Composition for promoting secretion of peptide yy

Abstract

This composition comprises 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof, and is for promoting secretion of peptide YY, or is for promoting heat production from diet, for promoting lipolysis, for promoting glucose-responsive insulin secretion, for suppressing gastric acid secretion, for promoting intestinal motility, for promoting differentiation of intestinal mucosa cells, for immunostimulation, or for promoting intestinal absorption of water and electrolytes.

Description

Composition for promoting peptide YY secretion

[0001] The present invention relates to a composition for promoting peptide YY secretion.

[0002] Peptide YY (hereinafter also referred to as "PYY") is a hormone consisting of 36 amino acids that is secreted mainly by L cells in the small intestine and large intestine. １－３６ PYY is known to exhibit various physiological activities. For example, PYY is known to enhance satiety and suppress appetite and food intake (Non-Patent Document 1), to be closely involved in the brain-gut axis, to activate neural activity in various areas of the brain (Non-Patent Document 2), and to improve memory function (Non-Patent Document 3).

[0003] After PYY is secreted from L cells, it is hydrolyzed by dipeptidyl peptidase-4, etc., and two amino acids at the N-terminus are removed to form peptide YY. ３－３６ (Hereinafter, “PYY ３－３６ " It is also called ". ) In humans, PYY ３－３６ It has been shown that when PYY is administered intravenously, postprandial heat production increases (Non-Patent Document 4). Therefore, it is expected that promoting PYY secretion will promote heat production after eating.

[0004] PYY in humans ３－３６ It has been shown that intravenous infusion of PYY increases lipolysis (ibid.). Therefore, it can be expected that promoting PYY secretion will promote lipolysis.

[0005] PYY in humans ３－３６ It has been shown that when administered intravenously, postprandial plasma glucose and serum insulin concentrations increased (ibid.). Therefore, it is expected that the promotion of PYY secretion will promote glucose-responsive insulin secretion.

[0006] It has been shown that treatment of rat proximal colon muscle tissue strips with PYY caused the tissue strips to contract in a dose-dependent manner (Non-Patent Document 5). Therefore, enhanced PYY secretion is expected to promote intestinal motility.

[0007] It has been reported that when PYY is intravenously infused into humans to bring the plasma PYY concentration to the same level as the postprandial plasma PYY concentration, gastric acid secretion is suppressed (Non-Patent Document 6). Therefore, it is expected that promoting PYY secretion will also suppress gastric acid secretion.

[0008] In rat small intestinal epithelial cell lines treated with PYY, responses of genes related to the cytoskeleton or extracellular matrix, including enhanced expression of the CD63 gene, were observed, and it has been suggested that CD63 plays an important role in the differentiation of small intestinal epithelial cell lines (Non-Patent Document 7). These findings suggest that PYY plays a role in regulating cell differentiation through cytoskeleton-associated proteins (ibid.). Therefore, it is expected that enhanced secretion of PYY will promote the differentiation of intestinal mucosal cells, particularly small intestinal epithelial cells.

[0009] After activating CD4-positive T cells with CD3 and CD28, PYY ３－３６ It has been shown that treatment with PYY promoted the secretion of IFN-γ, IL-4, and IL-17 from the cells (Non-Patent Document 8). Therefore, it is expected that the promotion of PYY secretion will stimulate the immune system.

[0010] It has been shown that administration of PYY to dogs increased the amount of water and electrolytes absorbed into the jejunum and ileum (Non-Patent Document 9). Therefore, it is expected that promotion of PYY secretion will promote the absorption of water and electrolytes into the intestine, particularly the small intestine.

[0011] Human milk oligosaccharides (hereinafter also referred to as "HMO") are a collective term for oligosaccharides contained in breast milk, and are the third most abundant solid component in breast milk after lactose and lipids. Representative HMOs include 2'-fucosyllactose (O-α-L-fucopyranosyl-(1→2)-O-β-D-galactopyranosyl-(1→4)-D-glucose, hereinafter also referred to as "2FL"), which is the most abundant in breast milk, and 3'-sialyllactose (O-(N-acetyl-α-neuramin), a major acidic HMO. Examples of HMOs include 6'-sialyllactose (O-(N-acetyl-α-neuraminosyl)-(2→6)-O-β-D-galactopyranosyl-(1→4)-D-glucose, hereinafter also referred to as "3SL") and 6'-sialyllactose (O-(N-acetyl-α-neuraminosyl)-(2→6)-O-β-D-galactopyranosyl-(1→4)-D-glucose, hereinafter also referred to as "6SL"). It has been reported that HMOs reach the intestine without being metabolized by human digestive enzymes and exert various physiological functions. For example, it has been reported that HMOs act as prebiotics that promote the proliferation and establishment of beneficial intestinal bacteria (Non-Patent Document 10), have antibacterial and antiviral effects (Non-Patent Documents 11 and 12), contribute to brain development and improvement of cognitive function (Non-Patent Documents 13 and 14), regulate food intake, and prevent obesity, overweight, etc. (Patent Documents 1 and 2), etc. However, the relationship between HMOs or their constituent units, sialic acids such as N-acetylneuraminic acid, and the promotion of PYY secretion is unknown.

[0012] International Publication No. 2021 / 011905 International Publication No. 2017 / 215721

[0013] McGowan, B. M. C., et al. "Peptide YY and appetite control." Current opinion in pharmacology 4.6 (2004): 583-588.Batterham, Rachel L., et al. "PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans." Nature 450.7166 (2007): 106-109.Stadlbauer, Ulrike, et al. "Possible mechanisms of circulating PYY-induced satiation in male rats." Endocrinology 154.1 (2013): 193-204.Sloth, Birgitte, et al. "Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects." American Journal of Physiology-Endocrinology and Metabolism 292.4 (2007): E1062-E1068.Ferrier, L., et al. "Pathways and receptors involved in peptide YY induced contraction of rat proximal colonic muscle in vitro." Gut 46.3 (2000): 370-375.Field, Benjamin CT, et al. "Bowels control brain: gut hormones and obesity." Nature Reviews Endocrinology 6.8 (2010): 444-453.Hallden, Gunnel, et al."Y receptor-mediated induction of CD63 transcripts, a tetraspanin determined to be necessary for differentiation of the intestinal epithelial cell line, hBRIE 380i cells." Journal of Biological Chemistry 274.39 (1999): 27914-27924.Han, Kim, et al. "Identification and validation of nutrient state-dependent serum protein mediators of human CD4+ T cell responsiveness." Nutrients 13.5 (2021): 1492.Bilchik, Anton J., et al. "Peptide YY is a physiological regulator of water and electrolyte absorption in the canine small bowel in vivo." Gastroenterology 105.5 (1993): 1441-1448.Yu, Zhuo-Teng, et al. "Utilization of major fucosylated and sialylated human milk oligosaccharides by isolated human gut microbes." Glycobiology 23.11 (2013): 1281-1292.Piotrowski, Michal, et al. "The prebiotic effect of human milk oligosaccharides 3'-and 6'-sialyllactose on adhesion and biofilm formation by Clostridioides difficile-pilot study." Microbes and Infection 24.3 (2022): 104929.Moore, Rebecca E., et al."Prospecting human milk oligosaccharides as a defense against viral infections." ACS infectious diseases 7.2 (2021): 254-263. Fumihiko Sakai, et al. "Effects of feeding sialyllactose and galactosylated N-acetylneuraminic acid on swimming learning ability and brain lipid composition in adult rats." Journal of Applied Glycoscience 53.4 (2006): 249-254.Jacobi, Sheila K., et al. "Dietary isomers of sialyllactose increase ganglioside sialic acid concentrations in the corpus callosum and cerebellum and modulate the colonic microbiota of formula-fed piglets." The Journal of nutrition 146.2 (2016): 200-208.

[0014] An object of the present invention is to provide a composition capable of promoting PYY secretion.

[0015] The present inventors have found that 6SL, N-acetylneuraminic acid (hereinafter also referred to as "Neu5Ac"), or a salt thereof promotes PYY secretion from an enteroendocrine cell line.

[0016] The present disclosure provides, for example, the inventions described in the following [1] to

[33] . [1] A composition containing 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof, for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes. [2] The composition described in [1], further containing fucose and / or glucose. [3] The composition described in [1] or [2], which is a food or pharmaceutical product. [4] A composition for promoting peptide YY secretion, containing 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof. [5] The composition described in [4], further containing fucose and / or glucose. [6] The composition described in [4] or [5], which is a food or pharmaceutical product. [7] A composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on promoting peptide YY secretion, containing 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof. [8] The composition according to [7], further containing fucose and / or glucose. [9] The composition according to [7] or [8], which is a food or pharmaceutical product.

[10] A method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, comprising ingesting or administering 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof.

[11] A method for promoting peptide YY secretion, comprising administering or having a subject in need thereof ingest 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof.

[12] A method for promoting dietary thermogenesis, lipolysis, glucose-responsive insulin secretion, suppression of gastric acid secretion, intestinal motility, differentiation of intestinal mucosal cells, immunostimulation, or intestinal absorption of water and electrolytes based on peptide YY secretion promotion, comprising ingesting or administering 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof.

[13] 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for use in a therapeutic method for promoting dietary thermogenesis, lipolysis, glucose-responsive insulin secretion, suppression of gastric acid secretion, intestinal motility, differentiation of intestinal mucosal cells, immunostimulation, or intestinal absorption of water and electrolytes.

[14] 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for use in a therapeutic method for promoting peptide YY secretion.

[15] 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for use in a therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on promoting peptide YY secretion.

[16] Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes.

[17] Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method for promoting peptide YY secretion.

[18] Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on promoting peptide YY secretion.

[19] Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes.

[20] Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition for promoting peptide YY secretion.

[21] Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on promotion of peptide YY secretion.

[22] A method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes, comprising administering or having a subject in need thereof 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose.

[23] A method for promoting peptide YY secretion, comprising administering or having a subject in need thereof 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose.

[24] A method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes based on promotion of peptide YY secretion, comprising ingesting or administering 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose to a subject in need thereof.

[25] 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for use in a therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes.

[26] 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for use in a therapeutic method for promoting peptide YY secretion.

[27] 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for use in a therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on promoting peptide YY secretion.

[28] Use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose in a non-therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes.

[29] Use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose in a non-therapeutic method for promoting peptide YY secretion.

[30] Use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose in a non-therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on promotion of peptide YY secretion.

[31] Use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for the manufacture of a composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes.

[32] Use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for the production of a composition for promoting peptide YY secretion.

[33] Use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for the manufacture of a composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on the promotion of peptide YY secretion.

[0017] The present invention provides a composition that can promote PYY secretion. The composition of the present invention can also promote dietary thermogenesis, lipolysis, glucose-responsive insulin secretion, suppress gastric acid secretion, stimulate intestinal motility, promote differentiation of intestinal mucosal cells, stimulate the immune system, or promote intestinal absorption of water and electrolytes.

[0018] 1 shows the PYY concentration (pg / mL) in the culture supernatant of a mouse enteroendocrine cell line after addition of various human milk oligosaccharides (2FL, 3SL, or 6SL), Neu5Ac, fucose, or glucose. In Fig. 1, data are shown as mean ± standard error, and "**" indicates a p value of less than 0.01 compared to the control reagent-treated group in Dunnett's test.

[0019] Hereinafter, embodiments of the present disclosure will be described in detail.

[0020] A. Compositions Containing 6SL, Neu5Ac, or Salts Thereof The compositions for promoting PYY secretion according to the present disclosure contain 6SL, Neu5Ac, or salts thereof.

[0021] The compositions disclosed herein for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating effects, or promoting intestinal absorption of water and electrolytes contain 6SL, Neu5Ac, or a salt thereof.

[0022] The composition according to the present disclosure for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes based on promoting PYY secretion contains 6SL, Neu5Ac, or a salt thereof.

[0023] Hereinafter, the terms "composition for promoting PYY secretion according to the present disclosure," "composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes according to the present disclosure," and "composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes based on PYY secretion promotion" are collectively referred to as "composition according to the present disclosure."

[0024] The composition according to the present disclosure can promote secretion of PYY by containing 6SL, Neu5Ac, or a salt thereof. The promotion of PYY secretion may be achieved by promoting the production of PYY or by promoting the secretion of PYY from inside the cell to outside the cell. In addition, PYY may be secreted by hydrolysis of PYY. ３－３６ is produced, which promotes PYY secretion and increases PYY production in the body. ３－３６ The production of can be promoted.

[0025] Here, the secretion of PYY can be confirmed by, for example, secretion of PYY from enteroendocrine cells such as L cells present in the small intestine or large intestine. The secretion of PYY can be confirmed by secreting PYY, hydrolysates of PYY (PYY ３－３６The PYY activity can be confirmed by measuring at least one selected from the group consisting of PYY fragments and salts thereof. Examples of the salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine, with sodium salts being preferred.

[0026] Whether or not a substance can promote PYY secretion can be determined, for example, by adding the substance to an enteroendocrine cell line (e.g., NCI-H716 cells or STC-1 cells, preferably STC-1 cells), culturing for 20 minutes to 24 hours, preferably 60 minutes, and then measuring the concentration of the PYY in the culture supernatant by a known measurement method using an anti-PYY antibody that selectively binds to PYY, such as ELISA using an enzyme-linked immunosorbent assay (ELISA) kit such as EIAM-PYY-1 (manufactured by RayBiotech). If the PYY concentration is higher than that in a control culture supernatant under similar conditions except for the absence of the substance, it can be determined that the substance promotes PYY secretion. Here, the comparison of PYY concentrations measured using the ELISA kit may be performed by comparing the respective mean values, and for example, if the mean value in the substance-added group is, for example, 1.1-fold, 1.5-fold, 1.9-fold, 2.0-fold, 2.5-fold, 2.7-fold, or 2.8-fold or more greater than the mean value in the control, it can be determined that the substance promotes PYY secretion. Furthermore, the PYY concentration can also be measured by known measurement methods, such as Western blotting (WB) or ELISA other than ELISA using the ELISA kit, using a binding substance such as an anti-PYY antibody that selectively binds to PYY.

[0027] The composition according to the present disclosure can promote PYY secretion, and therefore promote thermogenesis through diet. Here, the promotion of thermogenesis through diet may be based on the promotion of PYY secretion, but more specifically, for example, ３－３６ For example, by comparing the composition according to the present disclosure with a control that does not contain the composition using known indirect calorimetry or the like, it can be confirmed that the composition according to the present disclosure promotes thermogenesis through diet.

[0028] The composition according to the present disclosure can promote PYY secretion, and therefore can promote lipolysis. Here, the promotion of lipolysis may be based on the promotion of PYY secretion, but more specifically, for example, ３－３６ For example, by comparing the composition according to the present disclosure with a control that does not contain the composition using a known method for measuring the concentration of free fatty acids in blood, it can be confirmed that the composition according to the present disclosure promotes lipolysis.

[0029] The composition according to the present disclosure can promote PYY secretion, and therefore promote glucose-responsive insulin secretion. Here, the promotion of glucose-responsive insulin secretion may be based on the promotion of PYY secretion, but more specifically, for example, ３－３６ The promotion of glucose-responsive insulin secretion may be based on the promotion of the production of glucose-responsive insulin. The promotion of glucose-responsive insulin secretion may be achieved by promoting the production of glucose-responsive insulin, or by promoting the secretion of glucose-responsive insulin from inside the cell to outside the cell. For example, by comparing a composition according to the present disclosure with a control that does not contain the composition using a known method for measuring insulin concentration in blood, it can be confirmed that the composition according to the present disclosure promotes glucose-responsive insulin secretion.

[0030] The composition according to the present disclosure can promote PYY secretion and thus promote intestinal motility. Here, the promotion of intestinal motility can be based on the promotion of PYY secretion. For example, the promotion of intestinal motility by a known method of measuring contractions in cells derived from the intestine of a human or rat, etc., can be confirmed by comparing the composition according to the present disclosure with a control that does not contain the composition.

[0031] The composition according to the present disclosure can promote PYY secretion and therefore suppress gastric acid secretion. Here, the suppression of gastric acid secretion can be based on the promotion of PYY secretion. For example, by inserting a known nasogastric tube, aspirating gastric contents, and measuring the amount of gastric acid secretion, the suppression of gastric acid secretion by the composition according to the present disclosure can be confirmed by comparing the composition with a control that does not contain the composition.

[0032] The composition according to the present disclosure can promote PYY secretion and thus promote the differentiation of intestinal mucosal cells, particularly small intestinal epithelial cells. The promotion of intestinal mucosal cell differentiation may be based on the promotion of PYY secretion. More specifically, it may be based on, for example, the promotion of PYY secretion, which promotes the expression of genes associated with the cytoskeleton or extracellular matrix, particularly the CD63 gene. For example, by comparing the composition according to the present disclosure with a control that does not contain the composition using known WB or ELISA, it can be confirmed that the composition according to the present disclosure promotes the differentiation of intestinal mucosal cells.

[0033] The composition according to the present disclosure can stimulate PYY secretion and thus stimulate immunity. Here, the stimulation of immunity may be based on the promotion of PYY secretion, but more specifically, for example, ３－３６ and may be based on promoting the production of PYY ３－３６The immunostimulatory effect of the composition of the present disclosure may be based on promoting the secretion of at least one selected from the group consisting of IFN-γ, IL-4, and IL-17 by promoting the production of IFN-γ, IL-4, and IL-17. It is known that IFN-γ is typically secreted by Th1 cells, IL-4 by Th2 cells, and IL-17 by Th17 cells. For example, by measuring the amount of IFN-γ, IL-4, or IL-17 in T cells derived from known animals using ELISA or the like, it can be confirmed that the composition of the present disclosure activates the immune system by comparing the composition with a control that does not contain the composition.

[0034] The composition according to the present disclosure can promote PYY secretion, and therefore promote the absorption of water and electrolytes into the intestine, particularly the small intestine. Here, the promotion of water and electrolyte absorption into the intestine, particularly the small intestine, can be based on the promotion of PYY secretion. For example, by comparing the composition according to the present disclosure with a control that does not contain the composition using a known method for measuring the flux of water and electrolytes using an intestinal perfusate, it can be confirmed that the composition according to the present disclosure promotes the absorption of water and electrolytes into the intestine.

[0035] The salt of 6SL or Neu5Ac may be a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine.

[0036] 6SL, Neu5Ac, or salts thereof may exist in the form of crystalline polymorphs, but are not limited to any particular type, and may be a single crystalline form or a mixture of crystalline forms. 6SL, Neu5Ac, or salts thereof also include amorphous forms. 6SL, Neu5Ac, or salts thereof also include anhydrates and solvates (particularly hydrates).

[0037] As 6SL, Neu5Ac or a salt thereof, 6SL, sodium salt of 6SL, Neu5Ac or sodium salt of Neu5Ac are preferred.

[0038] 6SL or a salt thereof can be produced by a known method; for example, the sodium salt of 6SL can be produced by the method described in WO 2017 / 086443. Neu5Ac or a salt thereof can be produced by a known method, for example, the known method described in Yamaguchi, Shinya, et al. "Simple and large-scale production of N-acetylneuraminic acid and N-acetyl-D-mannosamine," Trends in Glycoscience and Glycotechnology 18.102 (2006): 245-252. Alternatively, commercially available 6SL, Neu5Ac, or a salt thereof can be used; for example, the sodium salt of 6SL or Neu5Ac available from Tokyo Chemical Industry Co., Ltd. can also be used.

[0039] The composition according to the present disclosure may further contain fucose and / or glucose from the viewpoint of further enhancing the effect of promoting PYY secretion, or from the viewpoint of further enhancing the effects of promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes. Fucose and / or glucose can promote PYY secretion. Fucose or glucose includes the L-form, the D-form, or a mixture thereof. While crystalline polymorphism may exist for fucose or glucose, the present invention is not limited to either of these, and the fucose or glucose may be a single crystalline form or a mixture. Fucose or glucose also includes amorphous forms. Furthermore, fucose or glucose includes anhydrous forms and solvates (particularly hydrates).

[0040] The composition according to the present disclosure may be a food, food additive, pharmaceutical, or quasi-drug, and is preferably a food or pharmaceutical. Examples of subjects to which the composition according to the present disclosure can be applied include humans and non-human mammals, with humans being preferred. Non-human mammals include, for example, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, sheep, pigs, cows, horses, goats, and monkeys, and the composition according to the present disclosure can be used as feed, which is a form of food. The human may be an adult, elderly person, child, infant, or newborn.

[0041] The composition according to the present disclosure can be administered or ingested orally or parenterally, but is preferably administered or ingested orally. When the composition according to the present disclosure is administered or ingested orally, 6SL, Neu5Ac, or a salt thereof can easily reach the small intestine and large intestine, thereby further promoting PYY secretion by enteroendocrine cells.

[0042] The content of 6SL, Neu5Ac, or a salt thereof in the composition according to the present disclosure is not particularly limited, and may be, for example, preferably 0.01% by mass to 90% by mass, more preferably 0.1% by mass to 80% by mass, based on the total amount of the composition.

[0043] The dosage or intake of the composition according to the present disclosure is not particularly limited, but for example, for a subject weighing 60 kg, the dosage or intake of 6SL, Neu5Ac, or a salt thereof per day can be preferably 50 mg to 30 g, and more preferably 100 mg to 10 g.

[0044] The number of times the composition according to the present disclosure is administered (or taken) is not particularly limited, but can be, for example, once to three times a day.

[0045] The food, food additive, drug, or quasi-drug can be produced according to a conventional method. The content of 6SL, Neu5Ac, or a salt thereof in the food, food additive, drug, or quasi-drug is not particularly limited and can be freely set depending on the purpose.

[0046] When the composition according to the present disclosure is a food, food additive, drug, or quasi-drug, the food, food additive, drug, or quasi-drug may contain ingredients that are typically used in foods, food additives, drugs, or quasi-drugs, respectively. The food, food additive, drug, or quasi-drug according to the present disclosure may contain bases, carriers, or additives that are typically used in foods, food additives, drugs, or quasi-drugs, respectively. Examples of additives include excipients, oils, powders, buffers, solubilizers, antioxidants, surfactants, thickeners, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, antiseptics, pigments, colorants, fragrances, gloss-imparting agents, gelling agents, alcohols, water-soluble polymers, film-forming agents, or resins. The bases, carriers, and various additives described above may be used singly or in combination as needed.

[0047] When the composition according to the present disclosure is a food, the food may be a general food, a food for specified health uses, a food with nutrient functions, a food with functional claims, a food for hospital patients, a supplement, etc. When the composition according to the present disclosure is a food for specified health uses, a food with nutrient functions, or a food with functional claims, the form of the composition may be a capsule, tablet, granule, powder, syrup, troche, etc.

[0048] When the composition according to the present disclosure is a food product, examples of the food product include seasonings, processed meat products, processed agricultural products, beverages (lactic acid bacteria drinks, soft drinks, alcoholic drinks, carbonated drinks, dairy drinks, fruit juice drinks, tea, coffee, energy drinks, etc.), powdered drinks (powdered juice, powdered soup, powdered milk, etc.), concentrated drinks, confectioneries (candy (throat lozenges), cookies, biscuits, gum, gummy candies, chewable tablets, tablets, chocolate, etc.), bread, cereal, etc.

[0049] When the composition according to the present disclosure is a pharmaceutical or quasi-drug, the dosage form of the pharmaceutical or quasi-drug may be, for example, a liquid, suspension, capsule, granule, pill, powder, tablet, syrup, troche, etc. Indications for use as a pharmaceutical include diseases related to the suppression of thermogenesis, suppression of lipolysis, suppression of glucose-responsive insulin secretion, suppression of gastric acid secretion, suppression of intestinal motility, suppression of differentiation of intestinal mucosal cells, immunocompromise, or suppression of intestinal absorption of water and electrolytes.

[0050] B. Methods Comprising Ingestion or Administration of 6'-Sialyl Lactose, N-Acetylneuraminic Acid, or a Salt Thereof to a Subject in Need thereof One aspect of the present disclosure relates to a method for promoting dietary thermogenesis, lipolysis, glucose-stimulated insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, comprising ingestion or administration of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof (hereinafter also referred to as "Method 1 of the present disclosure"). Another aspect of the present disclosure relates to a method for promoting peptide YY secretion, comprising ingestion or administration of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof (hereinafter also referred to as "Method 2 of the present disclosure"). One aspect of the present disclosure relates to a method for promoting dietary thermogenesis, lipolysis, glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes based on promotion of peptide YY secretion, comprising ingesting or administering 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof (hereinafter also referred to as "Method 3 of the present disclosure").

[0051] In Methods 1 to 3 according to the present disclosure, the administration (or ingestion) conditions (e.g., administration (or ingestion) subject, administration (or ingestion) amount, administration (or ingestion) frequency, etc.) can be, without limitation, the conditions described above in [A. Compositions containing 6SL, Neu5Ac, or a salt thereof] as the administration (or ingestion) conditions of the composition according to the present disclosure.

[0052] For example, 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof may be administered (or ingested) to a subject as is, or may be prepared as a composition according to the present disclosure described above in [A. Compositions containing 6SL, Neu5Ac, or a salt thereof] and administered (or ingested) to a subject. In the former case, 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof may be administered (or ingested) alone, or may be administered (or ingested) in combination with an additional component. The additional component may be a component that may be contained in the composition according to the present disclosure described above (e.g., fucose and / or glucose), etc.

[0053] [C. 6'-Sialyl lactose, N-acetylneuraminic acid, or a salt thereof for use in a therapeutic method] One aspect of the present disclosure relates to 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for use in a therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes (hereinafter also referred to as "6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof 1 according to the present disclosure"). One aspect of the present disclosure relates to 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for use in a therapeutic method for promoting peptide YY secretion (hereinafter also referred to as "6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof 2 according to the present disclosure"). One aspect of the present disclosure relates to 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof (hereinafter also referred to as "6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof 3 according to the present disclosure") for use in a therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes, based on promoting peptide YY secretion.

[0054] As specific embodiments of 6'-sialyllactose, N-acetylneuraminic acid, or salts thereof 1 to 3 according to the present disclosure, the embodiments relating to administration described above in [B. Methods comprising administering or ingesting 6'-sialyllactose, N-acetylneuraminic acid, or salts thereof to a subject in need thereof] can be applied without limitation.

[0055] That is, for example, each of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof 1 to 3 according to the present disclosure can be 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for use in the above-mentioned therapeutic methods.

[0056] As used herein, the term "therapeutic method" refers to a method of treating a mammalian body. For example, the method may be a method aimed at or involving medical treatment. More specifically, the method may involve, for example, a medical professional administering a substance to a mammalian body or instructing a medical professional to administer a substance to a mammalian body.

[0057] D. Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method One aspect of the present disclosure relates to the use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method of promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes (hereinafter also referred to as "Use D1 in the present disclosure"). Another aspect of the present disclosure relates to the use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method of promoting peptide YY secretion (hereinafter also referred to as "Use D2 in the present disclosure"). One aspect of the present disclosure relates to the use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof in a non-therapeutic method for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes, based on the promotion of peptide YY secretion (hereinafter also referred to as "Use D3 according to the present disclosure").

[0058] Specific embodiments of Uses D1 to D3 according to the present disclosure include, without limitation, the embodiments relating to ingestion described above in [B. Methods comprising ingestion or administration of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof].

[0059] That is, for example, each of Uses D1 to D3 according to the present disclosure can be the use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose in the non-therapeutic method described above.

[0060] As used herein, the term "non-therapeutic method" refers to a method that does not fall under the category of a therapeutic method. For example, it may be a method that is not intended for and / or does not involve medical treatment. More specifically, it may be a method that does not involve a medical professional administering a substance to a mammal and / or instructing a mammal to administer a substance. Furthermore, a non-therapeutic method may be, for example, a method for the purpose of promoting health.

[0061] E. Use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition. One aspect of the present disclosure relates to the use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulation, or promoting intestinal absorption of water and electrolytes (hereinafter also referred to as "Use E1 of the present disclosure"). One aspect of the present disclosure relates to the use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition for promoting peptide YY secretion (hereinafter also referred to as "Use E2 of the present disclosure"). One aspect of the present disclosure relates to use of 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof for the manufacture of a composition for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, immunostimulating, or promoting intestinal absorption of water and electrolytes, based on promotion of peptide YY secretion (hereinafter also referred to as "Use E3 of the present disclosure").

[0062] Specific embodiments of Uses E1 to E3 according to the present disclosure include, without limitation, the embodiments described above in [A. A composition containing 6SL, Neu5Ac, or a salt thereof] and [B. A method comprising ingesting or administering 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof to a subject in need thereof].

[0063] That is, for example, each of Uses E1 to E3 according to the present disclosure can be the use of 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof, and fucose and / or glucose for the production of the above-mentioned composition.

[0064] The present invention will be described in more detail below with reference to examples.

[0065] STC-1 cells (American Type Culture Collection; ATCC), a mouse enteroendocrine cell line, were cultured at 1.5 × 10６ The cells were seeded into a 6-well plate containing 3 mL of DMEM medium per well to give 100 cells / well, and cultured overnight at 37°C. After that, the cells were cultured in a 6-well plate containing 140 mM NaCl (Fujifilm Wako Pure Chemical Industries, Ltd.), 5 mM KCl (Fujifilm Wako Pure Chemical Industries, Ltd.), 10 mM HEPES (Dojindo Laboratories, Ltd.), 2 mM MgCl ２ (Fujifilm Wako Pure Chemical Industries, Ltd.), 2 mM CaCl ２ The cells were washed once with a buffer solution (pH 7.4) containing 10 mM ATP (Fujifilm Wako Pure Chemical Industries, Ltd.) and 10 mM glucose (Fujifilm Wako Pure Chemical Industries, Ltd.). Subsequently, 1 mL / well of the above buffer solution alone (control reagent) or the above buffer solution supplemented with 10 mg / mL 2FL, 3SL, or 6SL, 5 mg / mL Neu5Ac, 3.46 mg / L fucose, or 3.7 mg / mL glucose was added and incubated at 37°C for 60 minutes (n=4 for each). After incubation, the supernatant from each well was collected and centrifuged at 1000 rpm at 4°C for 5 minutes. The resulting supernatant was stored at -20°C. The PYY concentration (pg / mL) in the resulting supernatant was then measured using a commercially available ELISA kit, EIAM-PYY-1 (RayBiotech). The results are shown in Figure 1.

[0066] As shown in Figure 1, the 10 mg / mL 2FL group (mean PYY concentration: 0.81 pg / mL) and the 10 mg / mL 3SL group (mean PYY concentration: 0.59 pg / mL) had lower supernatant PYY concentrations compared to the control group (mean PYY concentration: 0.90 pg / mL). On the other hand, the 10 mg / mL 6SL group (mean PYY concentration: 2.82 pg / mL) and the 5 mg / mL Neu5Ac group (mean PYY concentration: 2.58 pg / mL) had significantly higher supernatant PYY concentrations compared to the control group (6SL group: 3.1-fold higher than the control group, Neu5Ac group: 2.8-fold higher than the control group). Furthermore, the mean PYY concentration in the supernatant was higher in the 3.46 mg / L fucose-added group (mean PYY concentration: 1.70 pg / mL) and the 3.7 mg / mL glucose-added group (mean PYY concentration: 1.38 pg / mL) than in the control reagent-added group (fucose-added group: 1.9-fold higher than the control reagent-added group, glucose-added group: 1.5-fold higher than the control reagent-added group). These results demonstrate that 6SL, Neu5Ac, fucose, and glucose can all promote PYY secretion, with 6SL and Neu5Ac being particularly effective in promoting PYY secretion.

Claims

1. A composition containing 6'-sialyllactose, N-acetylneuraminic acid or a salt thereof for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, stimulating immunity, or promoting intestinal absorption of water and electrolytes.

2. The composition according to claim 1, further comprising fucose and / or glucose.

3. The composition according to claim 1 or 2, which is a food or pharmaceutical product.

4. A composition for promoting peptide YY secretion, comprising 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof.

5. The composition according to claim 4, further comprising fucose and / or glucose.

6. The composition according to claim 4 or 5, which is a food or pharmaceutical product.

7. A composition containing 6'-sialyllactose, N-acetylneuraminic acid, or a salt thereof, for promoting dietary thermogenesis, promoting lipolysis, promoting glucose-responsive insulin secretion, suppressing gastric acid secretion, promoting intestinal motility, promoting differentiation of intestinal mucosal cells, stimulating immunity, or promoting intestinal absorption of water and electrolytes, based on promoting peptide YY secretion.

8. The composition according to claim 7, further comprising fucose and / or glucose.

9. The composition according to claim 7 or 8, which is a food or pharmaceutical product.

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