasing the thickness of the intrinsic muscle layer of the small intestine, a hydrolyzate of milk protein and fermented milk-derived protein as protein, fats and oils as lipid, and isomaltulose as carbohydrate Use of the composition.
[23] Use of a composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate in the manufacture of a composition for improving intestinal tract function.
[24] Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as a lipid, and isomaltulose as a sugar in the manufacture of a composition for preventing tissue damage in the small intestine .
[25] Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate in the manufacture of an anti-inflammatory composition.
[26] A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in a method for promoting villi growth in the small intestine.
[27] A composition containing a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in a method for increasing the thickness of the intrinsic muscle layer of the small intestine object.
[28] A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in the method for improving intestinal function.
[29] A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate for use in a method for preventing tissue damage in the small intestine.
[30] A composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in an inflammation suppression method.
[31] A composition for improving intestinal function, comprising a protein derived from fermented milk.
[32] A composition for improving intestinal function, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk and isomaltulose as a carbohydrate.
[33] The group wherein the milk protein is casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to [32], which is selected from the above.
[34] The composition according to any one of [31] to [33], wherein the protein derived from fermented milk is derived from fresh cheese.
[35] A composition for preventing tissue damage of the small intestine, comprising a protein derived from fermented milk.
[36] A composition for preventing tissue damage of the small intestine, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, and isomaltulose as a carbohydrate.
[37] The milk protein is a group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin [36] The composition described in [36].
[38] The composition according to any one of [35] to [37], wherein the fermented milk-derived protein is derived from fresh cheese.
[39] An anti-inflammatory composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as proteins.
[40] The composition according to [39], further comprising isomaltulose as a saccharide.
[41] The group wherein the milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to [39] or [40], which is selected from the above.
[42] The composition according to any one of [39] to [41], wherein the protein derived from fermented milk is derived from fresh cheese.
[43] A method for improving intestinal tract function, comprising a step of administering a composition comprising a protein derived from fermented milk.
[44] A method for improving intestinal tract function, comprising the step of administering a hydrolyzate of milk protein and a protein derived from fermented milk as protein and isomaltulose as sugar.
[45] The group wherein the milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The method according to [44], wherein the method is selected from:
[46] The method according to any one of [43] to [45], wherein the protein derived from fermented milk is derived from fresh cheese.
[47] A method for preventing tissue damage of the small intestine, comprising a step of administering a composition containing a protein derived from fermented milk.
[48] A method for preventing tissue damage of the small intestine, comprising a step of administering a hydrolyzate of milk protein and a protein derived from fermented milk as a protein and isomaltulose as a carbohydrate.
[49] The group wherein the milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The method according to [48], wherein the method is selected.
[50] The method according to any one of [47] to [49], wherein the protein derived from fermented milk is derived from fresh cheese.
[51] A method for suppressing inflammation, comprising a step of administering a composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein.
[52] The method of [51], wherein the composition further comprises isomaltulose as a carbohydrate.
[53] The group wherein the milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The method according to [51] or [52], which is selected from the above.
[54] The method according to any one of [51] to [53], wherein the protein derived from fermented milk is derived from fresh cheese.
[55] Use of a protein derived from fermented milk in the manufacture of a composition for improving intestinal tract function.
[56] Use of a hydrolyzate of milk protein and a protein derived from fermented milk as a protein and isomaltulose as a sugar in the manufacture of a composition for improving intestinal function.
[57] The group wherein milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The use according to [56], which is more selected.
[58] The use according to any one of [55] to [57], wherein the protein derived from fermented milk is derived from fresh cheese.
[59] Use of a protein derived from fermented milk in the manufacture of a composition for preventing tissue damage in the small intestine.
[60] Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein and isomaltulose as a carbohydrate in the manufacture of a composition for preventing tissue damage in the small intestine.
[61] The group wherein the milk protein is casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The use according to [60], which is more selected.
[62] The use according to any one of [59] to [61], wherein the fermented milk-derived protein is derived from fresh cheese.
[63] Use of a composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as a protein in the manufacture of an anti-inflammatory composition.
[64] The use according to [63], wherein the composition further comprises isomaltulose as a carbohydrate.
[65] The milk protein is a group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The use according to [63] or [64], which is selected from:
[66] The use according to any one of [63] to [65], wherein the protein derived from fermented milk is derived from fresh cheese.
[67] A composition comprising a protein derived from fermented milk for use in a method for improving intestinal tract function.
[68] A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as proteins and isomaltulose as a carbohydrate for use in a method for improving intestinal function.
[69] The group wherein the milk protein comprises casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin [68] The composition according to [68].
[70] The composition according to any one of [67] to [69], wherein the protein derived from fermented milk is derived from fresh cheese.
[71] A composition comprising a protein derived from fermented milk for use in a method for preventing tissue damage in the small intestine.
[72] A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as proteins and isomaltulose as a carbohydrate for use in a method for preventing tissue damage in the small intestine.
[73] The milk protein is a group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin [72] The composition according to [72].
[74] The composition according to any one of [71] to [73], wherein the protein derived from fermented milk is derived from fresh cheese.
[75] A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as proteins for use in an inflammation suppression method.
[76] The composition of [75], further comprising isomaltulose as a saccharide.
[77] The milk protein is a group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to [75] or [76], which is selected from the above.
[78] The composition according to any one of [75] to [77], wherein the protein derived from fermented milk is derived from fresh cheese.

It is the graph which compared the small intestine area. It is a photograph of a small intestine histopathological image (stained with hematoxylin and eosin). It is a photograph of normal small intestine tissue (H · E staining X150 times). It is a graph which shows the PSP urinary excretion rate. Mean ± SE, Student ’s t-test (day 0: n = 9, day 2: n = 9 to 10, day 4: n = 9 to 10, day 8: n = 8). It is the graph which showed the number of bacteria detected in the liver (upper figure) and mesenteric lymph node (lower figure) after indomethacin administration. Mean ± SE, Student ’s t test; *: p <0.05 (day 0: n = 6, day 4: n = 8 to 9, day 8: n = 8). It is a graph which shows the change of the number of blood neutrophils and monocytes after indomethacin administration. Mean ± SD, Student ’s t test; *: p <0.05 (day8: n = 7-8) It is the graph which showed the small intestine weight (upper figure) and cecal weight (lower figure) 24 hours after concanavalin A administration. Mean ± SD, Scheffe test; *: p <0.05 (n = 8-10) SF: general liquid food, ND: nutrition composition, -P: nutrition composition-whey protein hydrolyzate, -PI: nutrition composition -Whey protein hydrolyzate -Isomaltulose, -PIQ: Nutritional composition -Whey protein hydrolysate -Isomaltulose -Quark. It is the graph which showed the AST and ALT activity in plasma 8 hours after concanavalin A administration. Mean ± SD, Mann-Whitney test; *: p <0.05 (n = 5-9)

  The present invention provides a composition for promoting villus growth in the small intestine, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, fats and oils as lipids, and isomaltulose as a carbohydrate.

  Small intestinal villi growth promotes the proliferation of small intestinal epithelial cells. Eventually, villi growth in the small intestine is thought to promote nutrient absorption or promote repair of small intestinal disorders. Therefore, the composition of the present invention can be used as, for example, “small intestinal villous growth agent”, “small intestinal epithelial cell proliferating agent”, “nutrient absorption promoter”, “small intestinal disorder repair promoter”. In addition, the composition of the present invention can improve the function of the small intestine of healthy people, improve the nutrition of the elderly with malnutrition, maintain the intestinal tract function of patients with severe dysfunction (ICU patients) such as respiration, circulation, metabolism, etc. Nutritional supplementation and maintenance of intestinal function in patients with dysphagia with neuropathy, improvement of intestinal function and nutrition for chronic intestinal diseases such as ulcerative colitis and Crohn's disease, malnutrition in chronic obstructive pulmonary disease (COPD) It can be used to improve intestinal tract function and nutritional status, or improve intestinal tract function and nutritional status for patients with intestinal dysfunction caused by antibiotics or anticancer agents such as cancer patients.

  The present invention provides a composition for increasing the thickness of the intrinsic muscle layer of the small intestine, comprising a hydrolyzate of milk protein as protein and a protein derived from fermented milk, fat as fat, and isomaltulose as carbohydrate To do.

  An increase in the thickness of the intrinsic muscle layer of the small intestine is thought to promote peristaltic movement of the small and large intestines. In addition, it is considered that the intestinal regulation action is promoted by the increase in the thickness of the intrinsic muscle layer of the small intestine. Therefore, the composition of the present invention can be used, for example, as an “increase in the thickness of the intrinsic muscle layer of the small intestine”, an “intestinal peristalsis promoter”, or an “enteric agent”. In addition, the composition of the present invention can improve the function of the small intestine of healthy people, improve the nutrition of the elderly with malnutrition, maintain the intestinal tract function of patients with severe dysfunction (ICU patients) such as respiration, circulation, metabolism, etc. Nutritional supplementation and maintenance of intestinal function in patients with dysphagia with neuropathy, improvement of intestinal function and nutrition for chronic intestinal diseases such as ulcerative colitis and Crohn's disease, malnutrition in chronic obstructive pulmonary disease (COPD) It can be used to improve intestinal tract function and nutritional status, or improve intestinal tract function and nutritional status for patients with intestinal dysfunction caused by antibiotics or anticancer agents such as cancer patients.

  This invention provides the composition for improving intestinal tract function containing fermented milk origin protein. Moreover, this invention provides the composition for improving intestinal tract function containing the hydrolyzate and fermented milk origin protein of milk protein as protein, fats and oils as lipid, and isomaltulose as carbohydrate.

  Moreover, this invention provides the composition for improving intestinal tract function containing the hydrolyzate and fermented milk origin protein of milk protein as protein, and isomaltulose as carbohydrate.

Improvement of intestinal tract function means promotion of digestion and absorption of ingested nutrients and promotion of excretion of waste products by peristaltic movement of the intestinal tract. Intestinal dysfunction causes barrier breakdown including weakening of gut-associated lymphoid tissue (GALT), resulting in bacterial translocation (BT), sepsis, etc., leading to a reduction in biological defense functions. Intestinal dysfunction leads to malnutrition as well as poor production and secretion of gastrointestinal hormones and neurotransmitters that regulate biological functions. In the present invention, “intestine” includes both “small intestine” and “large intestine”.
Therefore, the composition for improving the intestinal tract function of the present invention has a digestive absorption promoting action or an intestinal regulating action, and includes, for example, “intestinal tract function improving agent”, “digestive absorption promoting agent”, “intestinal regulating agent”, It can be used as an “excretion promoter” or “intestinal immunity improving agent”.
Intestinal immunity is an immune response that occurs in the intestinal tract. An immune response is also called an immunological response. When an antigen (non-self) enters a living body, the living body produces antibodies that specifically react with the antigen or lymphocytes having a specific immune function (sensitized lymphocytes) to cause various biological reactions. A series of biological reactions that occur in response to antigen invasion is called an immune response.
The gastrointestinal tract is a place where it is easy to come into contact with foreign substances in the outside world, so lymphocytes surround the intestinal tract centering on the small intestine, and viruses in the food that are pathogens and foreign proteins decomposed by digestive enzymes are contained in the intestinal tract. It is captured. The intestinal tract is an important immune system that the organism first evolved to prevent these absorptions. One of the functions of the digestive tract is decreased intestinal immunity. Decreased intestinal immunity is an immune response that eliminates foreign substances such as viruses that have entered from the outside (ie, antigens), abnormal cells (ie, antigens) generated in the body such as cancer cells, and waste products (ie, antigens). Means that the incidence of various diseases that occur in the intestinal tract increases and delays healing. Improving the symptoms caused by these decreased intestinal immunity is called improving intestinal immunity.

  In addition, the composition of the present invention can improve the function of the small intestine of healthy people, improve the nutrition of the elderly with malnutrition, maintain the intestinal tract function of patients with severe dysfunction (ICU patients) such as respiration, circulation, metabolism, etc. Nutritional supplementation and maintenance of intestinal function in patients with dysphagia with neuropathy, improvement of intestinal function and nutrition for chronic intestinal diseases such as ulcerative colitis and Crohn's disease, malnutrition in chronic obstructive pulmonary disease (COPD) It can be used to improve intestinal tract function and nutritional status, or improve intestinal tract function and nutritional status for patients with intestinal dysfunction caused by antibiotics or anticancer agents such as cancer patients.

  The present invention provides a composition for preventing tissue damage of the small intestine, comprising a fermented milk-derived protein. The present invention also provides a composition for preventing tissue damage of the small intestine, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, an oil and fat as a lipid, and isomaltulose as a carbohydrate.

  The present invention also provides a composition for preventing tissue damage of the small intestine, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as proteins, and isomaltulose as a carbohydrate.

Small intestinal tissue damage is a disorder caused by cancer or ulcers in the intestinal tract, and destruction of tissues such as villi and mucosal intrinsic muscle layer by ingestion of antibiotics and anticancer agents such as cancer patients. The composition of the present invention is used for the prevention of such small intestinal tissue damage. In the present application, the term “disorder” is used in a broad sense including “function not sufficiently functioning”, “externally injured”, and “injury”.
The composition of the present invention has a villus repair promoting action and a mucosal native muscle layer repair promoting action, and includes, for example, “small bowel tissue disorder preventive agent”, “villus repair promoter”, “mucosal intrinsic muscle. It can be used as a “layer repair promoter”.
In addition, the composition of the present invention is an intestinal tract for patients with intestinal disorders due to improvement of intestinal function and nutritional status for chronic intestinal diseases such as ulcerative colitis and Crohn's disease, and antibiotics and anticancer agents such as cancer patients Can be used to improve function and improve nutritional status.

  The present invention provides an anti-inflammatory composition comprising a milk protein hydrolyzate and fermented milk-derived protein as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate.

  The present invention also provides an anti-inflammatory composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as proteins.

The anti-inflammatory composition of the present invention has an anti-inflammatory action against chronic intestinal diseases such as ulcerative colitis and Crohn's disease. Anti-inflammatory action is the action that suppresses the production of inflammatory cytokines, and at the same time, the production and suppression of inflammation is suppressed by suppressing the production of MCP-1, which is involved in the tissue infiltration of monocytes and T cells. The MCP-1 is also called MCAF (monocyte chemotactic and activating factor) and was found as a chemotactic factor for monocytes. The action on monocytes not only enhances chemotaxis, but also plays a role as a monocyte activator, such as enhanced release of lysosomal enzymes and active oxygen, enhanced antitumor activity, induction of IL-1 and IL-6 production It has become clear. Other than monocytes, basophils promote the release of chemical mediators and have T cell chemotactic activity. Production and secretion of MCP-1 is observed in various cells of the body by stimulation with LPS and inflammatory cytokines, and monocytes / macrophages, fibroblasts or vascular endothelial cells are representative. In addition, constitutive production of MCP-1 (independent of other stimulating factors) has been observed in certain tumor cells. Based on the research results so far, MCP-1 is thought to be involved in tissue infiltration of monocytes and T cells in various inflammatory diseases such as arteriosclerosis, delayed allergy, rheumatoid arthritis, or lung disease.
The anti-inflammatory composition of the present invention has an anti-inflammatory action or a tissue damage reducing action, and can be used, for example, as an “anti-inflammatory agent” or “tissue damage reducing agent”.
In addition, the composition of the present invention can be used to maintain intestinal function in patients with severe dysfunction (ICU patients) such as respiration, circulation, metabolism, etc., and to provide nutrition and maintain intestinal function in patients with dysphagia with brain / neuropathy. Improvement of intestinal function and nutrition for chronic long diseases such as ulcerative colitis and Crohn's disease, improvement of intestinal function and nutrition for malnutrition of chronic obstructive pulmonary disease (COPD), antibiotics and It can be used to improve intestinal function and nutritional status for patients with intestinal disorders due to cancer drugs.

  The active ingredient contained in each composition of the present invention is outlined below.

The composition of the present invention contains milk protein hydrolyzate and fermented milk-derived protein as proteins.
Examples of the hydrolyzate of milk protein of the present invention include casein, milk protein concentrate (MPC, Total Milk Protein = TMP), whey, whey protein, whey protein concentrate (Whey). Protein Concentrate (WPC), Whey Protein Isolate (WPI), α-lactalbumin (α-La), β-lactoglobulin (β-Lg) and lactoferrin hydrolysates.
For the definition, classification and production method of milk proteins, please refer to Japan Food Science July, 1989 issue p42-48, etc. or Milk General Dictionary, January 20, 1992 Editor Kunio Yamauchi, edited by Kenkichi Yokoyama, publisher Asakura Shoten.

  Casein is a major protein such as milk and is a kind of phosphoprotein to which phosphate is covalently bound. Casein is contained in about 3% of milk and about 0.9% of human milk, and accounts for about 80% of protein in milk.

On the other hand, whey is a water-soluble component that remains when, for example, fat, casein, fat-soluble vitamins, and the like are removed from milk. Whey generally produced acid casein and quark from cheese whey, rennet whey (or sweet whey) and skim milk obtained as by-products when natural cheese and rennet casein were produced. Casein whey and quark whey (or acid (acid) whey) obtained in some cases. The main components of whey are protein (β-lactoglobulin, α-lactalbumin, etc.), lactose, water-soluble vitamins, and salts (mineral components), each characteristic of which is a component of milk rather than research as a component of whey As revealed in research.
Whey protein is a general term for proteins excluding casein in, for example, milk. Whey protein is composed of a plurality of components such as β-lactoglobulin, α-lactalbumin, and lactoferrin, and does not include lactose, vitamins, minerals, and the like. When milk materials such as milk are adjusted to be acidic, the protein that precipitates is casein, and the protein that does not precipitate is whey protein.
“Whey-related products” include whey concentrated whey, whey powder dried whey, and whey protein, and whey dried after being concentrated by ultrafiltration (UF). Degreasing after drying the protein concentrate (Whey Protein Concentrate: hereinafter also referred to as “WPC”) and whey after removing the fat by microfiltration (MF) method, centrifugation, etc., concentrating by UF method Whey Protein Isolate (hereinafter referred to as “WPI”), which is obtained by selective fractionation of WPC (low fat / high protein), main proteins of whey, etc., by selective fractionation using an ion exchange resin method or gel filtration method. ), Desalted whey that has been desalted by nanofiltration (NF) method, electrodialysis method, etc., and then dried, derived from whey And mineral-concentrated whey obtained by precipitating the mineral component of the product and then concentrating it by centrifugation or the like. Among these, WPC containing 15% to 80% of milk protein in dry weight (solid content) is a protein-concentrated whey powder on 30 March 1998 due to a partial amendment of the Ministerial Ordinance of Milk. Defined in the product (concentrated whey, whey powder, WPC, whey protein concentrated powder, regardless of the presence or absence of a desalting step, as long as it has undergone the manufacturing process specified in the Ministerial Ordinance such as milk).

Milk protein concentrate (hereinafter also referred to as “MPC”) obtained by concentrating skim milk by the MF method or the UF method and then drying is free of lactose, salts, etc., as in WPC and WPI. Casein and whey proteins are relatively enhanced.
In addition, a general apparatus and method can be used for the concentration treatment, for example, a vacuum evaporator (evaporator), a vacuum kettle, a thin film vertical ascending tubular concentrator, a thin film vertical descending tubular concentrator, a plate concentrator. The method of heating under reduced pressure can be used. Also, a general apparatus and method can be used for the drying process, for example, spray drying (spray dryer) method, drum drying method, freeze vacuum drying (freeze dryer) method, vacuum (reduced pressure) drying method, or the like. be able to.
The standard manufacturing method of milk protein concentrate (MPC) is as follows.
(1) A step of concentrating skim milk after membrane separation. Or (2) A step of concentrating and drying skim milk after membrane separation.

A whey protein concentrate (WPC) is obtained by concentrating main protein of whey and the like by an ultrafiltration (UF) method and then drying. Generally, it is a collective term for those in which about 25% or more of the solid content is whey protein. It can be obtained by reducing lactose, salts, etc. from whey and relatively enhancing whey protein to a solid content of about 25% to about 80%. In particular, WPC containing milk protein in a dry weight of 15% to 80% is defined as a protein-enriched whey powder according to a ministerial ordinance such as milk.
The standard method for producing whey protein concentrate (WPC) is as follows.
(1) A step of concentrating whey after membrane separation. Or (2) A step of concentrating and drying the whey after membrane separation.
In addition, a general apparatus and method can be used for the concentration treatment, for example, a vacuum evaporator (evaporator), a vacuum kettle, a thin film vertical ascending tubular concentrator, a thin film vertical descending tubular concentrator, a plate concentrator. The method of heating under reduced pressure can be used. Also, a general apparatus and method can be used for the drying process, for example, spray drying (spray dryer) method, drum drying method, freeze vacuum drying (freeze dryer) method, vacuum (reduced pressure) drying method, or the like. be able to.

A whey protein isolate (WPI) is obtained by concentrating main proteins of whey and the like by an ion exchange resin method, an electrodialysis method, and the like, and then drying them. Generally, it is a collective term for those in which about 85% to about 95% of the solid content is whey protein. It can be obtained by reducing lactose and salts from whey and relatively strengthening whey protein to about 90% (85% to 95%) of the solid content.
The standard method for producing whey protein concentrate (WPI) is as follows.
(1) A step of concentrating whey after membrane separation, ion exchange resin treatment or electrodialysis treatment. Or (2) A step of concentrating and drying whey after membrane separation, ion exchange resin treatment or electrodialysis treatment.
In addition, a general apparatus and method can be used for the concentration treatment, for example, a vacuum evaporator (evaporator), a vacuum kettle, a thin film vertical ascending tubular concentrator, a thin film vertical descending tubular concentrator, a plate concentrator. The method of heating under reduced pressure can be used. Also, a general apparatus and method can be used for the drying process, for example, spray drying (spray dryer) method, drum drying method, freeze vacuum drying (freeze dryer) method, vacuum (reduced pressure) drying method, or the like. be able to.

  Taking the hydrolysis of whey protein as an example of the hydrolyzate of the milk protein of the present invention, the enzymes used for the hydrolysis of the protein are usually pepsin, trypsin and chymotrypsin. Research report using fungal protease (Food Technol., 48: 68-71, 1994; Trends Food Sci. Technol., 7: 120-125, 1996; Food Proteins and Their Applications, pp. 443-472, 1997 There is also. Enzymatic activity to hydrolyze whey protein varies greatly. Pepsin degrades α-La and modified α-La, but does not degrade native β-Lg (Neth. Milk dairy J., 47: 15-22, 1993). Trypsin hydrolyzes α-La slowly, but β-Lg remains almost undegraded (Neth. Milk dairy J., 45: 225-240, 1991). Chymotrypsin degrades α-La quickly while β-Lg degrades slowly. Papain hydrolyzed bovine serum albumin (BSA) and β-Lg, while α-La is resistant (Int. Dairy Journal 6: 13-31, 1996a). However, α-La not bound to Ca is completely degraded by papain at acidic pH (J. Dairy Sci., 76: 311-320, 1993).

  Enzyme and Chemical Modification of proteins in Food proteins and their Applications can be achieved by controlling the enzymatic degradation of milk proteins to modify the protein over a wide range of pH and processing conditions. , pp. 393-423, 1997, Marcel Dekker, Inc., New York, 1997; Food Technol., 48: 68-71, 1994).

  Hydrolysis of peptide bonds results in increased number of charged groups and hydrophobicity, lower molecular weight, and modification of the molecular configuration (J. Dairy Sci., 76: 311-320, 1993). The change in functional properties is largely dependent on the degree of hydrolysis. The biggest changes commonly seen in whey protein functionality are increased solubility and decreased viscosity. When the degree of hydrolysis is high, the hydrolyzate often does not precipitate upon heating and is highly soluble at pH 3.5-4.0. The hydrolyzate is also much less viscous than the intact protein. This difference is particularly noticeable when the protein concentration is high. Other effects are changes in gel properties, increased thermal stability, enhanced emulsification and foaming, reduced emulsification and foam stability (Int. Dairy journal, 6: 13-31, 1996a; Dairy Chemistry 4, pp. 347-376, 1989; J. Dairy Sci., 79: 782-790, 1996).

  Various biologically active oligopeptides derived from milk proteins are known (Masaaki Yoshikawa “Advanced Function of Milk”, Masaaki Yoshikawa et al., P 188-195, Hirogaku Publishing, 1998; Motoki Otani “Advanced Function of Milk” Yoshikawa Edited by Masaaki et al., P 97-99, Kogaku Publishing, 1998; Otani Gen, Milk Science 47: 183, 1998; Trends in Food Science and Technology, 9: 307-319, 1998). A peptide having an angiotensin converting enzyme (ACE) inhibitory activity (having a blood pressure lowering effect) is one of them.

  There are reports on a number of peptides with potential ACE inhibitory activity deduced from in vitro activity measurements (eg J. Dairy Res., 67: 53-64, 2000; Br. J. Nutr., 84 : S33-S37, 2000). There have been reports on the purification and identification of ACE inhibitory peptides from hydrolysates using various chromatographic techniques (eg, Maruyama, S., & Suzuki, H., Agricultural and Biological Chemistry, 46: 1393 -1394, 1982; Miyoshi S. et al., Agri. Biol. Chem., 55: 1313-1318, 1991; Food Science and Biotechnology, 8: 172-178, 1999; Biosci. Biotech. Biochem., 57: 922 -925, 1993).

  These reports suggest that ACE inhibitory activity is present in many fractions obtained by column operations based on various separation principles, indicating that the molecular properties of ACE inhibitors are quite diverse. ing. The fact that ACE inhibition is found in hydrolysates produced by various proteins, proteases and hydrolysis conditions suggests that various peptides with diverse amino acid sequences may also have ACE inhibitory activity doing. Due to the chemical diversity of such peptides, chromatographic purification of the hydrolyzate will always be accompanied by a partial loss of active peptide. During hydrolysis, ACE inhibitory activity is continuously formed while being degraded. The maximum activity of the hydrolyzate is the result of optimization of these two processes. The overall peptide composition of the hydrolyzate determines the ACE inhibitory activity, which depends on the specificity of the hydrolase and the process conditions.

  A report on the optimization of whey protein hydrolysis using response surface methodology to minimize the required hydrolysis and maximize ACE inhibitory activity (International Dairy Journal 12: 813- 820, 2002).

  The milk protein hydrolyzate used in the present invention has an action of suppressing LPS-induced TNF-α and IL-6 production in vivo. Therefore, optimization of milk protein hydrolysis conditions (denaturation temperature, pH, temperature, hydrolysis time, and enzyme / substrate ratio) is described above using the inhibitory effect of LPS-induced TNF-α and / or IL-6 production as an index. You can try referring to the literature (International Dairy Journal 12: 813-820, 2002).

On the other hand, there are many patents (published patents and patents) for milk protein hydrolysates in addition to the literatures exemplified above. For example, a patent that hydrolyzes casein and whey protein separately, adsorbs and removes the hydrophobic portion, and then mixes them together in a predetermined ratio (Japanese Patent No. 2,986,764). Whey protein is a protease derived from Bacillus and actinomycetes. Patent for removing enzyme and insoluble hydrolyzate after hydrolysis with protease derived from the origin (Japanese Patent No. 3,222,638), molar ratio of branched chain amino acid / aromatic amino acid obtained by enzymatic degradation of β-lactoglobulin 10% by weight or more, aromatic amino acid less than 2.0% by weight, average molecular weight of several hundred to several thousand peptide mixture patent (Japanese Patent No. 3,183,945), selective enzymatic degradation of β-lactoglobulin in whey protein Patent (Japanese Patent No. 2,794,305), or a whey protein protease derived from B. licheniformis and / or Bacillus subtilis B. subtilis), a non-pH-stat method that hydrolyzes to a degree of hydrolysis (DE) of 15 to 30% to obtain a permeate of ultrafiltration membrane with a cutoff value exceeding 10,000 ( (Japanese Patent No. 3167723).
Whether or not the hydrolyzate of the above-mentioned literature and patent has an action of suppressing LPS-induced TNF-α and IL-6 production is determined by a known assay system (for example, an experimental medicine separate volume, “Biomanual UP Experiment Series”, Cytokine experiment method, Atsushi Miyajima, Masaru Yamamoto, Yodosha Co., Ltd., 1997).

Five parameters for optimizing milk protein hydrolysis include, for example, preheating, enzyme to substrate ratio (E / S), pH, hydrolysis temperature, and hydrolysis time.
Preheating: 65 ~ 90 ℃
E / S: 0.01-0.2
pH: 2-10
Hydrolysis temperature: 30-65 ° C
Hydrolysis time: less than 3-20 hours

Examples of the enzyme used include the following from Novo Nordisk.
1) Endo protease
B. Protease from Risheniformis: Alcalase (registered trademark)
Protease from B. lentus: Esperase®
Bacillus subtilis-derived protease: Neutrase (registered trademark)
Bacteria-derived protease: Protamex (registered trademark)
Porcine pancreatic trypsin: PTN (registered trademark)
2) Protease derived from exo-type protease Aspergillus oryzae: Flavorzyme (registered trademark)
Carboxypeptidase from porcine or bovine viscera

  In addition to the above-mentioned enzymes, animal-derived pancreatin, pepsin, plant-derived papain, bromelain, microorganism-derived (for example, lactic acid bacteria, yeast, mold, actinomycetes, etc.) endoprotease and exoprotease, crudely purified products thereof, bacteria Examples include crushed body and the like. As a combination of enzymes, a combination of B. licheniformis-derived alcalase and porcine pancreas-derived PTN (trypsin) is often used.

  As a preparation method of a whey protein hydrolyzate, the method of the below-mentioned reference example 1 is mentioned, for example.

  The milk protein hydrolyzate used in the present invention is an enzyme hydrolyzate itself having an inhibitory effect on LPS-induced TNF-α and / or IL-6 production, a retentate after ultrafiltration membrane treatment, or a permeate ( Permeate), and commercial milk protein hydrolysates having similar activity.

Examples of the whey protein hydrolyzate that can be used in the present invention include the following. Japanese Patent No. 3183945 discloses that the heat-denatured whey protein isolate (WPI) is hydrolyzed with endopeptidase and exopeptidase, and then the aromatic amino acid in the hydrolyzate is adsorbed with an ion exchange resin so that the Fischer ratio is increased. A whey protein hydrolyzate (a peptide mixture having a molecular weight of 200 to 3,000) having 10 or more, branched chain amino acids of 15% or more and aromatic amino acids of less than 2% is disclosed.
JP-T-6-50756 discloses that after heat treatment of a 12% aqueous solution of whey protein concentrate (WPC) having a protein content of at least 65% at a temperature exceeding 60 ° C., licheniformis-derived alcalase and B. Hydrolysis to 15-35% DH with a subtilis-derived neutrase, and the hydrolyzate is subjected to ultrafiltration (UF) with a cutoff value exceeding 10,000 and then nanofiltration (NF). The whey protein hydrolyzate is odorless and low in bitterness by concentrating with NF and spray drying the NF retentate.

Milk protein hydrolyzate used in the present invention is commercially available, for example, Peptigen IF-3080, Peptigen IF-3090, Peptigen IF-3091 and Lacprodan DI-3065 (Arla Foods), WE80BG (DMV), Hyprol 3301, Hyprol 8361 and Hyprol 8034 (Kerry), Tatua2016, HMP406 (Tatua), Whey Hydrolysate 7050 (Fonterra), Biozate3 (Davisco), and the like, are not limited thereto. Examples of the method for preparing a protein hydrolyzate include a method for producing a whey protein hydrolyzate including the following steps 1) to 5).
1) Mix whey protein containing at least 65% protein calculated as dry matter with water to make a slurry with protein content up to 20%,
2) Perform heat treatment to a temperature exceeding 60 ° C.
3) Mixing the mixture from step 2) with a protease that can be made by B. licheniformis and / or with a protease that can be made by B. subtilis, non-pH -Proteolytic hydrolysis to DH between 15 and 35% by stat method,
4) Separate the mixture from step 3) on an ultrafiltration / microfiltration device with a cut-off value greater than 10,000 so that the permeate constitutes a protein hydrolysate, and 5) Hydrolysis is terminated by inactivation of the enzyme

  Preferably, the slurry in step 1) has a protein content of 7-12%.

  Preferably, the heat treatment in step 2) is carried out between 70 and 90 ° C.

  Preferably, the hydrolysis in step 3) is carried out to between 20-30% DH.

  Preferably, the ultrafiltration / microfiltration device has a cutoff value greater than 50,000.

  Preferably, the mixture at the end of step 3) or step 5) is in an amount corresponding to between 1 and 5% of carbon, calculated with respect to dry matter content, preferably at a temperature between 50 and 70 ° C. Treated with activated carbon for longer than 5 minutes and the activated carbon is removed.

  Preferably, after step 5) above, concentration is carried out by nanofiltration / hyperfiltration / reverse osmosis and / or evaporation, preferably at a temperature between 50 and 70 ° C., after which it is retained. The product is recovered as its protein hydrolyzate solution.

  Preferably, the protein hydrolyzate solution from step 5) above is spray dried to a moisture content below 6.5%.

Thus, the method for the production of whey protein hydrolysates is:
1) Mix whey protein containing at least 65% protein calculated as dry matter with water to make a slurry with protein content up to about 20%, preferably up to 12%,
2) Perform heat treatment to a temperature exceeding 60 ° C.
3) The mixture from step 2) is made by a protease that can be made by B. licheniformis, preferably by Alcalase® and / or by B. subtilis. Can be proteolytically hydrolyzed to a DH of between 15 and 35% by a non-pH-stat method with a protease, preferably Neutrase®
4) separating the mixture from step 3) on an ultrafiltration / microfiltration apparatus with a cut-off value greater than 10,000 so that the permeate constitutes the protein hydrolyzate; and
5) terminating the hydrolysis by inactivation of the enzyme,
It is characterized by.

  The amino acid composition of whey protein hydrolyzate (IF-3090) is shown in Table 1.

  The compounding quantity of a milk protein hydrolyzate can be mix | blended in the ratio of 0.1-22% with respect to the whole composition, for example, normally 4.1-14.0%, Preferably 5.5-10.0%. Alternatively, 0.9 to 3 g, preferably 1.2 to 2 g can be added per 100 ml of the composition.

  Examples of the blended raw material for the protein derived from fermented milk used in the present invention include fermented milk (yogurt) with reduced water (whey) (for example, Japanese Patent No. 3,179,555). The protein derived from fermented milk (yogurt) has an amino acid score of 100, the digestibility of the protein is enhanced by fermentation, and the nutritional value is high.

  Or as a protein derived from fermented milk used by this invention, Preferably, the protein derived from fresh cheese (non-aged cheese) is mentioned. Fresh cheese-derived protein contains casein as the main component, whey protein containing α-lactalbumin and β-lactoglobulin, and components in which milk protein is partially broken down into amino acids and peptides. It is characterized by that. There are many types of fresh cheese such as cottage, quark, string, Neuchâtel, cream cheese, mozzarella, ricotta, mascarpone, and quark is preferably used in the present invention. The method for producing quark is known (for example, JP-A-62-228013). Quark is characterized by low fat content, refreshing flavor and sourness.

  The general manufacturing method of non-aged cheese is demonstrated below. First, curd is produced from raw milk. After inoculating a raw milk with a starter and culturing, rennet is further added to form curd (curd). Prior to the production of the curd, the raw milk can be pretreated if necessary. For example, in order to reduce the quality difference between production lots, the quality can be adjusted by mixing many kinds of milk raw materials. Such processing is called standardization. Furthermore, a homogenize treatment that mechanically breaks fat globules in milk can be added. Alternatively, centrifugal sterilization or heat treatment can be performed to remove microorganisms mixed in the milk raw material.

  Solid content obtained by separating whey from the obtained curd (curd) is non-aged cheese (fresh cheese). Methods are known for separating whey from curd by centrifugation or membrane separation. For example, a centrifuge such as a quark separator is used for separating whey. Alternatively, the separation process can be made more efficient by cutting or heating the curd in advance as necessary.

More specifically, fresh cheese that can be obtained by the following raw materials and processes is preferred as a milk fermentation component in the present invention. During the following steps, mainly Lactobacillus bulgaricus and / or Streptococcus thermophilus can be used for fermentation.
Heat pasteurize bovine skim milk;
Inoculate 0.5-5% of lactic acid bacteria starter to start fermentation;
separating whey from curd formed when pH reaches 4.6;
Cooling the curd from which the whey has been separated to obtain non-aged cheese The non-aged cheese that can be produced in this way is generally sometimes referred to as Quark. An example of the composition of non-aged cheese is as follows.
17-19% total solids,
11-13% protein,
More than 1% fat,
2-8% carbohydrates,
Lactose 2% or more

  The compounding quantity of fermented milk origin protein can be mix | blended in the ratio of 0.1-30% with respect to the whole composition, for example normally 8.0-23.0%, Preferably 10.0-18.0%. Alternatively, 2 to 6 g, preferably 2.5 to 4.5 g can be added per 100 ml of the composition. Alternatively, the fermented milk-derived protein contained in the entire composition of the present invention is about 0.1 to about 90%, preferably about 1 to about 80%, more preferably about 30 to about 70, based on the amount of protein in the entire composition. %.

The composition of this invention contains fats and oils as a lipid.
The composition of the present invention preferably contains an n-3 fatty acid as a lipid. Examples of n-3 fatty acids contained in the composition of the present invention include EPA, DHA, α-linolenic acid, DPA, etc., preferably EPA, DHA, or / and α-linolenic acid, more preferably EPA or / And DHA. Examples of fats and oils containing n-3 fatty acids include perilla oil, linseed oil, sesame oil, fish oil, rapeseed oil, soybean oil, salad oil, and flux oil. In the present invention, these n-3 fatty acids may be included directly or in the form of fats and oils such as fish oil.
In addition, the composition of the present invention preferably contains medium-chain triglyceride (MCT) as a lipid. MCT is characterized in that it is quickly absorbed in the body and easily becomes energy, and the body is hard to get fat. Examples of fats and oils containing MCT include palm oil, palm kernel oil, and medium chain fatty acid-containing fats and oils. In the present invention, MCT may be included directly or in the form of fats and oils such as palm kernel oil.
Accordingly, the composition of the present invention comprises a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, medium chain fatty acid triglyceride, EPA and / or DHA as a lipid, and isomaltulose as a carbohydrate. Things are included.

  The composition of the present invention may contain fatty acids such as oleic acid, palmitic acid, palmitoleic acid, linoleic acid, stearic acid, linolenic acid, arachidonic acid, preferably oleic acid as a lipid. Examples of fats and oils containing these fatty acids include high oleic high oleic sunflower oil, rapeseed oil, olive oil, high oleic safflower oil, soybean oil, corn oil, and palm oil. Sunflower oil, rapeseed oil, olive oil, and mixtures with olive oil can also be used. Linoleic acid, arachidonic acid, γ-linolenic acid and the like are n-6 fatty acids. Examples of fats and oils containing n-6 fatty acids include safflower oil, sunflower oil, soybean oil, linseed oil, corn oil, and peanut oil.

The ratio of n-3 fatty acid to n-6 fatty acid is such that n-6 fatty acid is 5 or less, usually 0.5 or more and 4.0 or less, preferably 1.0 or more and 4.0 or less, relative to n-3 fatty acid 1. The ratio is preferably n-3 fatty acid: n-6 fatty acid = 1: 2.
The compounding quantity of n-3 type | system | group fatty acid can be mix | blended in the ratio of 0.01-10% with respect to the whole composition, for example, normally 0.05-7%, Preferably 0.1-5%. Alternatively, 0.05 to 2.2 g, preferably 0.1 to 1.0 g can be added per 100 ml of the composition.
The compounding quantity of MCT can be mix | blended in the ratio of 0.01-14.5% with respect to the whole composition, for example, 0.01-8.0% normally, Preferably it is 2.0-4.0%. Alternatively, 0.01 to 2.0 g, preferably 0.5 to 1.0 g can be added per 100 ml of the composition.
The blending amount of the oleic acid-containing fat can be blended, for example, at a ratio of 0.1 to 14.5%, usually 2.0 to 10.0%, preferably 4.0 to 8.0%, with respect to the entire composition. Alternatively, 0.5 to 2.0 g, preferably 1.0 to 1.8 g can be added per 100 ml of the composition.

Moreover, the composition of this invention may contain milk lecithin and soybean lecithin as a lipid.
Milk lecithin and soybean lecithin may be used alone or in combination.

  Milk lecithin consists of sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidylcholine (LPC), and milk fat globule membrane (MFGM) only Is localized. The component composition of the MFGM phospholipid fraction is shown in Table 2 (Bulletin of Japan Dairy Technical Association, Vol. 50: pp. 58-91, 2000).

  The term lecithin is used only for phosphatidylcholine in fields such as biochemistry, medicine, and pharmacy. It is used as a general term for a mixture of The 7th edition of the Food Additives (1999) defines that lecithin is "obtained from oil seeds or animal raw materials, the main component of which is phospholipid". In the present invention, milk-derived phospholipids are also collectively referred to as “milk lecithin”.

  As shown in Table 2, the characteristic of milk lecithin is that it contains a large amount of SM that is not contained in soybean lecithin. Milk lecithin, when administered to rats, increases DHA content in the brain and liver compared to soy lecithin, and is effective in improving hyperlipidemia and fatty liver compared to soy lecithin or yolk lecithin It is known. In addition, SM is involved in cholesterol metabolism, including regulation of HMG-CoA reductase activity, which is involved in cholesterol biosynthesis, and regulation of cholesterol absorption in the intestinal tract. Are known. From these, it is considered that SM further enhances the lipid metabolism improving effect of PC and PE (Kazu Sasaki, Milk Science 51 (2): 93-94, 2002).

  As a high content of MFGM, WPI by-product (MF retentate) produced by a combination of ultrafiltration (UF) and microfiltration (MF) freeze-dried, cream or butter to anhydrous milk fat ( An anhydrous milk fat (AMF) -excluded fraction (batase ram), a fraction obtained by removing AMF from whey cream (whey cream gelum), and the like. Methods for obtaining phospholipid concentrates using these as raw materials are known (for example, JP-A-7-173182 is included in the present invention).

  Soy lecithin is widely used in the food field as a natural food additive, while polyenephosphatidylcholine is also used as a pharmaceutical (indication: improvement of liver function in chronic liver disease, fatty liver, hyperlipidemia). The physiological effects of soy lecithin include (1) adjustment of morphology and function of biological membranes, (2) improvement of lung function, (3) improvement of arteriosclerosis, (4) improvement of lipid metabolism, (5) liver lipid metabolism Improvement and (6) Improvement / improvement of nerve function are mentioned (Food and Development, Vol. 29 (3): 18-21, 1994).

  The so-called “natural” series of lecithin products are usually ordered by the PC content in the product. Various types of lecithin that have been improved according to the use of lecithin are manufactured. For convenience, soy lecithin products are classified as shown in Table 3 due to differences in the main PC content due to the purification and fractionation of soy lecithin (Yamama Fujikawa, Oil Chemistry, Vol. 40 (10), pp.951- p58, 1991).

The composition of the present invention contains isomaltulose (palatinose (registered trademark)) as a carbohydrate. Isomaltulose is a substance represented by CAS Registry Number 13718-94-0, chemical formula C ₁₂ H ₂₂ O ₁₁ .
The isomaltulose includes reduced isomaltulose, palatinose syrup (registered trademark), or isomaltulose syrup. The isomaltulose starch syrup is a syrup-like liquid substance mainly composed of oligosaccharides such as tetrasaccharide, hexasaccharide, and octasaccharide produced by dehydration condensation of isomaltulose. As is the case with sucrose, isomaltulose is digested and absorbed by glucose and fructose (Toshinao Aida, Journal of Japanese Society of Nutrition and Food Science, Vol. 36 (3): 169-173, 1983), but its hydrolysis The blood glucose and insulin concentration after intake is constant because the rate is 1/5 slower than sucrose (Tsuji, Y. et al., J. Nutr. Sci. Vitaminol., 32: 93-100, 1986) Maintain the level for a long time (Kawai, K. et al., Endocrinol, Japan, 32 (6): 933-936, 1985).

  The blending amount of isomaltulose can be blended in a proportion of, for example, 10 to 70%, usually 15 to 60%, preferably 20 to 35% with respect to the entire composition. Alternatively, 4 to 13 g, preferably 5 to 8 g can be added per 100 ml of the composition.

The composition of the present invention is intended for the subject in order to promote villi growth in the small intestine, increase the thickness of the intrinsic muscle layer of the small intestine, improve intestinal function, prevent tissue damage of the small intestine, or suppress various inflammations. Is used as one purpose.
In the present invention, the “subject” is not particularly limited, but includes animals (eg, humans, domestic animal species, wild animals). The “subject” does not necessarily have to have a disease. For example, the composition of the present invention may be administered to a healthy human.
In the present invention, “administering” includes oral or parenteral administration, and the dosage form may be either a pharmaceutical product or a food or drink.

  That is, the composition of the present invention includes a pharmaceutical composition, a nutritional pharmaceutical composition, a pharmaceutical, a drug, a food and beverage composition, a food and drink, a nutritional composition, a special-purpose food, a nutritional functional food, a health food, a pharmaceutical additive, and a food additive. Any form such as an object can be used. For example, the composition of the present invention may be applied to a small intestine function-improving food for healthy, well-balanced healthy persons, a nutritionally-improving food for malnourished elderly people, patients with severe dysfunction such as respiration, circulation, and metabolism (ICU patients). ) Intestinal function maintenance food, nutritional support and intestinal function maintenance food for patients with dysphagia with brain / neuropathy, intestinal function improvement and nutritional status improvement food for chronic long diseases such as ulcerative colitis and Crohn's disease, chronic Intestinal function improvement and nutritional state improvement food for malnutrition of obstructive pulmonary disease (COPD), or intestinal function improvement and nutritional state improvement food for intestinal disorder patients due to antibiotics and anticancer drugs such as cancer patients You can also.

  Alternatively, the pharmaceutical composition, the nutritional pharmaceutical composition, the pharmaceutical product, and the drug of the present invention can be used by being contained in a food and beverage composition, a food and drink, a nutritional composition, a special-purpose food, a nutritional functional food, a health food, and the like. . For example, the pharmaceutical composition of the present invention, the nutritional pharmaceutical composition, the pharmaceutical product, the drug, the small intestine function improving food for healthy healthy people with nutritional balance, the nutrition improving food for malnourished elderly people, respiration, circulation, metabolism, etc. For intestinal function maintenance foods of severely dysfunctional patients (ICU patients), nutritional and intestinal function maintenance foods for dysphagia patients with brain / neuropathy, chronic long diseases such as ulcerative colitis and Crohn's disease Intestinal function improvement and nutritional state improvement food, Intestinal function improvement and nutritional state improvement food for malnutrition of chronic obstructive pulmonary disease (COPD), or intestinal function for intestinal disorder patients such as cancer patients due to antibiotics or anticancer drugs It can also be used in foods for improving and improving nutritional status.

  For example, by direct administration as a pharmaceutical, or by directly ingesting as a special-purpose food such as a food for specified health use or a nutritionally functional food, the subject promotes villi growth in the small intestine and increases the thickness of the intrinsic muscle layer of the small intestine. Expected to increase, improve intestinal function, prevent tissue damage in the small intestine, or suppress various inflammations.

  When the composition of the present invention is used as a pharmaceutical product, it can be administered in various forms. Examples of the form include enteral or oral administration through nasal tubes, gastrostomy, enterostomy, etc., such as enteral nutrients, liquids, etc., tablets, capsules, granules, powders, syrups, etc. It may be a dosage form processed into the formulation. These various preparations are pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, solvents, isotonic agents, etc. It can be formulated using known adjuvants that can be commonly used in the technical field. Further, it may contain an appropriate amount of calcium. Further, an appropriate amount of vitamins, minerals, organic acids, sugars, amino acids, peptides, etc. may be added.

  When the composition of the present invention is used in a pharmaceutical form, it can be administered orally or enterally. For example, oral administration of tablets, capsules, granules, powders, syrups, etc. and enteral administration by nasal tube, gastrostomy, intestinal fistula, etc. can be selected, and the administration method is appropriately determined depending on the age and symptoms of the patient Can be selected. The effective dose is selected in the range of 0.1 mg to 1500 mg per kg body weight at a time. Alternatively, a dose of 5 mg to 75 g per patient, preferably 100 mg to 50 g can be selected. Preferable dosage and administration method are, as specific examples, 0.1 mg to 1500 mg per kg body weight per time, more preferably 2 mg to 1000 mg once to 3 times a day for 1 month (4 weeks), For example, it may be administered before or after a meal. The number of administration is adjusted to the number according to the state while observing the state after administration and observing the trend of blood test values.

  When using the composition of this invention as food / beverage products, it can also be added to various food / beverage products regardless of forms, such as liquid form, paste form, solid, and powder, and can also be ingested as a foodstuff. Foods and drinks include milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crusts, prepared milk powder, liquid foods, food for the sick, nutritional foods, frozen foods, food compositions, processed foods, etc. Examples of such commercial foods can be given. When using the composition of this invention as food-drinks, it is preferable that it is a form which can be used directly. In this form, the composition can be taken orally via the nose-stomach, jejunum by tube. Such compositions may be in various forms, such as fruit juice type beverages, milk shake type beverages, and the like. The composition may also be a soluble powder that can be reconstituted before use.

The osmotic pressure of the composition can have an osmotic pressure of about 300-1000 mOsm / l, such as about 300-750 mOsm / l. When measured at room temperature, the viscosity of the composition is about 5 to 40 cp (1 cp = 0.001 Pa · s), preferably less than 20.
The calorie of the composition is about 1-2 kcal / ml, preferably 1-1.5 kcal / ml.

  When using the composition of this invention as food-drinks, the nutritional composition can be adjusted by mix | blending an additional nutrient further. Additional nutrients in the present invention include water, proteins, carbohydrates, lipids, amino acids, dietary fibers, vitamins, minerals, organic acids, organic bases, fruit juices, flavors, artificial sweeteners (such as aspartame), etc. Can be used.

  In addition, 5 mg to 500 mg (0.005% to 0.5%) of champignon extract, which has a fecal odor reducing effect, and carotenoid preparations (including α-carotene, β-carotene, lycopene, lutein, etc.) for the purpose of nutrition enhancement 10 μg to 200 μg (0.00001% to 0.0002%) can also be included.

  Furthermore, catechin, polyphenol, etc. can be included as an antioxidant.

  Furthermore, carnitine can also be included for the purpose of enhancing lipid metabolism and the like. Carnitine is a biological trace component made from lysine and methionine in the liver and kidney. It is known that the generation amount decreases with age. L-carnitine plays an important role in the metabolism of nutrients such as delivery of long chain fatty acids to muscle cells.

  Examples of the saccharide include a plurality of other saccharides in addition to the above-mentioned isomaltulose. As sugars other than isomaltulose, sucrose, glucose, fructose, honey and the like are used. Other examples include dextrin and indigestible dextrin.

Dietary fiber is divided into water-soluble dietary fiber and insoluble dietary fiber, and both can be used.
As the water-soluble dietary fiber, the indigestible oligosaccharides lactulose, lactitol, or raffinose can be used. Physiological functions of indigestible oligosaccharides are known to reach the large intestine as undigested substances, contribute to the activation and proliferation of intestinal bifidobacteria, and have an improved intestinal environment, ie, an intestinal regulating effect. Yes. Lactulose is a synthetic disaccharide composed of galactose and fructose and is used as a basic drug for hyperammonemia (Bircher, J. et al., Lancet i: 890, 1965). Chronic recurrent hepatic encephalopathy due to chronic liver failure responds well to lactulose administration, special amino acid infusion for liver failure (Fischer solution), and so on. The clinical effect of β-galactosyl-sorbitol, a second-generation lactulose, on chronic hepatic encephalopathy is similar to that of lactulose (Lanthier, PL. And Morgan, M., Gut, 26: 415, 1985; Uribe , M., et al., Dig. Dis. Sci., 32: 1345, 1987; Heredia, D. et al., J. Hepatol, 7: 106, 1988; Riggio, O., et al., Dig. Dis. Sci., 34: 823, 1989), currently used as a therapeutic agent for hyperammonemia.

  Other water-soluble dietary fiber candidates include pectin (protopectin, pectinic acid, pectinic acid) with improved lipid metabolism (reduced cholesterol and neutral fat), guar gum / enzymatic degradation products, tamarind seed gum, etc. . Degraded guar gum also has an inhibitory effect on blood glucose level and insulin saving (Kazuhiko Yamatoya et al., Journal of Japanese Society of Nutrition and Food, 46: 199, 1993). Furthermore, as water-soluble dietary fiber candidates, konjac glucomannan, alginic acid, low-molecular alginic acid, psyllium, gum arabic, seaweed polysaccharide (cellulose, lignin-like substance, agar, carrageenan, alginic acid, fucodyne) , Laminarin), microbial gum (welan gum, curdlan, xanthan gum, gellan gum, dextran, pullulan, lambzan gum) and other gums (locust bean gum derived from seed, tamarind gum, tara gum, caraya gum derived from sap, tragacanth gum) Examples include water-soluble dietary fiber polydextrose, indigestible dextrin, and maltitol.

  Insoluble dietary fiber increases the mass of indigestibles in the large intestine and shortens transit time. As a result, the number of defecations increases, resulting in an increase in stool volume. Examples of insoluble dietary fiber candidates include cellulose, hemicellulose, lignin, chitin, chitosan, soybean dietary fiber, wheat bran, pine fiber, corn fiber, and beet fiber.

Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. For example, folic acid can be used.
There are currently 13 known vitamins. Among them, vitamins A and B (B1, B2, nicotinic acid, B6, pantothenic acid, folic acid, B12, biotin) and K are known to have deep involvement in the liver. In relation to liver disorders, A deficiency and excess, group B deficiency, and K excess are the main problems.

  Vitamin A is obstructive jaundice, etc. If bile is insufficient in the intestinal tract, the absorption rate decreases and deficiency occurs. Moreover, in the protein undernutrition state, since the production of retinol binding protein (RBP) is reduced, vitamin A is not transported to the target organ and deficiency symptoms appear. In cases of decompensated cirrhosis, poisoning due to excessive vitamin A occurs in a relatively small amount. Chronic liver disease has impaired use of vitamin B. Vitamin K is also synthesized by intestinal bacteria, so deficiency is not usually observed, but if the bile is insufficient in the intestinal tract due to obstructive jaundice, the absorption rate decreases.

Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium and the like. As the organic acid, for example, malic acid, citric acid, lactic acid, tartaric acid and the like can be used.
The electrolytes that are usually problematic when managing body fluids are sodium, chlorine, potassium, phosphorus, calcium and magnesium. When assembling a mineral prescription, (1) whether the minerals that are taken up by the cells are adequately distributed, or (2) the patient's endocrine environment can adequately accommodate the amount and type of nutrient substrate being administered. (3) Consider the three points of estimation of the osmotic substance load on the kidney and the amount of water to administer to maintain proper urine osmotic pressure.
Iron or trace elements derived from natural products, such as mineral yeast copper, zinc, selenium, manganese, chromium and the like are included. Copper gluconate, zinc glucone and the like can also be used.

  Examples of the organic acid include malic acid, citric acid, lactic acid, and tartaric acid.

  As these additional nutrients, either chemically synthesized components or components derived from natural products can be used. Or the foodstuff containing the target component can also be mix | blended as a raw material. These components can be blended in at least one or a combination of two or more. The form of the composition may be solid or liquid. It can also be in the form of a gel or semi-solid.

  The composition of the present invention can be produced by a known method in the fields of liquid foods and enteral nutrients. For example, after sterilizing the liquid composition in advance and then aseptically filling the container (for example, a method using a combination of the UHT sterilization method and the aseptic packaging method), or after filling the container with the liquid composition A method of sterilization by heating with a container (for example, retort method, autoclave method) and the like can be employed. That is, when the usage form of the composition is liquid, a homogenized product (a homogenized sterilizing solution) based on the composition is heat-sterilized again at about 120 to 145 ° C. for about 1 to 10 seconds as necessary. Then, cool and aseptically fill, or fill into cans and soft bags and sterilize by retort. And when the usage form of a composition is powder, the said homogenized material is spray-dried or freeze-dried, for example.

  Hereinafter, the present invention will be described in detail, but the present invention is not limited to the individual forms described below. In the present invention, when whey protein is prepared (added / mixed), it is heated and prepared. For example, the temperature of the preparation (preparation temperature) is set to 55 ° C. or lower. This is because if the blending temperature is set to a high temperature such as 70 ° C., the protein coagulates (curds), and if the blending temperature is set to a low temperature such as 2 ° C., the protein is difficult to dissolve or disperse in water. Therefore, as a preparation process, the temperature is preferably 5 to 55 ° C, more preferably 40 to 55 ° C, still more preferably 40 to 53 ° C, and particularly preferably 40 to 50 ° C. At this time, it is preferable to adopt an appropriate preparation time while taking into consideration the growth of bacteria (contaminating bacteria, etc.) in the preparation liquid.

  Furthermore, in this invention, it homogenizes, after sterilizing a preparation liquid at high temperature. This is because high-temperature sterilization (heating) may denature proteins and increase viscosity (thickening), but homogenization after high-temperature sterilization can reduce the degree of thickening. Here, homogenization after high-temperature sterilization means homogenization after high-temperature sterilization and before filling into a container or the like to make a product. The number of times is not limited to one, but may be two or more times. There may be. For example, when the preparation liquid is sterilized and then sterilized for the second time, it is homogenized after the second sterilization. In addition, when the preparation liquid is sterilized after being sterilized and further sterilized for the second time, it is homogenized again for the second time after sterilization for the second time. Then, the preparation liquid may be homogenized after sterilization, and may be homogenized a second time without sterilization. That is, in the present invention, after pasteurizing the preparation liquid at high temperature, it is important to homogenize even once before filling the container into a product.

  On the other hand, even after the high-temperature sterilized preparation liquid (sterilization liquid) is homogenized, it may be sterilized again as long as the sterilization liquid does not thicken. For example, the preparation liquid may be sterilized after being sterilized, and sterilized a second time without being sterilized at high temperature. At this time, as the high temperature sterilization step, for example, the temperature is 100 to 150 ° C., the holding time is 1 to 30 seconds, preferably 115 to 145 ° C., 1 to 20 seconds, more preferably 120 to 145 ° C., 1 to 10 seconds, More preferably, it is a heat history corresponding to 125 to 140 ° C. and 1 to 5 seconds. When sterilized at high temperature, the protein is denatured and the sterilization solution tends to thicken. However, it is difficult to thicken without sterilization at high temperature, so the effect of reducing the degree of thickening by homogenization is particularly effective in high temperature sterilization. It becomes.

Moreover, when sterilizing at high temperature, the pressure may be adjusted (pressurized or depressurized) to the preparation liquid. In this case, for example, the sterilization pressure is usually about 1 to 10 kg / cm ² for the purpose of preventing boiling of the preparation liquid. That is, in the high temperature sterilization of the present invention, such pressure may be applied in addition to temperature (heating). Examples of the high-temperature sterilizer include a plate heat exchanger, a tube heat exchanger, a steam injection sterilizer, a steam infusion sterilizer, and an electric heating sterilizer. On the other hand, when homogenizing, using a homogenizer, for example, setting the temperature to about 10 to 60 ° C. and the flow rate to about 100 to 10,000 L / h, the pressure is 10 to 100 MPa, preferably 20 to 80 MPa, more preferably Is 30 to 70 MPa, more preferably 20 to 50 MPa. In addition, if necessary, the treatment may be performed a plurality of times by changing operation conditions such as high temperature sterilization and homogenization.

  Hereinafter, the present invention will be described with further detailed examples, but the present invention is not limited thereto. In the blending process, warm water at the above temperature is stirred in the tank, and the ingredients other than vitamin mix (mixed ingredients of vitamins) are added, mixed and stirred sequentially in consideration of ease of mixing and diffusing. To prepare a mixed solution. The order in which the raw materials are easily mixed and diffused varies depending on the amount and characteristics of the raw materials, and is charged in various orders at once or in a divided manner. For example, there is a method in which sugars, proteins, fats and minerals are charged in this order. . Another example is a method in which some sugars, proteins, other sugars, minerals, and fats are added in this order. As another example, there is a method in which oils and fats, proteins, sugars, and minerals are added in this order. This prepared solution was sterilized by heating with a steam injection method, and then homogenized with a homogenizer (homogenized with two-stage pressure) to obtain a sterilizing solution. Vitamin mix (mixed ingredient of vitamins), flavor (fragrance) and the like were added to and mixed with this sterilizing solution to obtain a final sterilizing solution. The final sterilizing solution was further heat sterilized (two-stage sterilization) using a steam infusion method, and then homogenized (homogenized with two-stage pressure) using a homogenizer to obtain a composition.

  To promote villi growth in the small intestine, increase the intrinsic muscle layer thickness of the small intestine, improve intestinal function, prevent tissue damage in the small intestine, or treat various inflammations, depending on symptoms, weight, etc. When administered (ingested) as a food or drink, the dosage is generally about 0.05 g to about 1000 g, preferably about 0.05 g to about 250 g, more preferably about 2.5 g to about 250 g in solid content per day. 50g. It can be administered to a subject in need of administration of the composition of the present invention at one time or dividedly, before meals, after meals, between meals and / or before going to bed. The dose can be appropriately adjusted individually according to the age, body weight, and purpose of administration. Further, the composition of the present invention can be used in place of a meal, and can also be used as a dietary aid.

  When the composition of the present invention is in the form of an acidic drug or food or drink, the pH can be adjusted to pH 2.0 to pH 6.0, preferably pH 3.0 to pH 5.0.

Moreover, the use of the composition of the present invention described above can also be expressed as (1) to (30) below.
(1) A method for promoting villus growth of the small intestine, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, a fat and oil as a lipid, and isomaltulose as a carbohydrate.
(2) Increasing the thickness of the intrinsic muscle layer of the small intestine, comprising the step of administering a hydrolyzate of milk protein and protein derived from fermented milk as protein, fat and oil as lipid, and isomaltulose as carbohydrate How to make.
(3) A method for improving intestinal tract function, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, an oil or fat as a lipid, and isomaltulose as a carbohydrate.
(4) A method for preventing tissue damage in the small intestine, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, a fat and oil as a lipid, and isomaltulose as a carbohydrate.
(5) A method for suppressing inflammation, comprising a step of administering a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, an oil or fat as a lipid, and isomaltulose as a carbohydrate.
(6) Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate in the production of a composition for promoting villi growth in the small intestine .
(7) In the manufacture of a composition for increasing the thickness of the intrinsic muscle layer of the small intestine, a hydrolyzate of milk protein and fermented milk-derived protein as protein, fats and oils as lipid, and isomaltulose as carbohydrate Use of the composition.
(8) Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate in the production of a composition for improving intestinal function.
(9) Use of a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as a lipid, and isomaltulose as a sugar in the manufacture of a composition for preventing tissue damage in the small intestine .
(10) Use of a composition comprising milk protein hydrolyzate and fermented milk-derived protein as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate in the production of an anti-inflammatory composition.
(11) A composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in a method for promoting villi growth in the small intestine.
(12) A composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in a method for increasing the thickness of the intrinsic muscle layer of the small intestine object.
(13) A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in the method for improving intestinal tract function.
(14) A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as lipids, and isomaltulose as a carbohydrate for use in a method for preventing tissue damage in the small intestine.
(15) A composition containing a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate for use in an inflammation suppression method.
(16) A method for improving intestinal tract function, comprising a step of administering a composition comprising a protein derived from fermented milk.
(17) A method for improving intestinal function, comprising a step of administering a hydrolyzate of milk protein and a protein derived from fermented milk as a protein and isomaltulose as a carbohydrate.
(18) A method for preventing tissue damage of the small intestine, comprising a step of administering a composition comprising a protein derived from fermented milk.
(19) A method for preventing tissue damage in the small intestine, comprising a step of administering a hydrolyzate of milk protein and a protein derived from fermented milk as a protein and isomaltulose as a carbohydrate.
(20) A method for suppressing inflammation, comprising a step of administering a composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein.
(21) Use of fermented milk-derived protein in the manufacture of a composition for improving intestinal function.
(22) Use of a hydrolyzate of milk protein and a protein derived from fermented milk as a protein and isomaltulose as a carbohydrate in the manufacture of a composition for improving intestinal function.
(23) Use of a protein derived from fermented milk in the manufacture of a composition for preventing tissue damage in the small intestine.
(24) Use of a composition comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, and isomaltulose as a carbohydrate in the manufacture of a composition for preventing tissue damage in the small intestine.
(25) Use of a composition containing a hydrolyzate of milk protein and a protein derived from fermented milk as a protein in the production of an anti-inflammatory composition.
(26) A composition comprising a fermented milk-derived protein for use in a method for improving intestinal tract function.
(27) A composition comprising, as a protein, a hydrolyzate of milk protein and a protein derived from fermented milk and isomaltulose as a carbohydrate for use in a method for improving intestinal function.
(28) A composition comprising a protein derived from fermented milk for use in a method for preventing tissue damage in the small intestine.
(29) A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as proteins and isomaltulose as a carbohydrate for use in a method for preventing tissue damage in the small intestine.
(30) A composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein for use in an inflammation suppression method.

  Examples of the composition of the present invention include MEIN (Meiji Dairies Co., Ltd.). The composition containing the MEIN component can be expressed as a composition containing the components shown in Table 4.

  Table 5 below shows composition examples of milk phospholipids (also referred to as milk-derived phospholipids and milk lecithin) for the fats in Table 4.

  Table 6 below shows examples of fatty acid compositions for the fats in Table 4.

  It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.

Effect of nutritional composition on reducing intestinal tissue damage (1)
Experiments were conducted using the nutritional composition of the present invention and a general liquid food (Maybalance: Meiji Dairies Co., Ltd.) and liquid food A (impact: Ajinomoto Pharma Co., Ltd.) as a comparative control, and the small intestine 24 hours after ConA administration The degree of tissue damage was measured.

As animals, C57BL / 6 mice (6 weeks old, male) were purchased from Nippon SLC Co., Ltd. and used. The breeding was performed in an environment of 21.0 ± 2.0 ° C., humidity 55.0 ± 15.0%, and light / dark switching every 12 hours (light period: 7-19 o'clock). Feed and drinking water were freely consumed throughout the experiment.
The purchased animals were acclimated for 1 week and then divided into 3 groups using body weight as an index. The experimental groups were Group 1: General Liquid Food (Meiji Dairy: May Balance), Group 2: Nutrient Composition (Meiji Dairy: MEIN), Group 3: Liquid Food A (Ajinomoto Pharma: Impact) and were raised for 2 weeks . Tables 7 and 8 show the compositions of the general liquid food, the nutritional composition, and the liquid food A. The isomaltulose used in this example is a substance represented by CAS Registry Number 13718-94-0 and chemical formula C ₁₂ H ₂₂ O ₁₁ .

  ConA (Sigma) was administered at a dose of 12 mg / kg into the tail vein, and blood was collected from the abdominal vena cava under ether anesthesia 24 hours after administration, and then the small intestine was removed. The small intestine was fixed with 6% to 3cm from the bottom of the stomach with a 10% formalin solution, then embedded in a normal manner, a tissue specimen was prepared, and hematoxylin / eosin staining was performed. The area of the mucosa layer including the villi and the entire intrinsic muscle layer in an image obtained by photographing a tissue specimen at 100 times using a digital microscope (Keyence) was measured. The results are shown as mean ± SD (n = 7-9). Statistical analysis was performed using SPSS one-way analysis of variance followed by Scheffe test, and p <0.05 was considered significant.

  The results are shown in FIGS. As a result of comparing the small intestine area, the nutritional composition intake group showed the highest value, and decreased in the order of the general liquid food and the liquid food A intake group (FIG. 1). There was a significant difference between the nutritional composition intake group and the liquid food A intake group. Further, from the histological image shown in FIG. 2, it was confirmed that the administration of ConA caused damage such as damage to the small intestinal mucosa epithelium, dropout, and decrease in the thickness of the muscle layer. On the other hand, it was the nutritional composition intake group that showed a histological profile close to normal (FIG. 2), and it was also shown from this result that the degree of such small intestinal damage was reduced by the intake of the nutritional composition. .

Effect of nutritional composition on reducing intestinal tissue damage (2)
Experiments were performed using the nutritional composition of the present invention and Maybalance as a comparative control to evaluate cytokine production in the small intestine 2 hours after ConA administration and the degree of tissue damage 24 hours later.

As animals, C57BL / 6 mice (6 weeks old, male) were purchased from Nippon SLC Co., Ltd. and used. The breeding was performed in an environment of 21.0 ± 2.0 ° C., humidity 55.0 ± 15.0%, and light / dark switching every 12 hours (light period: 7-19 o'clock). Feed and drinking water were freely consumed throughout the experiment.
The mice were acclimated for 1 week and then divided into 4 groups using body weight as an index. The experimental groups were: 1 group: general liquid food (necropsy 2 hours after ConA administration), 2 group: nutritional composition (necropsy 2 hours after ConA administration), 3 groups: general liquid food (necropsy 24 hours after ConA administration), 4 Group: Breeded for 2 weeks on each diet of nutritional composition (necropsy 24 hours after ConA administration). The same general liquid food and nutritional composition as in Example 1 were used.

ConA (Sigma) was administered at a dose of 12 mg / kg into the tail vein, blood was collected from the abdominal vena cava under ether anesthesia 2 hours and 24 hours after administration, and the liver, spleen, small intestine, and large intestine were removed. . The length of the small intestine was measured, the weight from 11 cm to 10 cm from the bottom of the stomach, and the large intestine was measured from 5 cm below the cecum. The organ weight was also measured for each organ. The small intestine was cut from 6 cm to 3 cm below the stomach, fixed with 10% formalin solution, and a tissue specimen was prepared by a usual method, followed by hematoxylin / eosin staining. Cytokines in an organ were prepared according to the method described below, and then measured using a Mouse inflammation kit (CBA method: Nippon Becton Dickinson Co., Ltd.), and the results were expressed as a concentration per organ weight. The results are shown as mean ± SD. Statistical analysis was performed using Student's t test or Mann-Whitney test after one-way analysis of variance with SPSS.
<Method for measuring cytokine concentration in organs>
1. The organ was added to 100 mg and 1 ml of lysis buffer, and homogenized with a glass-Teflon (registered trademark) homogenizer.
Lysis buffer
20 mM Tris / HCl (pH 7.4)
0.25M sucrose
2mM EDTA ・ 2Na
10 mM EGTA
1% Tritonx-100
+ 1tablet of Complete Mine protease inhibitor cocktail tablets / 10ml
2. The homogenate homogenized was centrifuged at 100,000 g for 40 minutes, and the supernatant was collected (operated with ice cooling).
3. The protein concentration in the supernatant was measured using a BCA protein assay kit. Further, the amount of cytokine per protein was also measured by the same method as that for plasma cytokines.
(Reference: Journal of Neuroinflammation 2008, 5:10, Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment Liya Qin, Jun He, Richard N Hanes, Olivera Pluzarev, Jau-Shyoung Hong and Fulton T Crews)

The results are shown in Tables 9-11.
There was no difference in body weight between groups. On the other hand, the small and large intestine weights showed a significant increase. It was also shown that the length of the intestine was significantly longer (Table 9).
Next, the results of measuring plasma and organ cytokine concentrations are shown (Table 10). Plasma cytokines and chemokines such as TNF-α, IFN-γ, MCP-1 and IL-6 were significantly elevated in the general liquid food group, and significantly lower in all of the nutritional composition groups. It was. IL-12 and IL-10 concentrations were below the detection limit. Cytokines in the organs were most produced in the spleen, and the concentrations of IFN-γ, MCP-1 and IL-6 in the nutrient composition group were significantly lower than those in the general liquid food group. In the liver, TNF-α (p = 0.07), IFN-γ, and MCP-1 were significantly lower in the nutrition composition group than in the general liquid food group. In the small intestine, MCP-1 and IL-6 were significantly low. ConA is known to cause significant damage to the liver, and suppression of liver damage in the nutritional composition group has been shown to be related to suppression of TNF-α production in the liver. . Since the increase in plasma IL-6 concentration cannot be explained only by the IL-6 concentration in the liver, it is considered that the production amount in the spleen contributed. In the small intestine, the concentration of inflammatory cytokines is lower than in other organs, but there is an increase in MCP-1 and IL-6 compared to normal, and the nutrient composition group is significantly lower than the general liquid food group Since the value was shown, it was considered to be involved in the reduction of disability.
Moreover, as a result of evaluating the pathological tissue of the small intestine 24 hours after administration of ConA at the level of 0 to 3 shown below, it was shown that the nutritional composition group reduces small intestinal disorders compared with the general liquid food group (Mann- whitney test, p = 0.021) (Table 11).

Growth-promoting action of mucosal epithelium and muscle layer of nutritional composition The small intestine, the large intestine weight and the small intestine tissue were evaluated after free intake of the nutritional composition of the present invention and the general liquid food for 2 weeks.

As animals, C57BL / 6 mice (6 weeks old, male) were purchased from Nippon SLC Co., Ltd. and used. The breeding was performed in an environment of 21.0 ± 2.0 ° C., humidity 55.0 ± 15.0%, and light / dark switching every 12 hours (light period: 7-19 o'clock). Feed and drinking water were freely consumed throughout the experiment.
After acclimation of the mice for 1 week, 5 mice per group were divided into 2 groups using body weight as an index. The experimental groups were group 1: general liquid food, group 2: nutrition composition, and were bred for 2 weeks. The same general liquid food and nutritional composition as in Example 1 were used.
Blood was collected from the abdominal vena cava under ether anesthesia, and then the liver, spleen, small intestine and large intestine were removed. The length of the small intestine was measured, the weight from 11 cm to 10 cm from the bottom of the stomach, and the large intestine was measured from 5 cm below the cecum. The organ weight was also measured for each organ. The small intestine was cut from 6 cm to 3 cm below the stomach, fixed with 10% formalin solution, and a tissue specimen was prepared by a usual method, followed by hematoxylin / eosin staining. Tissue specimens were biochemically tested for plasma ALT, AST, albumin, total protein, triglycerides, cholesterol, glucose, and urea nitrogen. The results are shown as mean ± SD. Statistical analysis was performed using Student's t test after one-way analysis of variance with SPSS.

Table 12 shows organ weights and blood biochemical test results of normal mice when a general liquid food and a nutritional composition were ingested for 2 weeks. In normal mice, there was no significant difference in body weight or liver between groups. In the relative weight of the spleen, the small intestine, and the large intestine, the nutrition composition group showed significantly higher values than the general liquid food group. On the other hand, no significant difference was found between all groups in the blood biochemical test results.
Next, normal small intestine tissue specimens were prepared, and the number of furs, the height of fur, and the thickness of the intrinsic muscle layer in one field of view taken at 150 times were measured (FIG. 3 and Table 13). In the nutrition composition group, there was no significant difference in the number of fur and the total length of the fur, compared with the general liquid food group, but the average fur length and intrinsic muscle layer thickness were significantly higher. Indicated. From these results, it was considered that the increase in the weight of the small intestine observed in the nutrition composition group was caused by the length of the fur and the thickness of the intrinsic muscle layer.

Increased intestinal permeability and inhibition of bacterial translocation of the nutritional composition Using the rat indomethacin-induced small intestinal injury model, the effect of the nutritional composition of the present invention on small intestinal injury was examined.

Animals were SD rats (6 weeks old, male) purchased from Japan SLC Co., Ltd. and used. The breeding was performed in an environment of 21.0 ± 2.0 ° C., humidity 55.0 ± 15.0%, and light / dark switching every 12 hours (light period: 7-19 o'clock). Feed and drinking water were freely consumed throughout the experiment.
The purchased animals were acclimated for 1 week and then divided into 6 groups using body weight as an index. They were bred for 2 weeks before administration of indomethacin with a general liquid food or nutritional composition. The same general liquid food and nutritional composition as in Example 1 were used. Thereafter, a solution of indomethacin in 5% NaHCO ₃ was administered subcutaneously at a dose of 10 mg / kg once a day for 2 consecutive days to induce small intestinal damage. Thereafter, the animals were reared with the same feed, and the first day of administration was set as day 0 and necropsied on days 4 and 8. Half of the normal groups not administered indomethacin were necropsied on day 4 and day 8.
Also, on day 1, day 3, day 7, phenolsulfonephthalein injection 0.6% “Daiichi Sankyo” (Daiichi Sankyo Co., Ltd.) was orally administered at 3 ml / body, and then urine was collected for 24 hours. The amount of PSP excretion was measured, and the result was expressed as the urinary PSP excretion rate. PSP is generally used in humans as an indicator of renal function. When PSP is administered orally, the excretion rate in the urine is very low, but when permeability increases due to ileal membrane damage, it penetrates the cell gap, enters the blood, and is excreted in the urine via the kidney The In this embodiment, it is used as an index of permeability of the intestinal membrane.
Fasting started at 5 pm the day before necropsy, and autopsy was performed after overnight fasting. After collecting blood under ether anesthesia, aseptically remove the mesenteric lymph node (MLN) and liver, measure the organ weight, and then homogenate the solution to a BL agar medium containing 5% horse defibrinated blood. At 37 ° C for 72 hours under aerobic and anaerobic conditions. In addition, Gram staining was performed to check whether the detected bacteria were Gram negative or Gram positive.
Next, the length of the small intestine was measured, the weight of the cecum and large intestine, and the pH of the cecum.
The general blood test was analyzed using an automated blood cell analyzer (Sysmex ST-1800i). The general blood test is used as an index for examining changes in various disease states. It is known that the increase in neutrophils and monocytes is caused by infection (bacteria).

Result 1
Increased permeability of the intestinal membrane was observed due to indomethacin-induced small intestinal injury, but it was shown that the enhanced intestinal permeability was significantly suppressed by intake of the nutritional composition as compared to the control group (FIG. 4). From the above results, it was shown that small intestine damage caused by indomethacin administration was suppressed by intake of the nutritional composition.
This result suggests that nutritional composition intake may prevent small intestinal disorders caused by nonsteroidal anti-inflammatory agents.

Result 2
Intestinal bacteria that remain in the digestive tract due to indomethacin-induced small intestinal damage breaks down the defense ability of the intestinal mucosa and decreases in immunity, transcends the barrier of the intestinal mucosal epithelium and migrates to the liver and mesenteric lymph nodes I know.
On days 4 and 8 of indomethacin administration, all mesenteric lymph nodes and liver (part) were taken, and the number of bacteria in the homogenized solution was measured by a culture method. From the results of this experiment, on the 4th day after indomethacin administration, the number of individuals in which no bacteria were detected in the mesenteric lymph nodes was 2 in 9 in the general liquid food group and 3 in 10 in the nutritional composition group. In the liver, it was detected in all individuals. On the 8th day, 1 out of 8 animals in the general liquid food group and 4 out of 8 animals in the nutritional composition group had no bacteria detected in the mesenteric lymph nodes. In the liver, no bacteria were detected in any individual in both the general liquid food group and the nutritional composition group. The result of the number of bacteria detected in each actual organ is shown in FIG. On day 4 of indomethacin administration, the number of bacteria detected in the mesenteric lymph nodes was not significantly different between the nutrient composition group and the general liquid food group (not shown). On the other hand, the nutrient composition group tended to be less in the liver (p = 0.068) (upper part of FIG. 5). Bacterial translocation (BT) to the liver was not observed on the 8th day of indomethacin administration, but the nutritional composition group significantly suppressed BT to the mesenteric lymph nodes compared to the general liquid food group (p <0.05) (bottom of FIG. 5).
The detected bacteria were aerobic Gram-positive bacteria.
From the above results, intake of the nutritional composition suppressed BT to the mesenteric lymph nodes and liver. In other words, it was shown that BT induced by small intestine damage by administration of indomethacin was suppressed by ingesting the nutritional composition. It was suggested that intake of the nutritional composition may protect the small intestine and prevent small intestinal disorders caused by non-steroidal anti-inflammatory agents.

Result 3
A general blood test was performed to examine changes before and after indomethacin administration. The general blood test is used as an index for examining changes in various disease states. It is known that the increase in neutrophils and monocytes is caused by infection (bacteria).
As a result of the test, no significant difference was observed between the nutritional composition group and the general liquid food group in normal individuals. On the other hand, in the indomethacin administration group, an increase in the white blood cell count was observed compared to normal individuals (FIG. 6). The increase in white blood cells was due to the increase in lymphocytes, neutrophils and monocytes (FIG. 6). The general liquid diet showed an increase in white blood cells on day 4 and continued to rise on day 7. On the other hand, in the nutritional composition, the increase in white blood cells peaked on day 4 and then decreased. Among leukocytes, neutrophil counts and monocyte counts were particularly different between groups. There was no difference between the groups on Day 4, but on day 7, the nutrient composition group showed lower values for neutrophils and monocytes than the general liquid food group.
From the above results, it is considered that the increase in the number of neutrophils and monocytes was suppressed as a result of the suppression of bacterial translocation induced by non-steroidal anti-inflammatory agent-induced small intestinal injury in the nutritional composition group.

Changes when the whey protein hydrolyzate, isomaltulose, and protein derived from fermented milk are removed from the composition of the nutritional composition 1
As animals, C57BL / 6 mice 6-week-old males were purchased from Nippon SLC Co., Ltd. and used. The purchased mice were acclimated for 1 week and then divided into 5 groups using body weight as an index.
Group composition:
Group 1: General liquid food (Meiji Dairies: May Balance)
Group 2: Nutritional composition (Meiji Dairy Industry: MEIN)
Group 3: Nutrient composition-whey protein hydrolyzate (nutrient composition-P)
(Nutrition composition excluding whey protein hydrolyzate)
Group 4: Nutrient composition-whey protein hydrolyzate-isomaltulose (nutrient composition-PI)
(Nutrition composition excluding whey protein hydrolyzate and isomaltulose)
Group 5: Nutrient Composition-Whey Protein Hydrolyzate-Isomalulose-Quark (Nutritional Composition-PIQ)
(Nutrition composition excluding whey protein hydrolyzate, isomaltulose and quark)
The 5 groups were raised for 2 weeks. It was prepared by adding casein instead of quark and whey protein hydrolyzate as protein sources in the nutritional composition, and dextrin instead of isomaltulose as a sugar source.
ConA (Sigma) was administered at a dose of 12 mg / kg into the tail vein, and blood was collected from the abdominal vena cava under ether anesthesia, and the liver, spleen, cecum, and small intestine were removed. The small intestine was weighed at the center 10 cm.

  The results of body weight and organ weight are shown in FIG. 7 and Table 14 (body weight 24 hours after administration of ConA and organ weight per body weight).

平均±SD (n=8〜10)

Mean ± SD (n = 8-10)

There were no significant differences between groups in body weight, liver per body weight, or spleen weight. The cecal weight was significantly increased in the nutritional composition group compared to the general liquid food group. The group with whey protein hydrolyzate, isomaltulose and quark removed from the nutritional composition showed significantly lower cecal weight than the nutritional composition group, so these three ingredients are involved in cecal fermentation. It was shown that. The small intestine weight was significantly higher in the nutritional composition group than in the general liquid food group. In the group where whey protein hydrolyzate, isomaltulose, and quark were removed from the nutritional composition, the weight of the small intestine was significantly lower than that of the nutritional composition group. The possibility of being involved in
The possibility that three components of whey protein hydrolyzate, isomaltulose and quark are involved in the intestinal protective action and anti-inflammatory action of the nutritional composition was shown.

Changes when the whey protein hydrolyzate, isomaltulose, and protein derived from fermented milk are removed from the composition of the nutritional composition 2
As animals, C57BL / 6 mice 6-week-old males were purchased from Nippon SLC Co., Ltd. and used. The purchased mice were acclimated for 1 week and then divided into 6 groups using body weight as an index.
Group composition (general liquid food, nutrient composition similar to Example 6 was used)
Group 1: General Liquid Food Group 2: Nutritional Composition Group 3: Nutritional Composition-Whey Protein Hydrolyzate (-P)
(Nutrition composition excluding whey protein hydrolyzate)
Group 4: Nutrient composition-isomaltulose (-I)
(Nutrition composition-excluding isomaltulose)
Group 5: Nutrient Composition--Quark (-Q)
(Nutrition composition without quark)
Group 6: Nutrient Composition-Whey Protein Hydrolyzate-Isomalulose-Quark (-PIQ)
(Nutrition composition excluding whey protein hydrolyzate, isomaltulose and quark)
The 6 groups were raised for 2 weeks. It was prepared by adding casein instead of quark and whey protein hydrolyzate as protein sources in the nutritional composition, and dextrin instead of isomaltulose as a sugar source.
ConA (Sigma) was administered at a dose of 12 mg / kg into the tail vein, and blood was collected from the tail vein 2, 4, and 8 hours after administration, and the next day, blood was collected from the abdominal vena cava under ether anesthesia. The spleen, cecum, small intestine, and large intestine were removed. Plasma ALT and AST were measured with Fuji Dry Chem.

Result 1
Table 15 shows the results of body weight and organ weight on the last day.

  There were no significant differences between groups in body weight and organ weight per body weight (liver, spleen). The small intestine and cecal weights were significantly higher in the nutrient composition group, group 3 (-whey protein hydrolyzate), and group 4 (-isomaltulose) compared to the general liquid food group.

Result 2
The results of AST and ALT 24 hours after ConA administration are shown in FIG. Compared with the nutritional composition group, an increase in AST and ALT was observed in the group excluding only whey protein hydrolyzate (group 3) and the group excluding only quark (group 5). In the group (group 4) excluding only isomaltulose, the AST and ALT values were almost the same as those in the nutritional composition group. In addition, when whey protein hydrolyzate and isomaltulose and quark were removed from the nutritional composition (Group 6), the ALT value was significantly higher than that of the nutritional composition group. Was mainly involved in whey protein hydrolyzate and quark.

  It was considered that whey protein hydrolyzate and quark were the main components of the anti-inflammatory effect of the nutritional composition. It was shown that quark is the main ingredient in maintaining intestinal function and protecting the intestinal tract of the nutritional composition, but three types of materials including whey protein hydrolyzate and isomaltulose are involved.

[Reference Example 1] Preparation of whey protein hydrolyzate Whey protein isolate (WPI, Davisco) with a protein content of approximately 90% as a dry product is dissolved in distilled water at a protein content of 8% (w / v). did. The solution was heat treated at 85 ° C. for 2 minutes to denature the protein. The pH of the solution after heating was about 7.5. In the hydrolysis, Alcalase 2.4L (enzyme, Novozymes) was added at a concentration of 2.0% with respect to the substrate and reacted at 55 ° C. for 3 hours. Next, PTN 6.0S (Novozymes Japan), a trypsin derived from swine, was added to the substrate at a concentration of 3.0% and reacted at 55 ° C. for 3 hours. Total hydrolysis time was 6 hours. The pH at the end of the reaction was about 7.0. The whey protein hydrolyzate was subjected to a UF membrane treatment (Millipore Ultra Free-MC) having a molecular weight cut-off of 10,000 after centrifugation (20,000 × g, 10 minutes).

The permeate (permeate) was subjected to reverse phase HPLC.
Conditions Sample: UF permeate of whey protein hydrolyzate Column: C18 SG120 (Shiseido) 4.6 mmφ × 250 mm
Eluent: A; 0.1% aqueous trifluoroacetic acid / acetonitrile 5/95
B; 0.1% trifluoroacetic acid aqueous solution / acetonitrile 32/68
A → B 60-minute linear concentration gradient Flow rate: 1 mL / min
Detection: 215 nm (ultraviolet / visible detector)

The composition of the present invention exhibits enhanced intestinal function such as promoting the growth of villi of the small intestine and increasing the thickness of the intrinsic muscle layer. Therefore, in patients with intestinal dysfunction caused by administration of antibiotics or anti-cancer drugs such as elderly people or cancer patients with intestinal tract function decline, and patients with intestinal tract function decline after long-term nutrition such as surgery and ICU. Useful for improving intestinal function. It is also useful for healthy individuals to grow intestinal villi and improve intestinal function.
The composition of the present invention is also useful in preventing tissue damage in the small intestine. Furthermore, since the composition of the present invention exhibits an anti-inflammatory action, it is also useful as an anti-inflammatory agent.

Claims (27)

A composition for promoting villi growth in the small intestine, comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, fats and oils as lipid, and isomaltulose as carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to claim 1. The composition according to claim 1 or 2, wherein the protein derived from fermented milk is derived from fresh cheese. A composition for increasing the thickness of the intrinsic muscle layer of the small intestine, comprising a hydrolyzate of milk protein as a protein and a protein derived from fermented milk, fats and oils as lipids, and isomaltulose as a carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to claim 4. The composition according to claim 4 or 5, wherein the fermented milk-derived protein is derived from fresh cheese. A composition for improving intestinal function, comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, fats and oils as lipid, and isomaltulose as carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to claim 7. The composition according to claim 7 or 8, wherein the fermented milk-derived protein is derived from fresh cheese. A composition for preventing tissue damage of the small intestine, comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein, fats and oils as a lipid, and isomaltulose as a carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to claim 10. The composition according to claim 10 or 11, wherein the fermented milk-derived protein is derived from fresh cheese. An anti-inflammatory composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as protein, fats and oils as lipid, and isomaltulose as carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to claim 13. The composition according to claim 13 or 14, wherein the fermented milk-derived protein is derived from fresh cheese. The composition for improving intestinal tract function containing fermented milk origin protein. A composition for improving intestinal function, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as sugar. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition according to claim 17. The composition according to any one of claims 16 to 18, wherein the fermented milk-derived protein is derived from fresh cheese. A composition for preventing tissue damage of the small intestine, comprising a protein derived from fermented milk. A composition for preventing tissue damage of the small intestine, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The composition of claim 21. The composition according to any one of claims 20 to 22, wherein the protein derived from fermented milk is derived from fresh cheese. An anti-inflammatory composition comprising a milk protein hydrolyzate and a fermented milk-derived protein as proteins. 25. The composition of claim 24, further comprising isomaltulose as a carbohydrate. The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin 26. The composition of claim 24 or 25. 27. The composition according to any one of claims 24 to 26, wherein the fermented milk-derived protein is derived from fresh cheese.

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