CN102665750A - Nutritional composition beneficial to small intestine - Google Patents

Abstract

Using the mouse ConA-induced hepatitis model, cytokine production in the small intestine and spleen and small intestinal damage were investigated for the composition ingestion group of the present invention. As a result, it was found that in the composition ingestion group of the present invention, not only the increase in the production of cytokines in the liver and blood plasma was suppressed, but also the effect of suppressing the increase in the production of MCP-1 and IL-6 in the small intestine and liver was confirmed, and it was also shown that Reduction of tissue damage in the small intestine. The small intestine weight and large intestine weight of normal mice after ingesting the composition of the present invention for 2 weeks were measured and evaluated. It was found that the weight of the small intestine and the weight of the large intestine showed a significant increase, and the average length of the villi and the thickness of the muscularis propria were significantly higher compared with the control group.

Description

Nutritional composition beneficial to the small intestine

technical field

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

Background technique

The increasing number of lifestyle diseases in recent years has an important relationship with eating habits. Intake of essential nutrients is important to maintain and improve health, and it is desirable to maintain normal intestinal function in order to efficiently digest and absorb these nutrients. But in reality, disordered lifestyles, irregular eating habits, and mental disorders such as fear, sorrow, panic, etc., lead to intestinal dysfunction such as constipation and diarrhea. Furthermore, the persistence of these intestinal abnormalities leads to the development of diseases such as enteropathy and cancer. So far, yogurt and fermented beverages using lactic acid bacteria such as Lactobacillus, bifidobacteria, etc. (probiotics) showing intestinal function-improving effects have been widely used as foods. In addition, foods that can regulate intestinal function, such as oligosaccharides and dietary fibers that help useful microorganisms in the intestinal tract proliferate, are also widely used. Although such foods are known to have the effect of repairing the intestinal environment alone, they are unlikely to have a function of promoting the growth/repair of small intestinal villi, and the development of foods having such a function has been desired.

From a clinical point of view, pathological conditions that reduce the functional surface area of the small intestine can be bowel resection, radiation, intestinal ischemia or trauma, Crohn's disease, ulcerative colitis, and the like. For these pathological conditions, it is necessary to repair the damaged small intestinal mucosa and to improve the compensation function. For this purpose, specific nutrients such as glutamine, n-3 polyunsaturated fatty acids, and zinc are known to be important. Supplementation/administration of nutrients through the intestinal lumen is necessary to promote intestinal metabolic responsiveness such as metabolic/endocrine compliance and proliferation/repair of the small intestinal mucosa, while the passage of physiological intestinal contents such as bile/pancreatic juice secretion is a prerequisite. Nutrition can be provided by intravenous hypernutrition, hypercaloric infusion, or comprehensive parenteral nutrition, but these measures often lead to atrophy of the small intestinal mucosa, thereby further reducing intestinal function. Therefore, it is desired to develop pharmaceuticals or foods that are beneficial to the intestinal tract. A variety of enteral nutritional foods have been developed, and foods containing dietary fiber and having an intestinal function regulating effect have been developed. However, agents or comprehensive nutritional foods that can be used to maintain/improve intestinal functions, such as promoting the growth of small intestinal villi and increasing the thickness of the muscularis propria, have not been developed.

prior art literature

[Patent Document]

[Patent Document 1] WO 2004/047556

[Patent Document 2] Japanese Patent Laid-Open (JP-A) 2004-99563 (Published Unexamined Japanese Patent Application)

Contents of the invention

[Problem to be solved by the invention]

An object of the present invention is to provide a composition useful for maintaining/improving intestinal function. Alternatively, an object of the present invention is to provide a composition for promoting the growth of small intestinal villi, a composition for increasing the thickness of the muscularis propria of the small intestine, a composition for improving intestinal function, a composition for preventing small intestinal tissue damage, and anti-inflammatory compositions.

[means to solve the problem]

The inventors of the present invention prepared tissue samples of the normal liquid diet and the nutritional composition of the present invention ingestion groups using a mouse model of ConA-induced hepatitis, and examined small intestinal tissue damage and cytokine production in the small intestine and spleen. For cytokines, the production of the chemokine MCP-1 was investigated in addition to the production of TNF-α and IL-6. As a result, in the group that ingested the nutritional composition of the present invention, the effects of suppressing the increased production of MCP-1 and IL-6 in the small intestine and spleen, and suppressing the increased production of cytokines in plasma and liver were confirmed. In addition, it was found that the damage of small intestinal tissue was reduced (Examples 1 and 2).

Based on these results, the inventors of the present invention guessed that the intake of the nutritional composition of the present invention brought about some changes in the intestinal tract, and then measured the weights of the small intestine and large intestine of normal rats 2 weeks after the intake. In addition, samples of small intestinal tissue were prepared and evaluated. As a result, the weight of the small and large intestines showed a marked increase. In addition, evaluation of the small intestinal tissue did not reveal a difference in the number of villi compared to the control group, but the average length of the villi and the thickness of the muscularis propria showed significantly higher values than the control group. These results show that there is a protective effect against small intestinal injury, as well as an effect of promoting the growth of the muscular layer and small intestinal mucosal epithelium (Example 3).

In addition, the inventors of the present invention examined the urinary excretion rate of phenolsulfphthalein, an indicator of intestinal permeability, for the ingestion group of the normal liquid diet or the nutritional composition of the present invention using an indomethacin-induced small intestinal injury rat model. . Furthermore, in addition to general blood tests, translocation of bacteria to the liver and mesenteric lymph nodes was investigated. As a result, in the ingestion group of the nutritional composition of the present invention, enhancement of the permeability of the small intestinal membrane and inhibition of translocation of bacteria to the liver and mesenteric lymph nodes were shown. In addition, the general blood test results showed that in the nutritional composition ingestion group, increases in the number of neutrophils and monocytes in the blood accompanying small intestinal damage by indomethacin administration were suppressed. From the above results, it can be seen that the intake of the nutritional composition can protect the intestinal tract, and has the effect of inhibiting small intestinal damage against agents such as non-steroidal anti-inflammatory agents. It can also effectively prevent infections such as sepsis and pneumonia induced by bacterial translocation caused by intestinal disorders, and maintain the immune system in a normal state (Example 4).

Furthermore, the inventors of the present invention used a mouse model of ConA-induced hepatitis to investigate which components are involved in the hepatitis-suppressive effect of the obtained nutritional composition and maintenance of intestinal function, and its protective effect on small intestinal damage. The results showed that whey protein hydrolyzate, isomaltulose and quark were involved in the maintenance of intestinal function (Example 5). Furthermore, it was shown that whey protein hydrolyzate and quark are mainly involved in the hepatitis inhibitory effect (Example 6).

Based on these findings, the present application provides the following inventions:

[1] A composition for promoting the growth of small intestinal villi, comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, fat as lipid, and isomaltulose as sugar;

[2] The composition of [1], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[3] The composition of [1] or [2], wherein the fermented milk-derived protein is derived from fresh cheese;

[4] A composition for increasing the thickness of the muscularis propria of the small intestine, comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as carbohydrate;

[5] The composition of [4], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[6] The composition of [4] or [5], wherein the fermented milk-derived protein is derived from fresh cheese;

[7] A composition for improving intestinal function, comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, fat as lipid, and isomaltulose as carbohydrate;

[8] The composition of [7], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[9] The composition of [7] or [8], wherein the fermented milk-derived protein is derived from fresh cheese;

[10] A composition for preventing small intestinal tissue damage, comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as carbohydrate;

[11] The composition of [10], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[12] The composition of [10] or [11], wherein the fermented milk-derived protein is derived from fresh cheese;

[13] An anti-inflammatory composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, oil and fat as a lipid, and isomaltulose as a carbohydrate;

[14] The composition of [13], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[15] The composition of [13] or [14], wherein the fermented milk-derived protein is derived from fresh cheese;

[16] A method for promoting the growth of small intestinal villi, comprising the step of administering a composition comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as sugar ;

[17] A method for increasing the thickness of the muscularis propria of the small intestine comprising administering a combination comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, fat as lipid, and isomaltulose as carbohydrate steps of things;

[18] A method for improving intestinal function, comprising the step of administering a composition comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, fat as lipid, and isomaltulose as carbohydrate;

[19] A method for preventing small intestinal tissue damage, comprising the step of administering a composition comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, fat as lipid, and isomaltulose as carbohydrate ;

[20] A method for suppressing inflammation, comprising the step of administering a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as carbohydrate;

[21] Use of a composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, oil as lipid, and isomaltulose as sugar in the preparation of a composition for promoting the growth of small intestinal villi;

[22] Use of a composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as sugar in the preparation of a composition for increasing the thickness of the muscularis propria of the small intestine use;

[23] Use of a composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as sugar in the preparation of a composition for improving intestinal function;

[24] Use of a composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as sugar in the preparation of a composition for preventing small intestinal tissue damage;

[25] Use of a composition comprising milk protein hydrolyzate and protein derived from fermented milk as protein, oil as lipid, and isomaltulose as sugar in the preparation of an anti-inflammatory composition;

[26] A composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as carbohydrate, for use in a method for promoting growth of small intestinal villi;

[27] A composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as carbohydrate, for use in a method for increasing the thickness of the muscularis propria of the small intestine;

[28] A composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as carbohydrate, for use in a method for improving intestinal function;

[29] A composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as carbohydrate, for use in a method for preventing small intestinal tissue damage;

[30] A composition comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, oil as lipid, and isomaltulose as carbohydrate, for use in a method for inhibiting inflammation;

[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 and a protein derived from fermented milk as protein, and isomaltulose as carbohydrate;

[33] The composition of [32], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[34] The composition of any one of [31] to [33], wherein the fermented milk-derived protein is derived from fresh cheese;

[35] A composition for preventing small intestinal tissue damage, comprising a protein derived from fermented milk;

[36] A composition for preventing small intestinal tissue damage, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as carbohydrate;

[37] The composition of [36], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[38] The composition of 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 protein derived from fermented milk as proteins;

[40] The composition of [39], which further comprises isomaltulose as a saccharide;

[41] The composition of [39] or [40], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[42] The composition of any one of [39] to [41], wherein the fermented milk-derived protein is derived from fresh cheese;

[43] A method for improving intestinal function, comprising the step of administering a composition comprising fermented milk-derived protein;

[44] A method for improving intestinal function, comprising the step of administering a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as carbohydrate;

[45] The method of [44], wherein 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;

[46] The method of any one of [43] to [45], wherein the fermented milk-derived protein is derived from fresh cheese;

[47] A method for preventing small intestinal tissue damage, comprising the step of administering a composition comprising a fermented milk-derived protein;

[48] A method for preventing small intestinal tissue damage, comprising the step of administering a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as carbohydrate;

[49] The method of [48], wherein 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;

[50] The method of any one of [47] to [49], wherein the fermented milk-derived protein is derived from fresh cheese;

[51] A method for suppressing inflammation, comprising the step of administering a composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as protein;

[52] The method of [51], wherein the composition further comprises isomaltulose as a saccharide;

[53] The method of [51] or [52], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[54] The method of any one of [51] to [53], wherein the fermented milk-derived protein is derived from fresh cheese;

[55] Use of protein derived from fermented milk in the preparation of a composition for improving intestinal function;

[56] Use of milk protein hydrolyzate and protein derived from fermented milk as protein, and isomaltulose as sugar in the preparation of a composition for improving intestinal function;

[57] the use of [56], wherein 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;

[58] The use of any one of [55] to [57], wherein the fermented milk-derived protein is derived from fresh cheese;

[59] Use of protein derived from fermented milk in the preparation of a composition for preventing small intestinal tissue damage;

[60] Use of milk protein hydrolyzate and protein derived from fermented milk as protein, and isomaltulose as sugar in the preparation of a composition for preventing small intestinal tissue damage;

[61] the use of [60], wherein 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;

[62] The use of 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 preparation of an anti-inflammatory composition;

[64] the use of [63], wherein the composition further comprises isomaltulose as a saccharide;

[65] The use of [63] or [64], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[66] The use of any one of [63] to [65], wherein the fermented milk-derived protein is derived from fresh cheese;

[67] A composition comprising a protein derived from fermented milk, for use in a method for improving bowel function;

[68] A composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as a protein, and isomaltulose as a carbohydrate, for use in a method for improving intestinal function;

[69] The composition of [68], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[70] The composition of any one of [67] to [69], wherein the fermented milk-derived protein is derived from fresh cheese;

[71] A composition comprising protein derived from fermented milk, for use in a method for preventing tissue damage in the small intestine;

[72] A composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as a protein, and isomaltulose as a carbohydrate, for use in a method for preventing small intestinal tissue damage;

[73] The composition of [72], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin;

[74] The composition of any one of [71] to [73], wherein the fermented milk-derived protein is derived from fresh cheese;

[75] A composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as a protein, for use in a method for inhibiting inflammation;

[76] The composition of [75], which further comprises isomaltulose as a saccharide;

[77] The composition of [75] or [76], wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin; and

[78] The composition of any one of [75] to [77], wherein the fermented milk-derived protein is derived from fresh cheese.

Brief description of the drawings

Figure 1 presents a graph comparing the areas of the small intestine.

Figure 2 shows photographs of histopathological images of the small intestine (hematoxylin-eosin staining).

Figure 3 shows photographs of normal small intestine tissue (H-E staining, x150 magnification).

Figure 4 presents a graph showing the rate of PSP urinary excretion. Mean±SE, Student's t-test (Day 0: n=9; Day 2: n=9-10, Day 4: n=9-10, Day 8: n=8).

Figure 5 presents a graph showing the bacterial counts detected in the liver (upper panel) and mesenteric lymph nodes (lower panel) following indomethacin administration. Mean ± SE, Student's t-test; *: p<0.05 (Day 0: n=6, Day 4: n=8-9, Day 8: n=8).

Figure 6 presents graphs showing changes in blood neutrophil and monocyte counts after administration of indomethacin. Mean ± SE, Student's t-test; *: p<0.05 (Day 8: n=7-8).

Figure 7 presents graphs showing the weight of the small intestine (upper panel) and villi (lower panel) 24 hours after concanavalin A administration. Mean ± SD, Scheffe's test; *: p<0.05 (n=8-10). SF: normal liquid diet; ND: nutritional composition; -P: nutritional composition-whey protein hydrolyzate; -P-I: nutritional composition-whey protein hydrolyzate-isomaltulose; and -P-I-Q: nutritional composition - Whey Protein Hydrolyzate - Isomaltulose - Quark.

Figure 8 presents graphs showing AST and ALT activities in plasma 8 hours after concanavalin A administration. Mean ± SE, Mann-Whitney test; *: p<0.05 (n=5-9).

Embodiment of the invention

The present invention provides a composition for promoting the growth of small intestinal villi, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as sugar.

The growth of intestinal villi promotes the proliferation of intestinal epithelial cells. In addition, the growth of small intestinal villi is thought to promote nutrient absorption or repair of small intestinal damage. Therefore, the composition of the present invention can be used as, for example, "small intestinal villi growth agent", "small intestinal epithelial cell growth agent", "nutrient absorption promoter", and "small intestinal damage repair promoter". In addition, the above-mentioned composition of the present invention can be used to improve small intestine function of healthy individuals, improve nutrition of malnourished elderly people, maintain intestinal function of patients (ICU patients) with serious dysfunctions such as respiratory, circulatory and metabolic systems, and maintain brain function. Nutritional supplementation and maintenance of intestinal function in dysphagia patients with neurological disorders, for the improvement of intestinal function and nutritional status in chronic intestinal diseases such as ulcerative colitis and Crohn's disease, for chronic obstructive pulmonary disease (COPD) and nutrition Improvement of poor intestinal function and improvement of nutritional status, or improvement of nutritional status of patients with intestinal disorders due to antibiotics and anticancer agents such as cancer patients.

The present invention provides a composition for increasing the thickness of the muscularis propria of the small intestine, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as carbohydrate.

An increase in the thickness of the muscularis propria of the small intestine promotes peristaltic motility in the small and large intestine. In addition, an increase in the thickness of the muscularis propria of the small intestine may promote intestinal regulatory effects. Therefore, the composition of the present invention is useful as, for example, an "increase in the thickness of the muscularis propria of the small intestine", an "intestinal peristalsis promoter", and an "intestine regulator". In addition, the above-mentioned composition of the present invention can be used to improve small intestine function of healthy individuals, improve nutrition of malnourished elderly people, maintain intestinal function of patients (ICU patients) with serious dysfunctions such as respiratory, circulatory and metabolic systems, and maintain brain function. Nutritional supplementation and maintenance of intestinal function in dysphagia patients with neurological disorders, for the improvement of intestinal function and nutritional status in chronic intestinal diseases such as ulcerative colitis and Crohn's disease, for chronic obstructive pulmonary disease (COPD) and nutrition Improvement of poor intestinal function and improvement of nutritional status, and improvement of nutritional status of patients with intestinal disorders due to antibiotics and anticancer agents such as cancer patients.

The present invention provides a composition for improving intestinal function comprising fermented milk-derived protein. Furthermore, the present invention provides a composition for improving intestinal function, comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as saccharide.

Furthermore, the present invention provides a composition for improving intestinal function, comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, and isomaltulose as saccharide.

Improving intestinal function means promoting digestion and absorption of ingested nutrients, and promoting excretion of waste by intestinal peristalsis. Intestinal hypofunction leads to barrier disruption (including gut-associated lymphoid tissue (GALT) fragility, bacterial translocation (BT), sepsis, etc., leading to hypofunction of biological defenses. Intestinal hypofunction leads to malnutrition and induces gastric Poor production/secretion of intestinal hormones and neurotransmitters. In addition, in the present invention, "intestine" includes "small intestine" and "large intestine".

Therefore, the composition for improving intestinal function of the present invention has the function of promoting digestion and absorption or the function of intestinal regulation, and can be used as, for example, "intestinal function improving agent", "digestion and absorption accelerator", "anti-flatulence medicine", "waste excretion accelerator", and "intestinal immunity improving agent".

The so-called intestinal immunity refers to the immune response that occurs in the intestinal tract. Immune response is also called immunological response. When an antigen (non-self) enters a living body, the living body produces antibodies specifically reacting with the antigen or lymphocytes (sensitized lymphocytes) having specific immune functions, and induces various biological responses. A series of biological reactions that occur in response to the invasion of antigens is called immune response.

Since the digestive tract is a site that is easily exposed to foreign substances, lymphocytes surround the intestinal tract centered on the small intestine, and viruses that can become pathogens in food and foreign proteins degraded by digestive enzymes are ingested into the digestive tract. The gut is an important immune tissue that the organism first evolved to inhibit the absorption of these substances. An example of a poorly functioning digestive tract is intestinal immune disorders. Intestinal immune disorder means the reduction of the immune response function to remove foreign substances (such as viruses entering from the outside world) (ie antigens), and abnormal cells (such as cancer cells) (ie antigens) produced in the body, as well as waste products (ie antigens), It can increase the incidence of various diseases that occur in the intestinal tract and delay the cure. Improvement of these symptoms caused by intestinal immune disorders is called improving intestinal immunity.

In addition, the above-mentioned composition of the present invention can be used to improve small intestine function of healthy individuals, improve nutrition of malnourished elderly people, maintain intestinal function of patients (ICU patients) with serious dysfunctions such as respiratory, circulatory and metabolic systems, and maintain brain function. Nutritional supplementation and maintenance of intestinal function in dysphagia patients with neurological disorders, for the improvement of intestinal function and nutritional status in chronic intestinal diseases such as ulcerative colitis and Crohn's disease, for chronic obstructive pulmonary disease (COPD) and nutrition Improvement of poor intestinal function and improvement of nutritional status, or improvement of nutritional status of patients with intestinal disorders due to antibiotics and anticancer agents such as cancer patients.

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

Furthermore, the present invention provides a composition for preventing small intestinal tissue damage, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as proteins, and isomaltulose as saccharides.

The so-called small intestinal tissue damage refers to the damage caused by the destruction of tissues such as villi and muscularis propria due to the occurrence of cancer, ulcers, etc. in the intestinal tract, or the intake of antibiotics, anticancer agents, etc. by cancer patients. The above-mentioned composition of the present invention is used to prevent such small intestinal tissue damage. In this application, the term "damage" is used broadly to refer to "deficiency", "external injury", and "injury".

The above-mentioned composition of the present invention has the effect of promoting repair of the villi and the repair of the muscularis propria, and can be used, for example, as a "damage-preventing agent for small intestinal tissue", a "repair promoting agent for villi", and a "protective agent for the muscularis propria". Repair Accelerator".

In addition, the above-mentioned composition of the present invention can be used for improvement of intestinal function and nutritional status of chronic intestinal diseases such as ulcerative colitis and Crohn's disease, as well as for patients with intestinal disorders caused by antibiotics and anticancer agents, such as cancer patients. Nutritional status improved.

The present invention provides an anti-inflammatory composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as saccharide.

Furthermore, the present invention provides an anti-inflammatory composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as proteins.

The anti-inflammatory composition of the present invention has anti-inflammatory effects against chronic intestinal diseases such as ulcerative colitis and Crohn's disease. The so-called anti-inflammatory effect refers to the effect of inhibiting the production of inflammatory cytokines and MCP-1, which involves the infiltration of monocytes and T cells into tissues, thereby inhibiting the persistence and progression of inflammation. MCP-1, also known as monocyte chemotactic and activating factor (MCAF), was discovered as a monocyte chemoattractant. In terms of activity against monocytes, it has been elucidated not only to enhance chemotaxis, but also to act as a monocyte activating factor, such as enhancing antitumor activity and release of lysosomal enzymes and reactive oxygen species, and Induces the production of IL-1 and IL-6. In addition to monocyte activity, MCP1 also has the activity of inducing the release of chemical transmitters from basophils, as well as the chemotactic activity of T cells. The production and secretion of MCP-1 is found in various cells in the organism under the stimulation of cellular inflammatory cytokines and LPS, these cells are typically monocytes/macrophages, fibroblasts, or vascular endothelial cells, in addition , Constitutive production of MCP-1 (not caused by other stimulatory factors) was observed in specific tumor cells. Based on the research results so far, MCP-1 is considered to be involved in the tissue infiltration of monocytes and T cells in various inflammatory diseases, such as arteriosclerosis, delayed type allergy, rheumatoid arthritis, and lung diseases.

The anti-inflammatory composition of the present invention has an anti-inflammatory effect or an effect of reducing tissue damage, and can be used, for example, as an "anti-inflammatory agent" and a "tissue damage reducing agent".

In addition, the above-mentioned composition of the present invention can be used for maintaining intestinal function of patients with severe dysfunction such as respiratory, circulatory and metabolic systems (ICU patients), nutritional supplementation and intestinal function maintenance for dysphagia patients with brain/nerve disorders. Improved bowel function and improved nutritional status in chronic bowel disorders such as ulcerative colitis and Crohn's disease, improved bowel function and improved nutritional status in chronic obstructive pulmonary disease (COPD) and malnutrition, or due to antibiotics and anticancer Improvement of the nutritional status of patients with bowel disorders such as cancer patients caused by drug therapy.

The active ingredients contained in the above-mentioned various compositions of the present invention are reviewed below.

The composition of the present invention contains a milk protein hydrolyzate and a protein derived from fermented milk as proteins.

Examples of the milk protein hydrolyzate of the present invention include casein, milk protein concentrate (MPC, also known as total milk protein=TMP), whey, whey protein, whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin (α-La), β-lactoglobulin (β-Lg), and lactoferrin hydrolyzate.

For the definition, classification and production methods of milk proteins, see Japan Food Science, July 1989, pp.42-48, etc., or "Miruku Sogo Jiten (Comprehensive Dictionary of Milk)", January 20, 1992, Yamauchi K . and Yokoyama K. eds., Asakura Shoten Publishing.

Casein is the main protein in milk, etc., and is a phosphoprotein to which phosphoric acid is covalently bound. Casein is about 3% in cow's milk, about 0.9% in human milk, and accounts for about 80% of the protein in cow's milk.

Meanwhile, whey is, for example, a water-soluble component remaining after removing fat, casein fat-soluble vitamins, and the like from cow's milk. Whey generally refers to whey and rennet whey (also known as sweet whey) that can be obtained as a by-product in the production of natural cheese or rennet casein, or Refers to casein whey or quark whey (also known as acid whey) obtained when acid casein or quark is produced from skim milk. The main components of whey are proteins (α-lactalbumin, β-lactoglobulin, etc.), lactose, water-soluble vitamins, and salts (mineral components), and the characteristics of each have been identified as components of milk rather than whey clarified in the research.

Whey protein is a general term for proteins other than casein in, for example, cow's milk. Whey protein is composed of various components, such as α-lactalbumin, β-lactoglobulin, lactoferrin, etc., excluding lactose, vitamins, minerals, etc. When a milk source such as cow's milk is adjusted to be acidic, the protein that precipitates is casein, and the protein that does not precipitate is whey protein.

Examples of "whey-related products" include concentrated whey produced by concentrating whey; whey powder produced by drying whey; The resulting whey protein concentrate (hereinafter also referred to as "WPC"); defatted WPC produced by removing fat from whey using the microfiltration (MF) method or centrifugation method, followed by concentration using the UF method and drying treatment ( low-fat, high-protein); whey protein isolate (hereinafter referred to as "WPI"); Demineralized whey produced by desalination treatment by nanofiltration (NF) method and electrodialysis method, followed by drying treatment; The resulting mineral-concentrated whey. Among them, WPC containing 15% to 80% of milk protein in terms of dry weight (solid content) was defined as protein-concentrated whey powder by partial revision of the provincial order on dairy products on March 30, 1998, And classified as dairy products (whey concentrate, whey powder, WPC, and whey protein concentrate powder, as long as they have gone through the production steps specified in the provincial ordinance on dairy products, regardless of whether there is a desalination step or not)

In addition, like WPC and WPI, a milk protein concentrate (hereinafter also abbreviated as "MPC") produced by concentrating skim milk by the MF method or UF method and then drying it contains reduced contents of lactose, salt, etc., while cheese The content of protein and whey protein is relatively high.

Common devices and methods can be used for the concentration treatment, for example, methods such as heating under reduced pressure using a vacuum evaporator, a vacuum kettle, an ascending thin-film tubular concentrator, a descending thin-film tubular concentrator, a flat-plate concentrator, etc. . In addition, common equipment and methods can also be used for drying treatment, for example, spray drying method, drum drying method, freeze drying method, and vacuum (reduced pressure) drying method can be used.

The standard method for producing milk protein concentrate (MPC) is described as follows:

(1) the step of subjecting the skim milk to membrane separation and then concentrating the skim milk; or

(2) A step of subjecting skim milk to membrane separation and then concentrating and drying the skim milk.

Whey protein concentrate (WPC) is a substance obtained by concentrating the main protein of whey by the ultrafiltration (UF) method or the like, followed by drying. Generally, it is a general term for substances in which about 25% or more of the solid content is whey protein. They can be obtained by reducing the lactose and salt in the whey to increase the relative whey protein content to about 25%-80% of the solid content. Specifically, WPC containing 15%-80% of dry weight of milk protein is defined as protein-concentrated whey powder according to the provincial order on dairy products.

The standard method for producing whey protein concentrate (WPC) is described as follows:

(1) a step of membrane separation of whey followed by concentration; or

(2) The whey is subjected to membrane separation and then concentrated and dried.

Common devices and methods can be used for the concentration treatment, for example, methods such as heating under reduced pressure using a vacuum evaporator, a vacuum kettle, an ascending thin-film tubular concentrator, a descending thin-film tubular concentrator, a flat-plate concentrator, etc. . In addition, common equipment and methods can also be used for drying treatment, for example, spray drying method, drum drying method, freeze drying method, and vacuum (reduced pressure) drying method can be used.

Whey protein isolate (WPI) is a substance that can be obtained by concentrating the main protein of whey using ion exchange resin method or electrodialysis method, followed by drying. Generally, WPI is a general term for substances in which about 85% to 95% of the solid content is whey protein. They can be obtained by reducing the lactose, salt, etc. in the whey to increase the relative whey protein content to about 90% (85%-95%) of the solid content.

The standard method for producing whey protein isolate (WPC) is described as follows:

(1) performing membrane separation, ion exchange resin treatment, or electrodialysis treatment on the whey, and then performing a step of concentration; or

(2) The whey is subjected to membrane separation, ion exchange resin treatment, or electrodialysis treatment, followed by the steps of concentration and drying.

Common devices and methods can be used for the concentration treatment, for example, methods such as heating under reduced pressure using a vacuum evaporator, a vacuum kettle, an ascending thin-film tubular concentrator, a descending thin-film tubular concentrator, a flat-plate concentrator, etc. . In addition, common equipment and methods can also be used for drying treatment, for example, spray drying method, drum drying method, freeze drying method, and vacuum (reduced pressure) drying method can be used.

For the milk protein hydrolyzate of the present invention, the enzymes normally used to hydrolyze whey protein are, for example, pepsin, trypsin, and chymotrypsin. Yet also have the report (Food Technol., 48: 68-71, 1994; Trends Food Sci. Technol., 7: 120-125, 1996; and Their Applications: pp. 443-472, 1997). Whey proteolytic enzyme activity varies widely. Pepsin degrades denatured α-La and α-La, but not natural β-Lg (Neth. Milk dairy J., 47:15-22, 1993). Trypsin slowly hydrolyzes α-La but hardly degrades β-Lg (Neth. Milk dairy J., 45:225-240, 1991). Chymotrypsin degrades α-La rapidly, whereas β-Lg is slow. Papain hydrolyzes bovine serum albumin (BSA) and β-Lg, but α-La shows resistance to it (Int. Dairy Journal 6:13-31, 1996a). However, α-La not bound to Ca is completely degraded by papain under acidic pH conditions (J. Dairy Sci., 76:311-320, 1993).

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

Hydrolysis of peptide chains increases the number of charged groups and hydrophobicity, reduces molecular weight, and changes molecular configuration (J. Dairy Sci., 76:311-320, 1993). Changes in functional characteristics largely depend on the degree of hydrolysis. The most commonly observed changes in whey protein function are increased solubility and decreased viscosity. Generally, at higher degrees of hydrolysis, the hydrolyzate does not precipitate, even with heating, and is highly soluble at a pH of 3.5-4.0. Hydrolysates also have a much lower viscosity than intact proteins. This difference is especially pronounced when the protein concentration is high. Other effects include changes in gelling properties, increased thermal stability, enhanced emulsification and foaming capabilities, and decreased emulsion and foam stability (Int. Dairy journal, 6:13-31, 1996a; Dairy Chemistry 4, pp.347-376 , 1989; J. Dairy Sci., 79:782-790, 1996).

A variety of bioactive oligopeptides derived from milk proteins are known ((Yoshikawa, M, "New Horizon in Milk Science", Yoshikawa, M.ed., pp.188-195, Kougaku Shuppan, 1998; Otani, H., " New Horizon in Milk Science", Yoshikawa, M.ed., pp.97-99, Kougaku Shuppan, 1998; Otani, H., Milk Science, 47:183, 1998; Trends in Food Science and Technology, 9:307-319 , 1998). One such example is a peptide with angiotensin-converting enzyme (ACE) inhibitor activity (hypertensive effect).

There are some reports on various peptides that may have ACE inhibitory activity, which were speculated by in vitro assays (for example, J.Dairy Res., 67:53-64, 2000; Br.J.Nutr., 84: S33-S37, 2000). There are also some research reports (for example, 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).

Based on these reports, ACE inhibitory activity is believed to be present in many fractions obtained using column-based separations. Therefore, the molecular characteristics of ACE inhibitory substances are diverse. In fact, ACE inhibition was found in a variety of proteins, proteases and hydrolysates produced under hydrolysis conditions. This fact suggests that various peptides with different amino acid sequences may have ACE inhibitory activity. Due to the chemical diversity of these peptides, purification of hydrolysates using chromatography is often accompanied by a loss of a fraction of the active peptides. During hydrolysis, ACE inhibitory activity is continuously produced and degraded. When these two processes are optimized, maximum hydrolyzate activity is obtained. ACE inhibitory activity was determined for all hydrolyzate peptide compositions and is dependent on the specificity of the hydrolase and the treatment conditions.

There is a report on whey protein hydrolyzate optimization (using a surface response methodology, response surface methodology) to maximize ACE inhibitory activity and keep the required hydrolysis to a minimum (International Dairy Journal 12:813-820, 2002 ).

The milk protein hydrolyzate used in the present invention has the effect of inhibiting the in vivo production of TNF-α and IL-6 induced by LPS. Therefore, taking the inhibitory effect on LPS-induced TNF-α and/or IL-6 production as an indication, the above-mentioned literature can be referred to to optimize the conditions of milk protein hydrolysis (denaturation temperature, pH, temperature, hydrolysis time and enzyme/substrate ratio) (International Dairy Journal 12:813-820, 2002).

In addition to the literature cited above, there are many patents (published patent applications and patents) related to milk protein hydrolysates. Examples include: a patent (JP 2,986,764) involving the separate hydrolysis of casein and whey proteins, followed by adsorption to remove hydrophobic components, followed by mixing casein and whey proteins in specified ratios; Patent for hydrolysis of whey protein by protease followed by removal of enzyme and insoluble hydrolyzate (JP 3,222,638); regarding the molar ratio of BCAA/aromatic amino acid produced by degradation of β-lactalbumin of 10% or higher, wherein aromatic amino acid is less than 2.0%, a patent on a mixture of peptides with an average molecular weight of several hundred to several thousand (JP 3,183,945); a patent on the selective enzymatic degradation of β-lactalbumin in whey protein (JP 2,794,305); (B.licheniformis) and/or Bacillus subtilis (B.subtilis) protease, using non-constant pH (non-pH-stat) technology to hydrolyze whey protein to 15% ~ 30% (glucose equivalent; DE), and then obtain Patent for ultrafiltration membrane filtrate with a molecular weight cut-off value greater than 10,000 (JP 3,167,723).

Whether the hydrolyzates described in the above documents, patents and patent applications inhibit the production of TNF-α and IL-6 induced by LPS can be determined using known detection systems (such as, Experimental Medicine Supplementary Vol. "Bio Manual UP Experiment Series" , Cytokine Experiment Methods, Miyajima, A., Yamamoto, M.ed., Yodosha, (1997)).

Five parameters such as preheating, enzyme-substrate ratio (E/S), pH, hydrolysis temperature, and hydrolysis time were selected as condition optimization.

Preheating: 65-90°C

E/S: 0.01-0.2

pH: 2-10

Hydrolysis temperature: 30-65°C

Hydrolysis time: 3 hours to less than 20 hours

Examples of enzymes used include the following enzymes from Nova Nordisk:

1) Endoprotease

Protease derived from Bacillus licheniformis: Alcalase (registered trademark)

Protease derived from Bacillus lentus: Esperase (registered trademark)

Protease derived from Bacillus subtilis: Neutrase (registered trademark)

Protease of bacterial origin: Protamex (registered trademark)

Porcine pancreas trypsin: PTN (registered trademark)

2) Exoprotease

Protease derived from Aspergillus oryzae: Flavorzyme (registered trademark)

Carboxypeptidase from porcine or bovine viscera

Examples of enzymes other than the above-mentioned enzymes include animal-derived pancreatin (pancreastin), pepsin, plant-derived papain, bromelain (bromeline), microorganisms (eg, lactobacillus, yeast, mold, and mycobacteria) Sources of endo- and exo-proteases, as well as their crude purifications and bacterial homogenates. In addition, an enzyme combination of Alcalase derived from Bacillus licheniformis and PTN (trypsin) derived from porcine pancreas is often used as an enzyme combination.

The method of Reference Example 1 described later is an example of a method for preparing a whey protein hydrolyzate.

Milk protein hydrolyzates used in the present invention include: enzymatic hydrolyzates that themselves inhibit LPS-induced TNF-α and/or IL-6 production; retentate or permeate after ultrafiltration; and commercial milk that exhibit similar activity protein hydrolyzate.

Whey protein hydrolyzates usable in the present invention include the following examples. Japanese Patent No. 3,183,945 discloses a whey protein hydrolyzate (a mixture of peptides with a molecular weight of 200 to 3,000), which is obtained by hydrolyzing heat-denatured whey protein isolate (WPI) with endopeptidase and exopeptidase, and then It is prepared by using ion exchange resin to absorb the aromatic amino acid in the hydrolyzate. The whey protein hydrolyzate has a Fischer ratio of 10 or more, a branched-chain amino acid content of 15% or more, and an aromatic amino acid content of less than 2%.

Japanese Patent Application Laid-Open No. Hei 6-50756 (unexamined Japanese national phase publication corresponding to non-Japanese international publication) discloses an odorless, slightly bitter whey protein hydrolyzate. The hydrolyzate was produced as follows. A 12% aqueous solution of whey protein concentrate (WPC) with a protein content of at least 65% is heated at 60°C or higher and then hydrolyzed to 15°C using Alcalase derived from Bacillus licheniformis and Neutrase derived from Bacillus subtilis % ~ 35% DH. The hydrolyzate was passed through an ultrafiltration (UF) membrane with a cutoff above 10,000, concentrated by nanofiltration (NF), and the NF retained solution was spray dried.

Without being limited thereto, commercial milk protein hydrolyzates used in the present invention include, for example, Peptigen IF-3080, Peptigen IF-3090, Peptigen IF-3091 and Lacprodan DI-3065 (Arla Foods), WE80BG (DMV), Hyprol 3301, Hyprol 8361, Hyprol 8034 (Kerry), Tatua2016, HMP406 (Tatua), Whey Hydrolysate 7050 (Fonterra), and Biozate3 (Davisco). An example of a method for preparing a protein hydrolyzate is a method for preparing a whey protein hydrolyzate comprising the following steps (1) to (5):

(1) mixing whey protein containing at least 65% protein on a dry matter basis with water to produce a slurry having a protein content of up to 20%;

(2) heated to a temperature higher than 60°C;

(3) Utilize the protease that can be produced from Bacillus licheniformis and/or Bacillus subtilis, carry out proteolysis to 15%～35% DH to the mixture from step (2) by non-constant pH (non-pH-stat) method;

(4) separating the mixture from step (3) on an ultrafiltration/microfiltration device with a cut-off of 10,000 or higher such that the permeate constitutes a protein hydrolyzate; and

(5) Stop hydrolysis by deactivating the above-mentioned enzymes.

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

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

Preferably, the hydrolysis in the above step (3) is carried out until 20%-30% DH.

Preferably, the above-mentioned ultrafiltration/microfiltration device has a cut-off value of 50,000 or higher.

Preferably, the mixture obtained after the above step (3) or step (5) is treated with activated carbon in a relative amount of 1% to 5% (calculated relative to the dry matter content), preferably at a temperature between 50°C and 70°C5 minutes or more, then remove the charcoal.

Preferably, after the above step (5), the product is concentrated by nanofiltration/ultrafiltration (hyperfiltration)/reverse osmosis, and/or evaporation, preferably at a temperature between 50°C and 70°C, and then the retained material is collected as 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 of producing whey protein hydrolyzate is characterized as follows:

(1) mixing whey protein containing at least 65% protein on a dry basis with water to produce a slurry having a protein content of up to about 20%, or preferably 12%;

(2) heated to a temperature higher than 60°C;

(3) using a protease which can be prepared from Bacillus licheniformis, preferably Alcalase (registered trademark), and/or a protease which can be obtained from Bacillus subtilis, preferably Neutrase (registered trademark), to the mixture from step (2) by a non-constant pH method Carry out proteolysis to 15% ~ 35% DH;

(4) separating the mixture from step (3) on an ultrafiltration/microfiltration device with a cut-off of 10,000 or higher such that the permeate constitutes a protein hydrolyzate; and

(5) Stop hydrolysis by deactivating the above-mentioned enzymes.

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

[Table 1]

The milk protein hydrolyzate can be mixed in an amount of 0.1% to 22%, usually 4.1% to 14.0%, preferably 5.5% to 10.0%, of the whole composition. Alternatively, 0.9 g to 3 g, preferably 1.2 g to 2 g may be mixed in 100 mL of the composition.

The protein-derived component of fermented milk used in the present invention includes, for example, a substance (whey) produced by reducing moisture from fermented milk (yogurt) (eg, Japanese Patent No. 3,179,555). The protein derived from fermented milk (yogurt) has an amino acid score of 100 and has high nutritional value due to improved digestion and absorption of protein through fermentation.

Alternatively, examples of fermented milk-derived protein used in the present invention include fresh cheese (unaged cheese)-derived protein. Proteins derived from fresh cheese are characterized by containing: casein as the main protein component, whey proteins including α-lactalbumin and β-lactoglobulin, and groups in which a portion of the milk protein is degraded into amino acids or peptides point. There are many types of fresh cheese, including cottage cheese, quark cheese, string cheese, neuchatel cheese, cream cheese, mozzarella ( mozzarella cheese), Italian ricotta cheese (ricotta cheese), and Italian milk soft cheese (mascarpone cheese), in the present invention, quark is preferably used. The method of producing quarks is well known (for example, Japanese Patent Application Laid-Open No. Hei 6-228013). Quark has a low fat content and is characterized by its refreshing aroma and sour taste.

The general production method of unripened cheese is as follows. First, curd is prepared from raw milk. The starter (starter) is inoculated into the raw milk, and after culturing, rennet is further added to produce curd. Raw milk may be pretreated if desired before producing curd. For example, in order to reduce the quality difference between production batches, the quality can be adjusted by mixing multiple milk sources. Such processing is called standardization. In addition, homogenization can be applied to mechanically disrupt fat globules in milk. Alternatively, microorganisms incorporated into the milk source can be removed by centrifugation and heat treatment for sterilization.

The solid component obtained by separating the whey from the resulting curd is called unripened cheese (fresh cheese). Methods for separating whey and curd by centrifugation and membrane separation are known. For example, the separation of whey uses a centrifugal separator, such as a quark separator. Alternatively, pre-cutting and heating the curd when needed can increase the efficiency of the separation process.

More specifically, fresh cheese obtainable through the sources and procedures described below is preferable as the milk fermentation component of the present invention. Fermentation can mainly use Lactobacillus bulgaricus and/or Streptococcus thermophilus in the following steps:

Heat sterilization of skim milk;

Inoculate the lactic acid bacteria starter with 0.5% to 5% to start fermentation;

The whey is separated from the curd formed when the pH reaches 4.6;

Unripened cheese is obtained by cooling the curd obtained by separating the whey.

Unripened cheeses that can be produced in this way are also known as quarks. An example of the composition of unripened cheese is as follows:

17% to 19% total solid content,

11% to 13% protein,

1% or less fat,

2% to 8% sugar,

2% or more lactose.

The protein derived from fermented milk can be mixed in a ratio of, for example, 0.1% to 30%, generally 8.0% to 23.0%, preferably 10.0% to 18.0% of the whole composition, or 2g to 6g can be mixed in 100mL of the composition , preferably 2.5g to 4.5g. Alternatively, the fermented milk-derived protein contained in the entire composition of the present invention may be about 0.1% to 90%, preferably about 1% to 80%, and more preferably about 30% to 70% of the protein amount in the entire composition. .

The composition of the present invention comprises oil as lipid.

The composition of the present invention preferably contains n-3-type fatty acids as lipids. Examples of n-3-type fatty acids contained in the composition of the present invention include EPA, DHA, α-linolenic acid, and DPA, preferably EPA, DHA and/or α-linolenic acid, more preferably EPA and/or DHA. Examples of oils and fats include oils and fats containing n-3-type fatty acids, including perilla oil, linseed oil, perilla oil, fish oil, rapeseed oil, soybean oil, salad oil, and flax oil. In the present invention, these n-3-type fatty acids may be contained as they are, or they may be contained in the form of fats and oils such as fish oil.

Furthermore, the composition of the invention preferably comprises medium-chain triglyceride (MCT) as lipid. MCTs are quickly absorbed and easily converted into energy in the body, and are not easily stored as fat in the body. Examples of MCT-containing oils include palm oil, palm kernel oil, and oils and fats containing medium-chain fatty acids. In the present invention, MCT may be contained directly, or may be contained in the form of oil such as palm kernel oil.

Accordingly, the composition of the present invention includes a composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, medium-chain triglycerides, EPA, and/or DHA as lipid, and isomaltulose as carbohydrate .

Furthermore, the composition of the invention may contain fatty acids such as oleic acid, palmitic acid, palmitoleic acid, linolic acid, stearic acid, linolenic acid, or arachidonic acid, preferably oleic acid, as lipids. Examples of oils containing these fatty acids include high-oleic sunflower oil, canola oil, olive oil, high-oleic safflower oil, soybean oil, corn oil, and palm oil oils, which are high-oleic-acid oils. They are available as a blend with sunflower oil, canola oil, olive oil, and olive oil. Linolenic acid, arachidonic acid, γ-linolenic acid, etc. are n-6-type fatty acids. Examples of oils and fats containing n-6-type fatty acids include safflower oil, sunflower oil, soybean oil, linseed oil, corn oil, and peanut oil.

The ratio between n-3-type fatty acid and n-6-type fatty acid is, for example, for each n-3-type fatty acid, there are 5 or less, generally 0.5 to 4.0, preferably 1.0 to 4.0 n-6-type fatty acid, more preferably the ratio is n-3-type fatty acid:n-6-type fatty acid=1:2.

The n-3-type fatty acid can be mixed in a ratio of, for example, 0.01% to 10%, generally 0.05% to 7%, preferably 0.1% to 5%, of the whole composition. Alternatively, 0.05 g to 2.2 g, preferably 0.1 g to 1.0 g may be mixed in 100 mL of the composition.

MCT can be mixed, for example, in a proportion of 0.01% to 14.5%, generally 0.01% to 8.0%, preferably 2.0% to 4.0%, of the whole composition. Alternatively, 0.01 g to 2.0 g, preferably 0.5 g to 1.0 g may be mixed in 100 mL of the composition.

Oils and fats containing oleic acid can be blended, for example, in a ratio of 0.1% to 14.5%, usually 2.0% to 10.0%, preferably 4.0% to 8.0%, of the entire composition. Alternatively, 0.5 g to 2.0 g, preferably 1.0 g to 1.8 g may be mixed in 100 mL of the composition.

Furthermore, the composition of the present invention may contain milk lecithin and soybean lecithin as lipids.

Milk lecithin and soybean lecithin may be used alone or in combination.

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

[Table 2]

Phospholipid components weight% Sphingomyelin twenty two Phosphatidylcholine 36 Phosphatidylethanolamine 27 Phosphatidylinositol 11 Phosphatidylserine 4 Lysophosphatidylcholine 2

In fields such as biochemistry, medicine and pharmacology, the term "lecithin" is used only for phosphatidylcholines. However, in commerce or industry, lecithin is used as a generic term for a mixture of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, and other phospholipids. In the 7th edition of Japan's Specifications and Standards for Food Additives (7thedition (1999)), lecithin is defined as "a substance obtained from oil seeds or animal sources, the main component of which is phospholipids". In the present invention, milk-derived phospholipids are collectively referred to as "milk lecithin".

As shown in Table 2, milk lecithin is characterized by containing a large amount of SM, which is not present in soy lecithin. Milk lecithin increased DHA content in the brain and liver more than soy lecithin when administered to rats. Moreover, compared with soybean or egg yolk lecithin, milk lecithin is more effective in improving hyperlipidemia and fatty liver. In addition, SM is known to be involved in cholesterol metabolism, for example, SM can regulate the activity of HMG-CoA reductase involved in cholesterol biosynthesis, and is involved in the regulation of cholesterol absorption in the intestine. Therefore, it was thought that SM might further enhance the ability of PC and PE to improve lipid metabolism (Sasaki, H., Milk Science 51(2):93-94, 2002).

Examples of materials with high MFGM content include: freeze-dried WPI by-product (MF retained solution) manufactured by a combination of ultrafiltration (UF) and microfiltration (MF), removal of anhydrous milk fat from cream or butter ( AMF) (butter serum), and a fraction obtained by removing anhydrous milk fat from whey cream (whey cream serum). Methods for obtaining phospholipid concentrates using these as raw materials are known (for example, Japanese Patent Laid-Open No. 7-173182 is included in the present invention).

Although soybean lecithin is widely used as a natural food additive in the food field, polyene phosphatidylcholine is also used as a medicine (application: for improving liver function in chronic liver disease, fatty liver, and hyperlipidemia). Examples of physiological functions of soybean lecithin include regulation of biofilm morphology and function; improvement of lung function, arteriosclerosis, lipid metabolism, and hepatic lipid metabolism; and improvement and enhancement of nerve function (Food Processing and Ingredients, Vol. .29(3):18-21, 1994).

"Natural" lecithin preparations are usually ranked according to their PC content. Various lecithins have been produced that have been upgraded according to their application. As shown in Table 3, for convenience, soybean lecithin products are classified according to the difference of the main component PC based on the purification and classification of soybean lecithin (Fujikawa, T., Oil Chemistry, Vol.40 (10): 951-958 , 1991).

[table 3]

The composition of the present invention contains isomaltulose (Palatinose (registered trademark)) as a saccharide. Isomaltulose is a substance registered under CAS Registry No. 13718-94-0 and represented by the chemical formula C ₁₂ H ₂₂ O ₁₁ .

Isomaltulose includes reduced isomaltulose, Palatinose Syrup (registered trademark) and isomaltulose starch syrup. Isomaltulose starch syrup is a liquid substance in the form of starch syrup containing oligosaccharides such as sucrose tetras, sucrose hexaose, and sucrose octas produced during dehydration condensation of isomaltulose as a main component. Isomaltulose, like sucrose, is digested into glucose and fructose and then absorbed (Goda, T. et al., Journal of Japanese Society of Nutrition and Food Science, Vol. 36(3): 169-173, 1983). However, since the hydrolysis rate of isomaltulose is slow, which is one-fifth of that of sucrose (Tsuji, Y. et al., J. Nutr. Sci. Vitaminol., 32: 93-100, 1986), glucose and The blood concentration of insulin maintains a constant level for a long time (Kawai, K. et al., Endocrinol, Japan, 32(6):933-936, 1985).

Isomaltulose can be mixed in, for example, 10% to 70% of the whole composition, generally 15% to 60%, preferably 20% to 35%. Alternatively, 4 g to 13 g, or preferably 5 g to 8 g, may be mixed into 100 mL of the composition.

In order to promote the growth of small intestinal villi, increase the thickness of small intestinal muscularis propria, improve intestinal function, prevent small intestinal tissue damage, or inhibit various types of inflammation, the composition of the present invention is administered to the subject, which is the use of the composition of the present invention. one of the purposes.

In the present invention, "subject" is not particularly limited, but includes animals (such as humans, domestic animal species, and wild animals). The "subject" does not necessarily need to be a diseased individual, for example, a healthy person can be the subject to which the composition of the present invention is administered.

In the present invention, "administration" includes oral or parenteral administration, and the form of administration may be either pharmaceutical or food.

That is to say, the composition of the present invention can be used in any form, such as pharmaceutical composition, nutraceutical composition, medicine, drug, dietary composition, food and drink, nutritional composition, food for special purpose, nutritional functional food, health Any form such as food, pharmaceutical additives, or food additives. For example, the composition of the present invention can also be used as a food for improving small intestine function for healthy individuals with balanced nutrition, a food for improving nutrition for malnourished elderly people, and patients with severe dysfunctions such as respiratory, circulatory, and metabolic systems (ICU patients) Intestinal function maintenance food, nutrition supplement and intestinal function maintenance food for patients with dysphagia with brain/nerve disorders, intestinal function improvement and nutritional status improvement food for chronic intestinal diseases such as ulcerative colitis or Crohn's disease, Foods for improving intestinal function and nutritional status for malnourished patients with chronic obstructive pulmonary disease (COPD), or foods for improving nutritional status for patients with intestinal disorders due to antibiotics and anticancer agents, such as cancer patients.

In addition, the pharmaceutical composition, nutraceutical composition, medicine, and drug of the present invention can be used by being contained in a dietary composition, food and drink, nutritional composition, food for special purposes, nutritional functional food, health food, and the like. For example, the pharmaceutical composition, nutraceutical composition, medicine, and drug of the present invention may also be included in food for improving small intestine function for nutritionally balanced healthy individuals, food for improving nutrition for malnourished elderly, respiratory, circulatory, and metabolic Intestinal function maintenance food for patients with severe dysfunction of the system (ICU patients), nutritional supplement and intestinal function maintenance food for patients with dysphagia with brain/nerve disorders, chronic intestinal function such as ulcerative colitis or Crohn's disease Food for improving intestinal function and nutritional status of diseases, food for improving intestinal function and nutritional status of malnourished patients with chronic obstructive pulmonary disease (COPD), or nutritional status of patients with intestinal disorders due to antibiotics and anticancer agents such as cancer patients Utilize in improving food.

For example, it is expected to promote the growth of small intestinal villi and increase the thickness of the small intestinal muscularis propria in the subjects by directly administering it to the subjects as pharmaceuticals, or directly ingesting it as special-purpose foods such as foods for specific health uses, etc., or nutritional functional foods , Improve intestinal function, prevent small intestinal tissue damage, or inhibit various types of inflammation.

When the compositions of the present invention are used as pharmaceuticals, they can be administered in various forms. Examples of such modalities include administration of enteral nutrition, liquid preparations, etc. by oral route, by nasal feeding tube, or by percutaneous endoscopic gastrostomy, percutaneous endoscopic jejunostomy, etc.; And the administration form may also involve processing into preparations such as tablets, capsules, granules, powders, and syrups. Every kind of preparation can use excipient, binding agent, disintegrating agent, lubricant, corrective agent, solubilizing agent, suspending agent, coating agent, solvent, isotonic agent etc. The auxiliary agent is prepared together with the main agent. In addition, calcium may be included in suitable amounts. In addition, vitamins, minerals, organic acids, sugars, amino acids, peptides, etc. may be added in appropriate amounts.

When the composition of the present invention is used in the form of a pharmaceutical, it can be administered orally or enterally. For example, oral administration of tablets, capsules, granules, powders, syrups, etc., or nasogastric feeding tube, enteral administration via percutaneous endoscopic gastrostomy or percutaneous endoscopic jejunostomy may be chosen; and The administration method can be appropriately selected depending on the age and symptoms of the patient. The effective dose is selected from the range of 0.1 mg to 1,500 mg per kilogram of body weight per administration. Alternatively, a dose of 5 mg to 75 g, or preferably 100 mg to 50 g per patient may be chosen. Specific examples of preferred doses and administration methods are administration of 0.1 mg to 1,500 mg per kilogram of body weight per dose, or preferably 2 mg to 1,000 mg, one to three times a day, before or after meals, for one month (4 weeks). The frequency of dosing is adjusted according to the post-administration condition and the trend observed in blood test values.

When the composition of the present invention is used as food and drink, it can be ingested by adding the composition to various food and drink regardless of its form (such as liquid, paste, solid and powder). Examples of food and beverages include milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crust, reconstituted milk powder, liquid food, sick food, nutritional food, frozen food, food combination foods, processed foods, and other commercially available foods. When the compositions of the present invention are used as food or drink, they are preferably in a form that can be used as they are. In this form, the composition can be ingested orally, or nasally through a tube into the stomach and jejunum. Such compositions may take a variety of forms, for example, fruit juice-type beverages or shake-type beverages. The composition may also be a soluble powder capable of being reconstituted before use.

The composition may have an osmotic pressure of about 300 mOsm/L to 1,000 mOsm/L, for example, about 300 mOsm/L to 750 mOsm/L. The composition has a viscosity of about 5 cp to 40 cp (1 cp=0.001 Pa·s), preferably less than 20, when measured at room temperature.

The calorie content of the composition is about 1 kcal/ml to 2 kcal/ml, preferably 1 kcal/ml to 1.5 kcal/ml.

In addition, when the composition of the present invention is used as a food or drink, its nutritional composition can be adjusted by mixing with additional nutrients. Water, protein, carbohydrate, lipid, amino acid, dietary fiber, vitamin, mineral matter, organic acid, organic base, fruit juice, flavoring agent, sweetener (such as aspartame) etc. can be used as in the present invention Additional nutrients.

In addition, 5mg-500mg (0.005%-0.5%) of mushroom extract can be added to reduce fecal odor, and 10μg-200μg (0.00001%-0.0002%) of carotenoid preparation (for example, α-carotene, β-carotene, lycopene (licopine), and lutein).

In addition, catechol, polyphenol, etc. may be contained as an antioxidant.

In addition, carnitine may be included to improve lipid metabolism, among other things. Carnitine is a biological trace ingredient that is produced in the liver or kidneys from lysine and methionine. Its production levels are known to decrease with age. L-Carnitine plays an important role in the metabolism of nutrients, such as the delivery of long-chain fatty acids to muscle cells.

In addition to the above-mentioned isomaltulose, sugars include other various sugars. As sugars other than isomaltulose, sucrose, glucose, fructose, honey, etc. are used. Other examples are dextrins and indigestible dextrins.

Dietary fiber can be classified into water-soluble dietary fiber and water-insoluble dietary fiber, and any of them can be used.

As the indigestible dietary fiber, indigestible oligosaccharides, lactulose, lactitol, or raffinose can be used. Indigestible oligosaccharides reach the large intestine in an undigested state and promote the activation and growth of intestinal bifidobacteria, thereby improving the intestinal environment. Lactulose, a synthetic disaccharide consisting of galactose and fructose, is used as an essential drug in hyperammonemia (Bircher, J. et al., Lancet: 890, 1965). Chronic relapsing hepatic encephalopathy due to chronic liver failure responds well to administration of lactulose, infusion of specific amino acids for liver failure (Fischer's solution), etc. Lactitol (β-galactitol-sorbitol), should be regarded as the second generation of lactulose, has similar clinical effects to 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), is currently used as a therapeutic agent for hyperammonemia.

Other water-soluble dietary fiber candidates include products that improve lipid metabolism (lower cholesterol and triglycerides) such as pectin (protopectin, pectic acid, pectic acid), products of enzymatic degradation of guar gum, and Tamarind seed gum. Guar gum degradation products inhibit the rise in blood sugar levels and save insulin (Yamatoya, K. et al., Journal of Japanese Society of Nutrition and FoodScience, Vol. 46: 199, 1993). In addition, candidates for water-soluble dietary fiber include, as high-molecular-weight water-soluble dietary fiber: konjac glucomannan, alginic acid, low-molecular-weight alginic acid, psyllium, acacia, seaweed polysaccharide (cellulose, lichen substances, agar, carrageenan, alginic acid, fucodine, and laminarin), gums produced by microorganisms (welangum, curdlan, xanthan gum) , gellan gum, dextran, pullulan, and rhamsan gum), other gums (carob gum from seeds, carob gum, tara gum (tara gum, karayagum from tree sap, and tragacanth gum); as low molecular weight water-soluble dietary fibers: polydextrose, indigestible dextrin, maltitol, etc.

Insoluble dietary fiber increases the bulk of undigested material in the large intestine and reduces its transit time. This increases bowel frequency and volume. Examples of candidates for insoluble dietary fiber include cellulose, hemicellulose, lignin, chitin, chitosan, soybean dietary fiber, wheat bran, pine fiber, corn fiber, and sugar 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, biological inositol, choline and folic acid.

There are 13 known vitamins. Among them, vitamins A, K, and B group (B ₁ , B ₂ , niacin, B ₆ , pantothenic acid, folic acid, B12, and biotin) are known to have a deep relationship with the liver. The main problems associated with liver disease are vitamin A deficiency and excess, vitamin B complex deficiency, and vitamin K excess.

When bile in the digestive tract is insufficient due to obstructive jaundice, etc., the absorption rate of vitamin A decreases, resulting in vitamin A deficiency. In addition, retinol-binding protein (RBP) production was reduced under low-protein nutritional conditions. Therefore, vitamin A is not delivered to the target organs, showing symptoms of deficiency. In the case of uncompensated cirrhosis, a relatively small excess of vitamin A will cause symptoms of toxicity. In chronic liver disease, vitamin B complex utilization disorder can be seen. Since vitamin K synthesized by gut bacteria can also be utilized, vitamin K deficiency is uncommon. However, when there is insufficient bile in the digestive tract due to obstructive jaundice, vitamin K absorption may decrease.

Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc and selenium. Examples of organic acids include malic acid, citric acid, lactic acid and tartaric acid.

Electrolytes that are often problematic in fluid regulation are sodium, chloride, potassium, phosphorus, calcium, and magnesium. When preparing a mineral prescription, three factors are considered: (1) whether the minerals to be taken into the cells are adequately supplied; (2) whether the patient's endocrine environment is adequate to cope with the amount and type of nutrient substrate to be administered , and (3) to measure the osmotic load on the kidney, and whether the amount of water administered is adequate to maintain proper urine osmolality.

Iron may also be included, as well as trace elements of natural origin, such as mineral yeasts, such as copper, zinc, selenium, manganese and chromium yeasts. Copper gluconate, zinc gluconate, and the like can also be used.

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

As such additional nutrients, any chemically synthesized substances or components derived from natural products can be used. Alternatively, a food product containing the component of interest can be mixed as a raw material. These components can be mixed by combining at least one, two or more. The form of the composition may be solid or liquid. In addition, it can be prepared in gel or semi-solid form.

The composition of the present invention can be produced by methods known in the field of liquid food and enteral nutrition. For example, a method of aseptically filling a liquid composition into a container after heat sterilization (for example, a method of combining UHT sterilization and aseptic packaging) can be used, and after the liquid composition is filled into the container, it can be combined with Methods of heat sterilization together with containers (for example, retort method and autoclave method). More specifically, when the composition is used in a liquid state, a homogenized product (homogenized sterile solution) based on the composition is heat-sterilized again at about 120° C. to 145° C. for 1 second to 10 seconds and cooled if necessary, It is then aseptically filled, or filled into cans or pouches for autoclave sterilization. Furthermore, when the composition is used in powder form, the homogenate is spray-dried or freeze-dried, for example.

The invention will be described in detail below, but should not be construed as being limited to the individual embodiments described hereinafter. When tempering (adding/mixing) whey protein, it is tempered while heating, for example, the temperature of the tempering liquid (tempering temperature) is set to 55° C. or lower. When the tempering temperature is set at a high temperature such as 70°C, the protein solidifies (coagulates), while when the tempering temperature is set at a low temperature such as 2°C, the protein is difficult to dissolve or disperse in water or the like. Therefore, for the tempering step, the temperature is preferably 5°C to 55°C, more preferably 40°C to 55°C, even more preferably 40°C to 53°C, particularly preferably 40°C to 50°C. At this time, it is preferable to adopt an appropriate conditioning time in consideration of the proliferation of bacteria (contaminating bacteria, etc.) in the conditioning solution.

In addition, in the present invention, the prepared liquid is homogenized after high-temperature sterilization. The reason is that the protein may be denatured and the viscosity may increase (thicken) under high-temperature sterilization (heating), but the degree of thickening can be reduced by performing homogenization after high-temperature sterilization. Herein, homogenization after high-temperature sterilization refers to homogenization after high-temperature sterilization and before filling into containers or the like to make products, and the number of times it is performed is not limited to one time, but may be multiple times, such as twice or More. For example, when the prepared liquid is sterilized and re-sterilized as it is, homogenization will be performed again after the second sterilization. In addition, the prepared solution may be homogenized after the sterilization, and when the second sterilization is further performed, the homogenization will be performed again in the second round after the second sterilization. In addition, the prepared solution may be homogenized after sterilization, and the homogenization may be performed again without sterilization. More specifically, in the present invention, it is important to perform homogenization at least once before filling the prepared liquid into a container or the like to make a product after high temperature sterilization.

On the other hand, even after the high-temperature sterilized prepared liquid (sterilized liquid) is homogenized, it can be sterilized again to such an extent that the sterilized liquid does not thicken. For example, the prepared solution may be sterilized and homogenized, and then sterilized again without high-temperature sterilization. At this time, as a high-temperature sterilization step, for example, the heating history corresponds to a temperature of 100°C to 150°C and a holding temperature of 1 second to 30 seconds; preferably 115°C to 145°C for 1 second to 20 seconds; more preferably 120°C to 145°C1 seconds to 10 seconds; more preferably 1 second to 5 seconds at 125°C to 145°C. When high-temperature sterilization is performed, the protein denatures, and the viscosity of the sterilizing solution tends to increase. In other words, the sterilizing solution does not tend to thicken unless it is sterilized at high temperature. Therefore, the effect of homogenization to reduce the degree of viscosity increase is particularly effective when high-temperature sterilization is performed.

In addition, when high-temperature sterilization is performed, the pressure on the prepared liquid can be adjusted (increased or reduced pressure). At this time, the sterilization pressure is generally set to, for example, about 1 kg/cm ² to 10 kg/cm ² for the purpose of preventing the liquid preparation from boiling. That is, in the high-temperature sterilization of the present invention, in addition to applying temperature (heating), such pressure may be applied. Devices used for high temperature sterilization include plate heat exchangers, tube heat exchangers, steam jet sterilizers, steam immersion sterilizers, and Joule heating sterilizers. On the other hand, when performing homogenization, if a homogenizer is used, and for example, the temperature is set at about 10°C to 60°C, the flow rate is set at about 100L/h to 10,000L/h, and the pressure is set at 10MPa to 100MPa, Preferably it is 20MPa-80MPa, more preferably 30MPa-70MPa, more preferably 20MPa-50MPa. In addition, if necessary, the conditions of operations such as high-temperature sterilization or homogenization may be changed to perform multiple treatments.

The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In the blending step, the warm water at the aforementioned temperature is stirred in a tank, and the raw materials other than the vitamin mixture (mixed vitamin components) are sequentially added, mixed, and stirred in consideration of the ease of mixing and dispersion to produce a blended liquid . The order of adding raw materials for convenient mixing and dispersing is different according to the amount and properties of raw materials, and they are added at one time or in different orders. For example, there is a method of adding sugar, protein, oil, and minerals in that order. Another example is adding them in the order certain sugars, protein, other sugars, minerals, and then fat. Also, another example is to add them in the order of fat, protein, sugar, and then minerals. The blended solution was subjected to steam jet heat sterilization, and then homogenized using a homogenizer (by two-stage pressure homogenization) to produce a sterilized solution. To this sterilized liquid, a vitamin mixture (mixed vitamin components), a flavoring agent (fragrance), etc. are added and mixed to produce a final sterilized liquid. This final sterilized solution was further subjected to steam immersion heat sterilization (two-step sterilization), and then homogenized using a homogenizer (homogenization by two-stage pressure) to produce a composition.

In order to promote the growth of small intestinal villi, increase the thickness of small intestinal muscularis propria, improve intestinal function, prevent small intestinal tissue damage, or treat various inflammations, the dosage varies according to symptoms, body weight, etc. For example, when administered (ingested) as food or drink, the dose is usually about 0.05 g to 1,000 g per day, preferably about 0.05 g to 250 g, more preferably about 2.5 g to 50 g (solid content). This may suitably be administered once or separately to a subject in need of administration of the composition of the invention before, after, or between meals, and/or before bedtime. The dose can be appropriately adjusted individually depending on the purpose of administration and the age and body weight of the subject to be administered. Furthermore, the compositions of the present invention may be used as a meal replacement or supplement.

When the composition of the present invention is made into the form of acidic medicine or food, their pH can be set to pH 2.0 to pH 6.0, preferably pH 3.0 to pH 5.0.

The above-mentioned purposes of the composition of the present invention can also be expressed as following (1)～(30):

(1) A method for promoting the growth of small intestinal villi, comprising administering a composition comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as carbohydrate step.

(2) A method for increasing the thickness of the muscularis propria of the small intestine, which comprises administering a composition comprising hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as carbohydrate A step of.

(3) A method for improving intestinal function, comprising the step of administering a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as saccharide.

(4) A method for preventing small intestinal tissue damage, comprising the step of administering a composition comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, fat as lipid, and isomaltulose as carbohydrate .

(5) A method for suppressing inflammation, comprising the step of administering a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as saccharide.

(6) Use of a composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as saccharide for the production of a composition for promoting the growth of small intestinal villi.

(7) Use of a composition comprising milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar for the preparation of a composition for increasing the thickness of the muscularis propria of the small intestine .

(8) Use of a composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar for the production of a composition for improving intestinal function.

(9) Use of a composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar for the production of a composition for preventing small intestinal tissue damage.

(10) Use of a composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar for the preparation of an anti-inflammatory composition.

(11) A composition comprising a hydrolyzate of milk protein and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar, for use in a method for promoting growth of small intestinal villi.

(12) A composition comprising a hydrolyzate of milk protein and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar, for use in a method for increasing the thickness of the muscularis propria of the small intestine.

(13) A composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, fat as lipid, and isomaltulose as sugar, for use in a method for improving intestinal function.

(14) A composition comprising a hydrolyzate of milk protein and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as saccharide, for use in a method for preventing small intestinal tissue damage.

(15) A composition comprising a hydrolyzate of milk protein and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar, for use in a method for suppressing inflammation.

(16) A method for improving intestinal function comprising the step of administering a composition comprising a fermented milk-derived protein.

(17) A method for improving intestinal function, comprising the step of administering a composition comprising 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 small intestinal tissue damage, comprising the step of administering a composition comprising a fermented milk-derived protein.

(19) A method for preventing small intestinal tissue damage, comprising the step of administering a composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as carbohydrate.

(20) A method for suppressing inflammation, comprising the step of administering a composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as proteins;

(21) Use of fermented milk-derived protein for the preparation of a composition for improving intestinal function.

(22) Use of a milk protein hydrolyzate and a protein derived from fermented milk as a protein, and isomaltulose as a sugar in the preparation of a composition for improving intestinal function.

(23) Use of a protein derived from fermented milk for the preparation of a composition for preventing small intestinal tissue damage.

(24) Use of a milk protein hydrolyzate and a protein derived from fermented milk as a protein, and isomaltulose as a sugar, for the preparation of a composition for preventing small intestinal tissue damage.

(25) Use of a composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as proteins for the production of an anti-inflammatory composition.

(26) A composition comprising a fermented milk-derived protein for use in a method for improving intestinal function.

(27) A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, and isomaltulose as a saccharide, for use in a method for improving intestinal function.

(28) A composition comprising a fermented milk-derived protein for use in a method for preventing small intestinal tissue damage.

(29) A composition comprising a hydrolyzate of milk protein and a protein derived from fermented milk as a protein, and isomaltulose as a saccharide, for use in a method for preventing small intestinal tissue damage.

(30) A composition comprising, as proteins, a hydrolyzate of milk protein and a protein derived from fermented milk, for use in a method for suppressing inflammation.

An example of the composition of the present invention includes MEIN (Meiji Dairies Corporation). Compositions comprising ingredients of MEIN can be described as compositions comprising ingredients as described in Table 4.

[Table 4]

Regarding the lipids in Table 4, an example of the composition of milk phospholipids (also known as milk-derived phospholipids or milk lecithin) is shown in Table 5 below.

[table 5]

Phospholipids %

Phosphatidylcholine 24.2 Phosphatidylethanolamine 20.4 Sphingomyelin 17.1

In addition, regarding the lipids in Table 4, Table 6 below shows an example of fatty acid composition.

[Table 6]

n-6:n-3≈2:1

*: Essential Fatty Acids

This specification incorporates by reference all references cited herein.

[Example 1]

Effect of nutritional composition on reducing small intestinal tissue damage (1)

Experiments were carried out using the composition of the present invention, and common liquid food (Meibalance: MeijiDairies Corporation) and liquid food A (Impact: Ajinomoto Pharma Co. Ltd.) as comparative controls. The extent of tissue damage in the small intestine 24 hours after ConA administration was measured.

C57BL/6 mice (6 weeks old, male) purchased from Japan SLC Inc. were used. Mice were reared in the following environment: 21.0±2.0° C., humidity 55.0±15.0%, 12-hour light-dark cycle (light period: from 7 am to 7 pm). Animals were allowed free access to food and water throughout the experiment.

After acclimating the purchased animals for 1 week, they were divided into three groups according to their body weight. The experimental groups were group 1: common liquid diet (Meiji Dairies Corporation: Meibalance); group 2: nutritional composition (MeijiDairies Corporation: MEIN); group 3: liquid diet A (Ajinomoto Pharma: Impact), and the animals were fed for 2 weeks. The composition of the common liquid food, nutritional composition, and liquid food A is shown in Table 7 and Table 8. Isomaltulose used in this example is a substance registered under CAS Registry No. 13718-94-0 and represented by the chemical formula C ₁₂ H ₂₂ O ₁₁ .

[Table 7]

Nutritional Information Sheet

[Table 8]

Nutritional Information Sheet

ConA (Sigma) was administered intravenously via the tail vein at a dose of 12 mg/kg. 24 hours after the administration, blood was collected from the abdominal aorta under ether anesthesia, and then the small intestine was excised. The small intestine 6 cm to 3 cm below the stomach was fixed in 10% formalin solution, and then embedded with the usual method. Tissue samples were prepared and stained with hematoxylin-eosin. Pictures of tissue samples were taken using a digital microscope (Keyence, Inc.) at 100X magnification, and the area of the muscularis propria and mucous layer including villi was determined. The results are expressed as mean ± SD (n = 7-9). Statistical analysis was performed by SPSS using one-way analysis of variance, using the Scheffe test, and p<0.05 was defined as significant.

The results are shown in Figure 1 and Figure 2. The comparison of the small intestine area showed that the nutritional composition intake group had the highest numerical value, and the numerical value decreased in the order of the ordinary liquid food group and the liquid food A intake group ( FIG. 1 ). A significant difference was observed between the nutritional composition intake group and the liquid food A intake group. Furthermore, the histology shown in Figure 2 confirmed that the administration of ConA resulted in damage or loss of small intestinal mucosal epithelium or decreased thickness of the muscle layer, among other injuries. On the other hand, the nutritional composition intake group showed almost normal histology ( FIG. 2 ), and the results showed that the intake of the nutritional composition could reduce the degree of such small intestinal damage.

[Example 2]

Effect of nutritional composition on reducing small intestinal tissue damage (2)

Cytokine production in the small intestine 2 hours after Con A administration and the degree of tissue damage 24 hours after Con A administration were evaluated by conducting experiments using the nutritional composition of the present invention and Meibalance as a comparative control.

C57BL/6 mice (6 weeks old, male) purchased from Japan SLC Inc. were used. Mice were reared in the following environment: 21.0±2.0° C., humidity 55.0±15.0%, 12-hour light-dark cycle (light period: from 7 am to 7 pm). Animals were allowed free access to food and water throughout the experiment.

After acclimating the mice for 1 week, they were divided into four groups according to their body weight. The experimental groups were fed with the following diet for 2 weeks: group 1: common liquid food (necropsy after 2 hours of ConA administration); group 2: nutritional composition (necropsy after 2 hours of ConA administration); group 3: common liquid food (24 hours after ConA administration). Necropsy after 2 hours); Group 4: nutritional composition (necropsy 24 hours after ConA administration). The common liquid food and nutritional composition used are the same as those used in Example 1.

ConA (Sigma) was administered intravenously via the tail vein at a dose of 12 mg/kg. Blood was collected from the abdominal aorta 2 hours and 24 hours after the administration under ether anesthesia, and then the liver, spleen, small intestine and large intestine were excised. The total length of the small intestine, its weight 11 cm to 10 cm below the stomach, and the weight of the large intestine 5 cm below the cecum were measured. The weight of each organ was also measured. The small intestine 6 cm to 3 cm below the stomach was fixed in 10% formalin solution, and then embedded with the usual method. Tissue samples were prepared and stained with hematoxylin-eosin. Cytokines in the organs were prepared in the following manner, and measured using a Mouse inflammation kit (CBA method: Japan Becton and Dickenson Co.). Results are expressed as concentrations per organ weight. Results are presented as mean ± SD. After performing one-way analysis of variance with SPSS, statistical analysis was performed using Student's test or Mann-Whitney test.

<Method for Measuring Cytokine Concentration in Organs>

1. Add 1 ml of lysis buffer to 100 mg of organ, and homogenize it using a glass-teflon (registered trademark) homogenizer

Lysis buffer

20mM Tris HCl (pH 7.4)

0.25M sucrose

2mM EDTA·2Na

10mM EGTA

1% Tritonx-100

+1 Complete Mine protease inhibitor combination tablet/10ml

2. Centrifuge the homogeneous homogenate at 100,000g for 40 minutes and collect the supernatant (operate while cooling on ice).

3. Use the BCA protein assay kit to measure the protein concentration in the supernatant. In addition, the amount of cytokines per unit protein was determined using a method similar to that for cytokines in plasma.

(Reference: Journal of Neuroinflammation 2008, 5:10, Increased systemic and brain cytokine production and neuroinflammation by endotoxin fbllowingethanol treatment Liya Qin, Jun He, Richard N Hanes, Olivera Pluzarev, Jau-Shyoung Hong and Fults

The results are shown in Tables 9-11.

No difference in body weight was observed between the groups. On the other hand, the weight of the small and large intestines increased significantly. Furthermore, the length of the intestine was shown to be significantly longer (Table 9).

Next, the results of measuring cytokine concentrations in plasma and in organs are shown (Table 10). The plasma concentrations of cytokines and chemokines TNF-α, IFN-γ, MCP-1, and IL-6 were significantly increased in the normal liquid food group, but were significantly lower in the nutritional composition group. IL-12 and IL-10 concentrations were below detection limits. In each organ, cytokines were most produced in the spleen, and the concentrations of IFN-γ, MCP-1, and IL-6 in the nutritional composition group were significantly lower than those in the common liquid food group. In the nutritional composition group, TNF-α (p=0.07), IFN-γ, and MCP- showed significantly lower values in the liver compared with the normal liquid food group. In the small intestine, MCP-1 and IL-6 showed significantly lower values. ConA is known to cause significant liver damage, and the suppression of liver damage in the nutritional composition group indicated that suppression of TNF-α production in the liver was involved. Since the increase in plasma IL-6 concentration cannot be explained solely by the concentration of IL-6 in the liver, production in the spleen may have contributed to the increase. Concentrations of inflammatory cytokines are low in the small intestine compared to other organs. However, since MCP-1 and IL-6 were increased compared to normal in the small intestine and showed significantly lower values in the nutritional composition group compared to the normal liquid food group, they may be involved in the reduction of damage.

In addition, as a result of evaluating the histopathological tissue of the small intestine with the following 0-3 grades after 24 hours of ConA administration, it was shown that the damage of the small intestine was reduced in the nutritional composition group compared with the common liquid food group (Mann-Whitney test, p =0.021) (Table 11).

[Table 9]

Organ weights and blood biochemical test results

Mean±SD, n=5～7, Student's test*: p<0.05

[Table 10]

plasma

IL-12 and IL-10 below detection limit

spleen

liver

small intestine

Mean ± SD *: p<0.1, **: p<0.05, ***: p<0.01

[Table 11]

Mann-Whitney test

p=0.021

[Example 3]

Effect of nutritional composition on promoting growth of mucous epidermis and muscle layer

After freely ingesting ordinary liquid food or the nutritional composition of the present invention for 2 weeks, the small and large intestines and the weight of the small intestine tissue were evaluated.

C57BL/6 mice (6 weeks old, male) purchased from Japan SLC Inc. were used. Mice were reared in the following environment: 21.0±2.0° C., humidity 55.0±15.0%, 12-hour light-dark cycle (light period: from 7 am to 7 pm). Animals were allowed free access to food and water throughout the experiment.

After acclimating the mice for 1 week, they were divided into two groups according to their body weight, with 5 mice in each group. The experimental groups were: group 1: common liquid food; group 2: nutritional composition; the animals were fed for two weeks. The common liquid food and nutritional composition used are the same as those used in Example 1.

Blood was collected from the abdominal aorta under ether anesthesia, and then the liver, spleen, small intestine, and large intestine were excised. The total length of the small intestine, its weight 11 cm to 10 cm below the stomach, and the weight of the large intestine 5 cm below the cecum were measured. The weight of each organ was also measured. The small intestine 6 cm to 3 cm below the stomach was fixed in 10% formalin solution, and then embedded with the usual method. Tissue samples were prepared and stained with hematoxylin-eosin. Biochemical assays for ALT, AST, albumin, total protein, triglycerides, cholesterol, glucose, and urine nitrogen in serum were performed on tissue samples. Results are expressed as mean ± SD. After performing one-way analysis of variance with SPSS, statistical analysis was performed using Student's test.

Table 12 shows the results of blood biochemical tests and organ weights after normal mice ingested common liquid food or nutritional composition for 2 weeks. In normal mice, no significant differences in body weight and liver weight were seen between the groups. Compared with the ordinary liquid food group, the spleen relative weight and the small intestine and large intestine weights of the nutritional composition group showed significantly higher values. On the other hand, blood biochemical test results showed no significant differences among the groups for all values.

Then, normal small intestinal tissue samples were prepared, and the number and height of villi in a single 150-fold magnification field of view and the thickness of the muscularis propria were measured ( FIG. 3 and Table 13 ). Compared with the common liquid food group, the number of villi and the total length of villi showed no significant difference in the nutritional composition group, but the average villi length and muscularis propria thickness showed significantly higher values. From these results, the increase in the weight of the small intestine seen in the nutritional composition group may be due to the length of the villi and the thickness of the muscularis propria.

[Table 12]

Organ weights and biochemical test results

Mean ± SD, n = 5, Student's test *: p <0.05

[Table 13]

[Table 13]

Intestinal villi length and muscularis propria thickness (normal)

Mean ± SD, n = 5 **: p < 0.01

[Example 4]

Effect of nutritional composition on improving intestinal permeability and inhibiting bacterial translocation

Using the rat model of small intestine injury induced by indomethacin, the effect of the nutritional composition of the present invention on small intestine injury was investigated.

SD rats (6 weeks old, male) purchased from Japan SLC Inc. were used. They were raised under the following environment: 21.0±2.0° C., humidity 55.0±15.0%, 12-hour light-dark cycle (light period: from 7 am to 7 pm). Animals were allowed free access to food and water throughout the experiment.

The purchased animals were acclimated for one week and then divided into six groups according to their body weight. Animals were fed for 2 weeks with common liquid food or nutritional composition, and then administered with indomethacin. The common liquid food and nutritional composition used are the same as those used in Example 1. After that, a solution of indomethacin dissolved in 5% NaHCO ₃ was subcutaneously administered at a dose of 10 mg/kg once a day for two consecutive days to induce small intestinal injury. Thereafter, the animals were fed with the same feed, the first day of administration was defined as day 0, and necropsy was performed on the 4th and 8th days. In the normal group not administered with indomethacin, half of the animals were necropsied at the time of the 4th day and the 8th day.

In addition, on day 1, day 3, and day 7, 0.6% phenolsulfonphthalein injection "DAIICHISANKYO" (Daiichi Sankyo Co. Ltd.) was orally administered at 3 mL/body, and urine was collected 24 hours later to measure urine PSP excretion levels, results expressed as urinary PSP excretion rate. Typically, PSP is used as an indicator of kidney function in humans. When PSP is orally administered, excretion into urine is very low, but when permeability is increased due to intestinal membrane damage, PSP penetrates the intercellular space, enters the blood, and then enters the urine through the kidneys. In this example, it was used as an indicator of intestinal membrane permeability.

Fasting began at 5:00 p.m. on the day before the necropsy, and the necropsy was performed after fasting overnight. Heart blood was collected under anesthesia, and the liver and mesenteric lymph nodes (MLN) were removed under aseptic conditions. After measuring organ weights, the solutions produced by organ homogenization were incubated on BL agar matrix supplemented with 5% equine defibrinated blood at 37°C for 72 hours under aerobic and anaerobic conditions, and then the number of bacterial cells was determined. In addition, Gram staining was performed to check whether the detected bacteria were Gram-negative bacteria or Gram-positive bacteria.

The total length of the small intestine, the weight of the cecum and large intestine, and the pH of the cecum were then determined.

In addition, general blood tests were performed using an automated blood cell counter (Sysmex ST-1800i). General blood tests are indicated to investigate changes in various pathological conditions. Increases in neutrophils and monocytes are known to be caused by infection (bacteria).

result 1

It was observed that the permeability of the intestinal membrane was increased as a result of indomethacin-induced small intestinal damage, but the ingestion of the nutritional composition significantly inhibited the increase in intestinal permeability compared with the control group ( FIG. 4 ). The above results show that the ingestion of the nutritional composition suppresses the small intestinal damage caused by the administration of indomethacin.

These results suggest that the intake of the nutritional composition may prevent small intestinal damage caused by non-steroidal anti-inflammatory agents and the like.

result 2

It is known that indomethacin-induced small intestinal injury leads to the destruction of intestinal mucosal defenses, immunosuppression, etc., causing intestinal bacteria that should normally reside in the gastrointestinal tract to pass through the intestinal mucosal epithelial barrier and transfer to the liver and mesenteric lymph nodes.

On the 4th and 8th day of indomethacin administration, all mesenteric lymph nodes and liver (section) were removed, and the bacterial count in the homogenate was determined by culture. From the results of this experiment, on the 4th day of indomethacin administration, there were 2 out of 9 animals in the common liquid food group and 3 out of 10 animals in the nutritional composition group for individuals whose mesenteric lymph nodes had no bacteria detected. Only. Bacteria were detected in the liver of all subjects. On the 8th day, there was 1 out of 8 animals in the common liquid food group and 4 out of 8 animals in the nutritional composition group in which no bacteria were detected in the mesenteric lymph nodes. In addition, no bacteria were detected in the liver of any animal in both the common liquid food group and the nutritional composition group. Figure 5 shows the results of counts of bacteria actually detected in each organ. On the 4th day of indomethacin administration, there was no significant difference in the count of bacteria detected in the mesenteric lymph nodes between the nutritional composition group and the ordinary liquid food group (picture not shown). On the other hand, in the liver, the counts of the nutritional composition group tended to be lower (p=0.068) (Figure 5, upper panel). On the 8th day of indomethacin administration, bacterial translocation (BT) to the liver was not observed, but compared with the common liquid food group, the nutritional composition group significantly inhibited the BT to the mesenteric lymph node (p<0.05) ( Figure 5, lower panel).

In addition, the bacteria detected were aerobic Gram-positive bacteria.

From the above results, it can be seen that ingestion of the nutritional composition suppressed BT to mesenteric lymph nodes and liver. That is, it was shown that ingestion of the nutritional composition suppressed small intestinal injury-induced BT by indomethacin administration. It is suggested that the intake of the nutritional composition may protect the small intestine and prevent damage to the small intestine caused by non-steroidal anti-inflammatory agents and the like.

result 3

General blood tests were performed to investigate changes before and after indomethacin administration. General blood tests are indicated to investigate changes in various pathological conditions. Increases in neutrophils and monocytes are known to be caused by infection (bacteria).

As a result of the examination, in normal individuals, no significant difference was seen between the nutritional composition group and the common liquid food group. On the other hand, the leukocyte count was found to be increased in the indomethacin-administered group compared with normal individuals ( FIG. 6 ). The increase in leukocytes was caused by increases in lymphocytes, neutrophils, and monocytes (Fig. 6). In the normal liquid food group, an increase in white blood cells was observed on the 4th day, and further increased on the 7th day. On the other hand, in the nutritional composition group, the increase in leukocytes peaked on the fourth day, and thereafter, leukocytes decreased. Among white blood cells, neutrophil counts and monocyte counts were found to be particularly different between the two groups. There was no difference between the two groups on the 4th day, but on the 7th day, the neutrophil count and monocyte count decreased in the nutritional composition group compared with the ordinary liquid food group.

From the above results, in the nutritional composition group, the increase in neutrophil count and monocyte count may be due to the inhibition of bacterial translocation induced by small intestinal injury caused by non-steroidal anti-inflammatory agents. small intestinal damage due to thenon-steroidal anti-inflammatory agent) was inhibited.

[Example 5]

Changes when whey protein hydrolyzate, isomaltulose, and fermented milk-derived protein are removed from the composition of the nutritional composition 1

Six-week-old male C57BL/6 mice purchased from Japan SLC Inc. were used. The purchased mice were acclimatized for 1 week, and then divided into 5 groups according to their body weight.

Group composition:

Group 1: Ordinary liquid food (Meiji Dairies Corporation: Meibalance);

Group 2: nutritional composition (Meiji Dairies Corporation: MEIN);

Group 3: nutritional composition - whey protein hydrolyzate (nutritional composition-P) (substance produced by removing whey protein hydrolyzate from nutritional composition);

Group 4: Nutritional composition-whey protein hydrolyzate-isomaltulose (nutritional composition-P-I) (a substance produced by removing whey protein hydrolyzate and isomaltulose from the nutritional composition); and

Group 5: Nutritional Composition-Whey Protein Hydrolyzate-Isomaltulose-Quark (Nutritional Composition-P-I-Q) (Substance Produced by Removing Whey Protein Hydrolyzate, Isomaltulose and Quark from the Nutritional Composition ).

The animals were divided into the above-mentioned 5 groups and bred for 2 weeks. Casein was added to the nutritional composition in place of quark and whey protein hydrolyzate as a protein source, and dextrin was added in place of isomaltulose as a sugar source to the nutritional composition.

ConA (Sigma) was intravenously administered at a dose of 12 mg/kg through the tail vein, and the next day, blood was collected from the abdominal aorta under ether anesthesia, and then the liver, spleen, cecum and small intestine were excised. The weight of the central 10 cm of the small intestine was measured.

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

[Table 14]

Mean ± SD (n = 8 ~ 10)

No significant differences were observed between the groups in body weight and liver and spleen weights relative to body weight. The cecum weight showed a significant increase in the nutritional composition group compared with the common liquid food group. Since the group from which whey protein hydrolyzate, isomaltulose and quark were removed from the nutritional composition showed significantly lower values for cecal weight compared to the nutritional composition group, suggesting that these three materials are involved in cecal fermentation. In the nutritional composition group, the small intestine weight showed a significantly higher value than the normal liquid food group. Since the group from which whey protein hydrolyzate, isomaltulose and quark were removed from the nutritional composition showed significantly lower values for the small intestine weight compared to the nutritional composition group, suggesting that these three materials are involved in injury and inflammation of the small intestine .

Three components: whey protein hydrolyzate, isomaltulose, and quark, may be involved in the enteroprotective and anti-inflammatory effects of the nutritional composition.

[Example 6]

Change 2 when whey protein hydrolyzate, isomaltulose, and fermented milk-derived protein are removed from the nutritional composition

Six-week-old male C57BL/6 mice purchased from Japan SLC Inc. were used. The purchased mice were acclimated for 1 week, and then divided into 6 groups according to their body weight.

Composition (common liquid food and nutritional composition are the same as those used in Example 6):

Group 1: ordinary liquid food;

Group 2: nutritional composition;

Group 3: nutritional composition-whey protein hydrolyzate (-P) (substance produced by removing whey protein hydrolyzate from nutritional composition);

Group 4: nutritional composition-isomaltulose (-I) (substance produced by removing isomaltulose from nutritional composition);

Group 5: Nutritional Composition - Quark (-Q) (a substance resulting from the removal of Quark from a nutritional composition); and

Group 6: Nutritional composition-whey protein hydrolyzate-isomaltulose-quark (-P-I-Q) (substance produced by removing whey protein hydrolyzate, isomaltulose, and quark from the nutritional composition).

The animals were divided into the above 6 groups and bred for 2 weeks. In the preparation, casein is added in the nutritional composition instead of quark and whey protein hydrolyzate as protein source, and dextrin is added in place of isomaltulose as sugar source.

ConA (Sigma) was administered intravenously through the tail vein at a dose of 12 mg/kg, blood was collected from the tail vein 2, 4, and 8 hours after the administration, and on the next day, blood was collected from the abdominal aorta under ether anesthesia, and then the liver was removed. , spleen, cecum, small and large intestines. ALT and AST in plasma were measured using Fuji DRI-CHEM.

result 1

Table 15 shows the results for body and organ weights on the last day.

[Table 15]

Mean ± SD, Dunnett's t test; *: p<0.05 (n=5～8)

No significant differences were observed between the groups in body weight and organ weight relative to body weight (liver and spleen). Compared with the common liquid food group, the weights of the small intestine and cecum were at significantly high levels in the nutritional composition group, group 3 (-whey protein hydrolyzate) and group 4 (-isomaltulose).

result 2

AST and ALT results 24 hours after ConA administration are shown in FIG. 8 . The group from which only whey protein hydrolyzate was removed (group 3) and the group from which only quark was removed (group 5) showed increases in AST and ALT compared to the nutritional composition group. In the group from which only isomaltulose was removed (group 4), AST and ALT were almost the same as those in the nutritional composition group. Furthermore, when whey protein hydrolyzate, isomaltulose and quark were removed from the nutritional composition (group 6), since the ALT level became significantly higher compared to the nutritional composition group, it was suggested that the effect of suppressing hepatitis mainly involves whey protein Hydrolysates and quarks.

For the anti-inflammatory effect of the nutritional composition, whey protein hydrolyzate and quark may be the main components. It was shown that three components including quark as a main component, and whey protein hydrolyzate and isomaltulose participate in intestinal function maintenance and intestinal protection of the nutritional composition.

[Reference Example 1] Preparation of whey protein hydrolyzate

Whey protein isolate (WPI, Davisco) containing approximately 90% dry protein was dissolved in distilled water to form a protein solution with a concentration of 8% (w/v). The solution was heat-treated at 85°C for 2 minutes to denature the protein. The pH of the solution after this heat treatment was approximately 7.5. Then 2.4 L of Alcalase (enzyme, Novozymes) with a concentration of 2.0% relative to the substrate was added for hydrolysis, and the mixture was reacted at 55° C. for 3 hours. Porcine trypsin PTN 6.0S (Novozymes Japan) was added at a concentration of 3.0% relative to the substrate, and the mixture was reacted at 55°C for 3 hours. It took 6 hours for complete hydrolysis. The pH at the completion of the reaction was about 7.0. The whey protein hydrolyzate was centrifuged (20,000×g, 10 min) and then treated with a UF membrane (Millipore, Ultrafree-MC) with a fractional molecular weight of 10,000.

The permeate was subjected to reverse phase HPLC chromatography.

condition

Sample: UF permeate of whey protein hydrolyzate

Column: C18 SG120 (Shiseido)

Eluent A; 0.1% trifluoroacetic acid in water/acetonitrile 5/95

B; 0.1% aqueous trifluoroacetic acid/acetonitrile 32/68

A-->B 60-minute linear concentration gradient

Flow rate: 1mL/min

Detection: 215nm (UV/visible detector)

Industrial Applicability

The compositions of the present invention show an improvement in intestinal function, such as promoting the growth of small intestinal villi, and increasing the thickness of the muscularis propria. Therefore, they can be used to promote intestinal dysfunction in the elderly, patients with intestinal disorders due to administration of antibiotics or anticancer agents such as cancer patients, and patients with intestinal dysfunction due to long-term inability to receive nutritional support, such as in the ICU. Bowel function in patients with or after surgery. In addition, they can also be used for the growth of small intestinal villi and the improvement of intestinal function in healthy people.

In addition, the compositions of the present invention can be used to prevent tissue damage in the small intestine. Furthermore, the compositions of the present invention are useful as anti-inflammatory agents since they exhibit anti-inflammatory effects.

Claims (27)

CLAIMS 1. A composition for promoting growth of small intestinal villi comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as sugar. 2. The composition of claim 1, wherein 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), Alpha-lactalbumin, beta-lactoglobulin, and lactoferrin. 3. The composition according to claim 1 or 2, wherein the protein derived from fermented milk is derived from fresh cheese. 4. A composition for increasing the thickness of the muscularis propria of the small intestine, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as sugar. 5. The composition of claim 4, wherein 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), Alpha-lactalbumin, beta-lactoglobulin, and lactoferrin. 6. The composition according to claim 4 or 5, wherein the protein derived from fermented milk is derived from fresh cheese. 7. A composition for improving intestinal function, comprising a hydrolyzate of milk protein and protein derived from fermented milk as protein, oil and fat as lipid, and isomaltulose as sugar. 8. The composition of claim 7, wherein said 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. 9. The composition according to claim 7 or 8, wherein the protein derived from fermented milk is derived from fresh cheese. 10. A composition for preventing small intestinal tissue damage, comprising a hydrolyzate of milk protein and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as sugar. 11. The composition of claim 10, wherein said 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. 12. The composition of claim 10 or 11, wherein the protein derived from fermented milk is derived from fresh cheese. 13. An anti-inflammatory composition comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, oil and fat as lipid, and isomaltulose as saccharide. 14. The composition of claim 13, wherein 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), Alpha-lactalbumin, beta-lactoglobulin, and lactoferrin. 15. The composition of claim 13 or 14, wherein the protein derived from fermented milk is derived from fresh cheese. 16. A composition for improving intestinal function comprising fermented milk-derived protein. 17. A composition for improving intestinal function, comprising a milk protein hydrolyzate and fermented milk-derived protein as protein, and isomaltulose as saccharide. 18. The composition of claim 17, wherein 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. 19. The composition according to any one of claims 16 to 18, wherein the fermented milk-derived protein is derived from fresh cheese. 20. A composition for preventing tissue damage of the small intestine, comprising fermented milk-derived protein. 21. A composition for preventing small intestinal tissue damage, comprising a hydrolyzate of milk protein and a protein derived from fermented milk as protein, and isomaltulose as saccharide. 22. The composition of claim 21, wherein said 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. 23. The composition according to any one of claims 20 to 22, wherein the protein derived from fermented milk is derived from fresh cheese. 24. An anti-inflammatory composition comprising a milk protein hydrolyzate and a protein derived from fermented milk as proteins. 25. The composition of claim 24, further comprising isomaltulose as a carbohydrate. 26. The composition of claim 24 or 25, wherein 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), alpha-lactalbumin, beta-lactoglobulin, and lactoferrin. 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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