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WO2019199094A1 - Nouvelle souche de bifidobacterium longum ou de lactobacillus rhamnosus ayant pour effet de prévenir ou de traiter l'obésité, et utilisation correspondante - Google Patents

Nouvelle souche de bifidobacterium longum ou de lactobacillus rhamnosus ayant pour effet de prévenir ou de traiter l'obésité, et utilisation correspondante Download PDF

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Publication number
WO2019199094A1
WO2019199094A1 PCT/KR2019/004395 KR2019004395W WO2019199094A1 WO 2019199094 A1 WO2019199094 A1 WO 2019199094A1 KR 2019004395 W KR2019004395 W KR 2019004395W WO 2019199094 A1 WO2019199094 A1 WO 2019199094A1
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strain
adipocytes
obesity
culture
lactic acid
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PCT/KR2019/004395
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English (en)
Korean (ko)
Inventor
김용식
박두상
손미영
기수진
김지선
오현우
이유리
전준형
정선아
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Korea Research Institute of Bioscience and Biotechnology KRIBB
Industry Academy Cooperation Foundation of Soonchunhyang University
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Korea Research Institute of Bioscience and Biotechnology KRIBB
Industry Academy Cooperation Foundation of Soonchunhyang University
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Application filed by Korea Research Institute of Bioscience and Biotechnology KRIBB, Industry Academy Cooperation Foundation of Soonchunhyang University filed Critical Korea Research Institute of Bioscience and Biotechnology KRIBB
Priority to CN202311636456.2A priority Critical patent/CN117701424A/zh
Priority to CN201980025040.2A priority patent/CN112672749B/zh
Publication of WO2019199094A1 publication Critical patent/WO2019199094A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/332—Promoters of weight control and weight loss

Definitions

  • the present invention relates to a novel Bifidobacterium longgum strain or Lactobacillus rhamnosus strain having a prophylactic or therapeutic effect on obesity and its use.
  • the mechanism of reaching obesity is that by over-ingesting the sugar, the sugar in the food is digested and becomes monosaccharide and absorbed into the body through the small intestine.Increased blood sugar increases insulin secreted by the stimulus and acts on fat cells to release the monosaccharide in the blood. Fat cells are taken in and converted into fat.
  • Obesity is a problem that obesity itself causes a lot of constipation, indigestion, gastrointestinal disorders due to the pressure of the abdomen by the fat tissue, as well as the risk factors of many adult diseases.
  • Obesity is known to be directly linked to diabetes, hypertension, coronary artery disease and cancer, and WHO defines it as a chronic disease in the 21st century.
  • the prevalence of Korean adults is expected to increase by more than 50% in 2030, and the national and individual economic burdens are expected to increase significantly. Therefore, a lot of attention and investment in research to prevent and treat obesity at home and abroad has been made.
  • Mouse adipocytes 3T3-L1 are cells that have already differentiated to mature into white adipocytes and are the most used cell line for obesity research.
  • using the fat cell line to investigate the effect of brown fat localization (Browning: the process of changing the white fat cells storing energy to brown fat cells consuming energy exothermic reaction, heat homeostasis)
  • brown fat cell factor and beige fat cell factor-specific gene expression patterns in C3H10T1 / 2 mouse mesenchymal stem cells revealed a new paradigm for the prevention and treatment of obesity.
  • Korean Patent No. 1778734 discloses an ESBP separated from Bifidobacterium long gum KACC 91563 and an antiallergic composition using the same, and Korean Patent No. 1401530 Bifidobacterium producing conjugated linoleic acid.
  • Long gum strain and use thereof are disclosed, but as in the present invention, Bifidobacterium longgum strain or Lactobacillus rhamnosus having the effect of preventing or treating obesity by inducing the formation of beige adipocytes and brown adipocytes Strain and its use 'is not known at all.
  • the present invention is derived from the above requirements, in the present invention, unlike the general method for identifying the anti-obesity effect in terms of reducing the number of white adipocytes, the present invention is most frequently used for obesity research that has already been differentiated Browning of adipocytes 3T3-L1 by treatment of Bifidobacterium longgum DS0956 strain and Lactobacillus rhamnosus DS0508 strain culture medium using pro-fat cells 3T3-L1, which mature into the used white adipocytes.
  • the white fat cells that store the energy consumption in the exothermic reaction, the process of changing to brown fat cells maintaining heat homeostasis) was confirmed.
  • the Bifidobacterium longgum of the present invention Lactobacillus rhamnosus strain or culture solution was administered to obese mice induced through a high-fat diet to confirm the inhibitory or improvement effect of obesity, a significant weight gain compared to the negative control group Inhibitory effect of the mouse, white fever-specific gene or brown fat-cell / beige fat-cell specific gene expression level was induced and increased, and the effect of lowering total cholesterol and low-density lipoprotein (LDL) was confirmed. Thus, it was confirmed that this has the effect of improving the lipid metabolism profile of obese mice.
  • LDL low-density lipoprotein
  • Bifidobacterium longgum strains and Lactobacillus rhamnosus strains not only oxidize fat in the body but also reduce fat metabolism and fat accumulation through the activity of gene expression related to fat cell oxidation in the body, By confirming that the effect of improving the lipid metabolism profile in the animal administered was completed, the present invention was completed.
  • the present invention provides a novel Bifidobacterium longum strain or Lactobacillus rhamnosus strain.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of obesity, containing one or more selected from the group consisting of the strain, the culture of the strain, the concentrated solution of the culture, the dried product of the culture and the extract of the culture as an active ingredient. do.
  • the present invention is a health functional food composition for preventing or improving obesity containing one or more selected from the group consisting of the strain, the culture of the strain, the concentrated solution of the culture, the dried product of the culture and the extract of the culture as an active ingredient. To provide.
  • the present invention provides a feed composition for preventing or improving obesity containing at least one selected from the group consisting of the strain, the culture of the strain, the concentrate of the culture, the dried product of the culture and the extract of the culture as an active ingredient. do.
  • lactic acid bacteria Bifidobacterium long gum and Lactobacillus rhamnosus strains or the culture medium of the present invention are administered to a subject, weight gain due to the ingestion of a high-fat diet is suppressed and fever-related genes and brown fat / beige fat cells are specific. It was confirmed that the expression level of the enemy gene is increased, and the amount of lipid components such as cholesterol and LDL is decreased.
  • the Lactobacillus Bifidobacterium long gum strain and Lactobacillus rhamnosus strain each exhibit an anti-obesity effect, and thus can be usefully used as food, medicine or feed for the prevention or treatment of obesity and the improvement of lipid metabolism. Very useful for
  • Figure 1a shows a selection flow for screening anti-obesity strains from 55 kinds of lactic acid bacteria using adipose precursor cells 3T3-L1 cells.
  • 1B is a screening result after treatment with primary 1, 5, and 10 ⁇ l of lactic acid bacteria culture medium using quantification of triglyceride (TG).
  • A lactic acid bacteria culture solution 1 ⁇ l treatment group
  • B lactic acid bacteria culture solution 5 ⁇ l treatment group
  • C lactic acid bacteria culture solution 10 ⁇ l treatment group
  • t excluded from secondary screening for cytotoxicity.
  • PA Negative control group not treated with MDI differentiation medium as pre-adipocyte
  • MDI M: methyl-isobutyl-xanthine
  • D dexamethasone, I: insulin
  • Positive control Rosi (Rosiglitazone) treatment. Rosi is a PPAR gamma agonist.
  • Figure 2a is a graph showing the relative accumulation of triglycerides (TG) compared to the control of the selected strain culture (strains 30, 51). PA, MDI and Rosi are the same as described in FIG. 1B.
  • Figure 2b is a micrograph of the cells observed through TEM by treating strain cultures selected in 3T3-L1 cells (5,000X magnification). White arrows point to lipid droplets (LD).
  • Figure 2c shows the ORO stain (Oil Red O dye) of selected strain cultures (strains 30 and 51).
  • 1st lactic acid bacteria culture solution 1 ⁇ l treatment group
  • 2nd lactic acid bacteria culture solution 5 ⁇ l treatment group
  • 3rd lactic acid bacteria culture solution 10 ⁇ l treatment group
  • (-) Negative control not treated with MDI differentiation medium
  • (+) Group treated with MDI differentiation medium
  • Positive control Rosi (Rosiglitazone) treatment.
  • Rosi is a PPAR gamma agonist.
  • 30 and 51 are the culture solution of the selected lactic acid bacteria.
  • 3a shows the effect of the selected lactic acid bacteria culture medium (strains 30 and 51) on the expression of brown adipocyte-specific genes in 3T3-L1, the progenitor cells of the mouse, and compares the relative mRNA expression levels of the genes.
  • 3b shows the effect of the selected lactic acid bacteria culture medium (strains 30 and 51) on brown adipocyte-specific expression genes in C3H10T1 / 2 cells, which are mouse mesenchymal stem cells. It is a graph comparing the expression level of the relative mRNA.
  • MDI M: methyl-isobutyl-xanthine, D: dexamethasone, I: insulin
  • adipocyte differentiation medium treatment negative control Positive control, Rosi (Rosiglitazone) treatment.
  • Rosi is a PPAR gamma agonist.
  • 30 and 51 are the culture solution of the selected lactic acid bacteria.
  • Figure 4a shows the effect of the selected lactic acid bacteria culture (strains 30, 51) on the expression of beige adipocyte-specific genes in 3T3-L1, a mouse progenitor cells
  • the relative mRNA expression of the gene 4b shows the effect of the selected lactic acid bacteria cultures (strains 30 and 51) on the beige adipocyte-specific expression genes in C3H10T1 / 2 cells, which are mouse mesenchymal stem cells.
  • Is a graph showing the comparison of relative mRNA expression levels.
  • MDI M: methyl-isobutyl-xanthine, D: dexamethasone, I: insulin
  • Positive control Rosi (Rosiglitazone) treatment. Rosi is a PPAR gamma agonist.
  • 30 and 51 are the culture solution of the selected lactic acid bacteria.
  • Figure 5a is a graph comparing the expression of the lipolysis-related genes measured by the relative amount of mRNA when treated with lactic acid bacteria culture medium (strains 30 and 51) selected from 3T3-L1 cells
  • Figure 5b is a lipid It is a graph comparing the expression level of ⁇ -oxidation-related genes by measuring the relative mRNA levels.
  • Figure 6 confirms the activation of PKA signaling when treated with lactic acid bacteria culture medium of strain 30, 51 to 3T3-L1 cells.
  • A confirms whether or not PKA is phosphorylated
  • B shows results when H89, a PKA phosphorylation inhibitor, is treated.
  • C is a graph measuring the expression level of fever-related genes by H89 treatment in terms of the relative mRNA amount
  • D to F are the expression levels of the fever-related genes and the differentiation-related genes of the adipocytes using siPKA cat a1. It is a graph comparing the amount of protein measured.
  • Figure 7 was treated with lactic acid bacteria culture medium 30, 51 to 3T3-L1 cells, and confirmed the expression changes of genes associated with lipolytic enzymes (left picture, HSL S-660 and HSL S-563 are respectively the Ser 563 of HSL , Phosphorylated at Ser 660 ), AMPK phosphorylation and transcription regulator CREB activation (middle), and the change of the lipolytic enzyme-related gene and CREB phosphorylation following treatment with H89, a PKA inhibitor (Pictured right).
  • HSL S-660 and HSL S-563 are respectively the Ser 563 of HSL , Phosphorylated at Ser 660 ), AMPK phosphorylation and transcription regulator CREB activation (middle), and the change of the lipolytic enzyme-related gene and CREB phosphorylation following treatment with H89, a PKA inhibitor (Pictured right).
  • FIG. 8 shows the weight change of the mice measured after 12 weeks of administration of the lactic acid bacteria strain or culture medium in the obesity-induced mouse through a high-fat diet.
  • FIG. 9 shows the results of H & E (Hematoxylin and Eosin) staining of white fat of mice measured after 12 weeks of administration of the lactic acid bacteria strain or culture medium in obesity-induced mice through a high-fat diet.
  • FIG. 10 is a blood glucose level (Glucose), total cholesterol (T-chol), high-density lipoproteins of mice measured after 12 weeks of administration of the lactic acid bacterium strain or culture medium in obesity-induced mice through a high fat diet. (HDL) and low density lipoprotein (LDL) numerical changes.
  • Glucose blood glucose level
  • T-chol total cholesterol
  • HDL high-density lipoprotein
  • Figure 11 targets obesity-induced mice through a high-fat diet, after 12 weeks of administration of the lactic acid bacteria strain or culture of the mouse white fat cells (WAT), gonad white fat cells (Gonadal WAT), peritoneal white fat cells ( Peritoneal WAT) and mesenteric white fat cells (Mesenteric WAT).
  • WAT mouse white fat cells
  • gonad white fat cells Gonadal WAT
  • Peritoneal WAT peritoneal white fat cells
  • Mesenteric WAT mesenteric white fat cells
  • 12a is a graph comparing the expression level of mRNAs of mice containing M1 macrophage inflammation-related cytokines after 12 weeks of administration of the lactic acid bacteria strain or culture medium in obesity-induced mice through a high-fat diet. .
  • Figure 12b is a graph comparing the expression of the relative mRNA expression of M2 macrophage-specific genes in mice after the administration of the lactic acid bacteria strain or culture medium for 12 weeks in mice inducing obesity through a high-fat diet.
  • One aspect of the present invention provides a novel Bifidobacterium longum strain or Lactobacillus rhamnosus strain.
  • the Bifidobacterium longgum strain may be a Bifidobacterium longgum DS0956, preferably a Bifidobacterium longgum DS0956 strain having an accession number of KCTC13505BP, but is not limited thereto.
  • the Bifidobacterium long gum DS0956 strain was deposited with KCTC13505BP as of March 26, 2018 to the Korea Research Institute of Bioscience and Biotechnology.
  • the Lactobacillus rhamnosus strain may be Lactobacillus rhamnosus DS0508, and preferably may be Lactobacillus rhamnosus DS0508 strain having an accession number of KCTC13504BP, but is not limited thereto.
  • the Lactobacillus rhamnosus DS0508 strain was deposited with KCTC13504BP dated March 26, 2018 to the Korea Research Institute of Bioscience and Biotechnology.
  • the Bifidobacterium longgum strain or Lactobacillus rhamnosus strain induces the formation of beige adipocytes and brown adipocytes to induce anti-obesity effects.
  • the Bifidobacterium longgum strain or Lactobacillus rhamnosus strain increases the gene expression associated with the pyogenic genes and brown fat cells specifically in 3T3-L1 adipocytes and mouse mesenchymal stem cells C3H10T1 / 2.
  • beige adipocytes and brown adipocytes more preferably Ucp1 (uncoupling protein 1), Pgc1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), Prdm16 (PR / SET domain 16), beige adipocytes by increasing the expression of Pparg (peroxisome proliferator activated receptor gamma), CD137, fibroblast growth factor 21 ( Fgf21 ), purinergic receptor P2X 5 ( P2RX5 ) and Tbx1 (T-box 1) genes (beige adipocyte) and may induce the formation of brown adipocytes.
  • Ucp1 uncoupling protein 1
  • Pgc1a peroxisome proliferator-activated receptor gamma coactivator 1-alpha
  • Prdm16 PR / SET domain 16
  • beige adipocytes by increasing the expression of Pparg (peroxisome proliferator activated receptor gamma), CD137, fibro
  • 3T3-L1 adipocytes and mouse mesenchymal stem cells C3H10T1 / 2 specific to heat-related genes in Ucp1, Pgc1a, increasing the Prdm16 and CD137, gene expression Fgf21 related to brown fat cells beige fat It may be to induce the formation of cells (beige adipocyte) and brown adipocytes, but is not limited thereto.
  • the CD137 gene is also called TNFRSF9 (TNF receptor superfamily member 9).
  • the expression amount of the Past1, Resistin or Sarpina3k gene which is a gene specifically expressed in white adipocytes, may be reduced.
  • the strain of the present invention may increase the expression of brown adipocytes or beige adipocyte-specific genes in white adipocytes, which have already been differentiated, and thereby convert the white adipocytes into brown adipocytes or beige adipocytes.
  • Brown adipocytes and beige adipocytes are characterized by promoting the action of fat decomposition for energy production, the strain of the present invention has the effect of inhibiting or improving obesity.
  • the Bifidobacterium longgum strain or Lactobacillus rhamnosus strain increases the expression level of Atgl, HSL, Plin1 or Plin5 genes , which are genes involved in fat degradation , or ⁇ -oxidation of lipids. It may be to increase the expression level of the gene associated with LCAD , MCAD, LCPT or Abhd5 gene. Since the lipolysis-related gene or ⁇ -oxidation-related gene may promote the action of decomposing and removing accumulated fat, the strain of the present invention may reduce or reduce obesity by reducing the accumulation of fat and lowering weight gain. It is effective.
  • the Bifidobacterium longgum strain or Lactobacillus rhamnosus strain may be to activate PKA signaling.
  • PKA signaling By activating the PKA signaling process, the amount of phosphorylated PKA, phosphorylated AMPK, phosphorylated transcriptional regulator CREB is increased, and thus Ucp1, Pgc1a, Pparg or Ceba genes , which are genes related to differentiation of fever-related genes or adipocytes.
  • Ucp1, Pgc1a, Pparg or Ceba genes which are genes related to differentiation of fever-related genes or adipocytes.
  • the Bifidobacterium longgum strain or Lactobacillus rhamnosus strain of the present invention has an effect of improving or treating obesity by improving a lipid metabolism profile when administered to an obese individual.
  • a specific embodiment of the present invention by administering a strain or culture of Bifidobacterium longgum or Lactobacillus rhamnosus to a mouse inducing obesity through a high fat diet
  • the strain and the culture medium of the present invention have the effect of inhibiting the increase in body weight, the expression level of fever-related genes, brown fat cells, beige fat cells specific genes increased in the white fat cells of the mouse. It was confirmed.
  • the process of differentiating the white fat cells of the individual into brown fat cells or beige fat cells may be used to inhibit or improve obesity, and the cholesterol of the individual to which the strain or culture is administered.
  • Lipid metabolism can be improved by reducing the amount of lipid components such as LDL.
  • the Bifidobacterium longgum or Lactobacillus rhamnosus strain or culture was administered to an obese individual to confirm the expression level of the gene, resulting in inflammation in the white adipose cells of the individual. It was confirmed that the expression levels of the CD11c, CD68, IL-1b, Mcp1, and TNF-a genes , which are promoted M1 macrophage markers, were decreased, and the expression levels of Arg1 and CD206 genes, which were anti-inflammatory M2 macrophage markers, were increased.
  • the strain or the culture medium of the present invention when the strain or the culture medium of the present invention is administered to an obese individual, the amount of M1 macrophages is reduced and the amount of M2 macrophages is increased, so that the obesity when the strain or culture is administered to an obese individual It can be seen that there is an effect that is suppressed or improved.
  • Another aspect of the invention provides a composition comprising lactic acid bacteria.
  • the lactic acid bacteria include the Bifidobacterium longum strain or the Lactobacillus rhamnosus strain.
  • composition comprising the lactic acid bacteria may comprise at least one selected from the group consisting of the strain, the culture of the strain, the concentrate of the culture, the dried product of the culture and the extract of the culture as an active ingredient.
  • composition comprising the lactic acid bacteria of the present invention is prepared in unit dosage form by formulating with a carrier, excipients and / or additives according to a method which can be easily carried out by those skilled in the art to which the present invention pertains. Or may be prepared by incorporating into a multi-dose container.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or an aqueous medium, or may be in the form of extracts, powders, granules, tablets, capsules, gels (eg hydrogels) or lyophilizers. It may further comprise a stabilizer or cryoprotectant.
  • the strain is lyophilized with a lyoprotectant to use in the form of a powder
  • the lyophilizer is skim milk powder, maltodextrin, dextrin, trehalose, maltose, lactose, mannitol, cyclo Dextrin, glycerol and / or honey.
  • the present invention includes mixing with a storage carrier, adsorbing, drying and solidifying the carrier, and the storage carrier may be diatomaceous earth, activated carbon, and / or degreasing steel.
  • composition comprising the lactic acid bacterium of the present invention comprises at least one selected from the group consisting of a strain, a culture solution of the strain, a concentrate of the culture solution, a dried product of the culture solution and an extract of the culture solution with any one of the carrier, excipient or additive. It may be prepared through a mixing step.
  • the composition including the lactic acid bacteria is mixed with the strain and the cryoprotectant, and after the process of freezing the mixture at -45 °C to -30 °C, dried at 30 °C to 40 °C Grinding by a blender may be prepared in the form of lyophilized powder.
  • the freezing process may be a process of vacuum freezing for 65 to 75 hours at a temperature condition of -45 °C to -30 °C, a pressure of 5 to 50 mTorr.
  • Another aspect of the present invention provides a use for preventing, treating or ameliorating obesity of a composition comprising the lactic acid bacteria.
  • the composition containing the lactic acid bacteria may be a medicine, food or feed.
  • the composition comprising the lactic acid bacteria may be a pharmaceutical composition for preventing or treating obesity when the composition is a medicine, when the composition is a food, may be a health functional food for preventing or improving obesity, the composition is a feed It may be a feed composition for preventing or improving obesity.
  • the present invention provides a pharmaceutical composition for preventing or treating obesity, containing one or more selected from the group consisting of the strain, the culture of the strain, the concentrate of the culture, the dried product of the culture and the extract of the culture as an active ingredient.
  • the pharmaceutical composition is pharmaceutically acceptable, according to the method that can be easily carried out by those of ordinary skill in the art
  • Formulated with carriers and / or excipients may be prepared in unit dose form or may be prepared within a multi-dose container.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of extracts, powders, granules, tablets, capsules or gels (eg hydrogels), and may further include a dispersant or stabilizer. have.
  • the strain included in the pharmaceutical composition may be carried in a pharmaceutically acceptable carrier such as colloidal suspensions, powders, saline, lipids, liposomes, microspheres, or nano spherical particles. They may be complexed with or related to the vehicle and are known in the art such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation reagents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances or fatty acids. It can be delivered in vivo using known delivery systems.
  • a pharmaceutically acceptable carrier such as colloidal suspensions, powders, saline, lipids, liposomes, microspheres, or nano spherical particles. They may be complexed with or related to the vehicle and are known in the art such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation reagents, polysaccharides, polya
  • pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like, but are not limited thereto. In addition to the above components, it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences, 19th ed., 1995.
  • the pharmaceutical composition according to the present invention can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical preparations. That is, the pharmaceutical composition of the present invention can be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, diluents such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, or Formulated using excipients.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or It is prepared by mixing lactose and gelatin.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • uthepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used as the base of the suppository.
  • the pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers for the inhibition and treatment of obesity.
  • the concentration of the active ingredient included in the composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the period of time, etc., and is not limited to a specific range of concentration.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • 'pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is a type of disease, severity, drug activity, or drug of a patient. Sensitivity to, time of administration, route of administration and rate of administration, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
  • the pharmaceutical composition according to the present invention may be administered as a separate therapeutic agent, or in combination with a therapeutic agent for improving skin aging or a treatment for diseases caused by other contaminants, and simultaneously, separately, or sequentially with conventional therapeutic agents. It may be a single or multiple administration. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, absorbance of the active ingredient in the body, inactivation rate, excretion rate, disease type, the drug used in combination, administration route, obesity It can be increased or decreased depending on the severity, sex, weight, age, etc., for example, the peptide of the present invention can be administered from about 0.0001 ⁇ g to 500 mg, such as 0.01 ⁇ g to 100 mg per kg of patient body weight per day. It may also be administered several times a day, such as two to three times daily, at regular time intervals, as determined by the physician or pharmacist.
  • the present invention provides a method for preventing or treating obesity, comprising administering the pharmaceutical composition to a subject.
  • the subject may be a human or an animal except a human, and may be in a state other than obesity or a state of obesity.
  • the pharmaceutical composition may be administered to the subject in a pharmaceutically effective amount to prevent obesity.
  • the pharmaceutical composition may be in a pharmaceutically effective amount in the subject. Administration can be used to treat obesity.
  • Formulation, administration method, dosage amount of the pharmaceutical composition and the concentration of the active ingredient contained in the composition are as described above.
  • the present invention is a health functional food composition for preventing or improving obesity containing one or more selected from the group consisting of the strain, the culture of the strain, the concentrated solution of the culture, the dried product of the culture and the extract of the culture as an active ingredient. To provide.
  • the dietary supplement composition can inhibit the increase in weight or accumulation of fat.
  • the health functional food composition of the present invention When used as a food additive, the health functional food composition may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the amount of the active ingredient may be appropriately used depending on the purpose of use (prevention or improvement).
  • the nutraceutical composition of the present invention is added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less with respect to the raw material.
  • the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • dietary supplement there is no particular limitation on the type of dietary supplement.
  • foods to which the health functional food composition may be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products, including ice cream, various soups, drinks, tea Drinks, alcoholic beverages, vitamin complexes, and the like, and include all health foods in the conventional sense.
  • the nutraceutical composition of the present invention may be prepared as a food, in particular a functional food.
  • Functional foods of the present invention include ingredients that are commonly added in food production, and include, for example, proteins, carbohydrates, fats, nutrients and seasonings.
  • natural carbohydrates or flavoring agents may be included as additional ingredients in addition to the active ingredient.
  • the natural carbohydrates can be monosaccharides (e.g. glucose, fructose, etc.), disaccharides (e.g. maltose, sucrose, etc.), oligosaccharides, polysaccharides (e.g. dextrins, cyclodextrins, etc.) or sugar alcohols (e.g.
  • the flavourant may be a natural flavourant (eg, taumartin, stevia extract, etc.) and a synthetic flavourant (eg, saccharin, aspartame, etc.).
  • the carbonation agent etc. which are used for a drink can be contained further.
  • the ratio of the above-mentioned ingredients is not critical, it is generally selected from 0.01 to 0.1 parts by weight based on 100 parts by weight of the health functional food composition of the present invention.
  • the present invention provides a feed composition for preventing or improving obesity containing at least one selected from the group consisting of the strain, the culture of the strain, the concentrate of the culture, the dried product of the culture and the extract of the culture as an active ingredient. do.
  • the strain is as described above, and may be added as a feed additive composition for the purpose of preventing or improving obesity.
  • the feed additive of the present invention corresponds to a feed supplement in the Feed Control Act.
  • feed in the present invention may refer to any natural or artificial diet, one meal, or the like or a component of the one meal for the animal to eat, ingest and digest.
  • the kind of the feed is not particularly limited, and may be used a feed commonly used in the art.
  • Non-limiting examples of the feed may include plant feeds such as cereals, fruits, food processing by-products, algae, fibres, pharmaceutical by-products, oils, starches, gourds or grain by-products; And animal feeds such as proteins, minerals, fats and oils, minerals, fats and oils, single cell proteins, zooplankton or foods. These may be used alone or in combination of two or more thereof.
  • Dexamethasone IBMX (isobutyl-1-metylxanthine), insulin, rosiglitazone (Rosi), Oil Red O dye, MTT (3- (4,5-dimethylthiazol-2-yl) -2,5 -diphenyltetrazolium bromide and 4% formaldehyde were purchased from Sigma Aldrich (St. Louis, MO, USA).
  • Dulbecco Modified Eagle's Media (DMEM), newborn calf serum (NBCS) and recombinant human BMP4 were purchased from Gibco (Grand Island, NY, USA). Fetal bovine serum was purchased from Atlas Biologics (Fort Collins, Co., USA). Penicillin-streptomycin solution was purchased from Hyclone Laboratories, Inc. (South Logan, NY, USA).
  • MRS medium Separation of various lactic acid bacteria using MRS medium in the absolute anaerobic conditions, sterilization after removing the oxygen present in the medium using N2 gas for anaerobic conditions.
  • 0.1 grams of the collected fecal samples were suspended in 10 ml MRS medium, diluted in steps, and plated into 100 ⁇ l of MRS plate medium or blood agar medium and incubated at 37 ° C. for 2 days under anaerobic conditions. The resulting single colonies were subcultured, purely separated and used for long term preservation.
  • 3T3-L1 cells were incubated at 37 ° C. in a 5% CO 2 incubator with 10% NBCS and 1% penicillin-streptomycin mixed in DMEM glutamax.
  • the cell concentration of 3T3-L1 cells is 70-80%, inoculate into 48 well plates.
  • the adipocyte differentiation medium was changed to MDI (Insulin, Dexamethasone, Isobutyl-1-methylxanthine (IBMX)).
  • Day 2 was treated with insulin, insulin and ROSI, insulin and sample (strain culture), and Day 4 was treated only with insulin. And on day 6 cells were fixed without sample treatment.
  • the samples were added to the medium 1, 5, and 10 ⁇ l on Day 0, 2, respectively.
  • This MDI was carried out by changing every other day during cell differentiation. The day when the cell concentration was 100% was designated as Day 0.
  • MDI, ROSI and MDI, and sample and MDI were configured and treated.
  • three independent replicates were performed for each sample.
  • 3T3-L1 cells were incubated in a 24-well plate for 6 days, and then stained using a fixed, Oil Red O (ORO) staining reagent.
  • ORO Oil Red O
  • the cells were washed once with 1X PBS, and then the cells were fixed at room temperature for 1 hour with 10% formalin. And dyed for 20 minutes at room temperature using 0.3% ORO solution and washed four times with distilled water. After washing, the phenotype was observed and photographed by the Axiovert-25 microscope. Thereafter, the stained cells were dissolved in 100% isopropanol, and the amount of ORO was measured with an absorbance of 520 nm in Victor TM X3.
  • C3H10T1 / 2 mouse mesenchymal stem cells were purchased from Korean Cell Line Bank (KCLB-10226), and 5% CO2 in high concentration glucose DMEM medium containing 10% NBCS and 1% penicillin-streptomycin. The culture was incubated at 37 °C state. To induce differentiation, C3H10T1 / 2 cells were inoculated at a cell concentration of 20-30%. For differentiation into adipocytes, cells were treated with 50 ng / mL of human recombinant BMP4 until the concentration of the cells was 100%. The medium was then replaced with fresh medium on day 2-3.
  • the medium was treated with 10% FBS, 0.5 mM IBMX, 1 ⁇ M Dexamethasone, and 10 ⁇ g / ml under conditions treated with Rosiglitazone (Rosi) or lactic acid bacteria culture medium at the designated concentration.
  • Rosi Rosiglitazone
  • lactic acid bacteria culture medium at the designated concentration.
  • Differentiation was induced by alteration to DMEM containing insulin (MDI). Differentiated cells were exposed to 500 ⁇ M dibutyryl-cAMP for 4 hours to stimulate the heat generation program.
  • the sequences for the primers are listed in Table 1.
  • the expression amount was quantified by Gapdh (Glyceraldehyde 3-phosphate dehydrogenase) (Yoon D, Imran KM, Kim YS. 2018 Toxicol Appl Pharmacol. Feb 1; 340: 9-20).
  • mice While the mice were fed a high fat diet to induce an obesity model, the intestinal microbial culture or cells were administered to the mice for 12 weeks to compare the efficacy.
  • the mice used in this study were C57BL / 6 and SPF male mice obtained at 3 weeks of age, and only healthy animals were used for the test after 7 days of acclimation.
  • the high-fat diet was fed for 12 weeks using a 45% kcal high fat diet, D12451 (Research Diet) to establish a diet-induced obesity (DIO) obesity model.
  • the group composition used in the experiment is illustrated in Table 2 below.
  • the administered lactic acid bacteria was 10 9 cell / kg, and the culture medium was lyophilized 1 ml per animal and then dissolved once in 150 ⁇ l of distilled water.
  • brown adipocytes in the group treated with 10 ⁇ l of the relatively high concentration among those that increased the proliferation by 10 to 20% in adipocytes treated with lactic acid bacteria concentrate individually, 1, 5, and 10 ⁇ l, as in the control Rosi. Primary screening was performed. In the case of 51, which showed the inhibitory effect of adipocyte formation, the cells were selected from the group treated with 10 ⁇ l of relatively high concentration in three separate concentration experiments. After the first screening by the accumulation amount of triglycerides as described above, four selected candidates were selected through the second to third screening process again through the experiment of confirming the expression of ucp1 , one of brown fat cell specific genes. Lactobacillus strains 30 and 51 were finally selected.
  • Beige adipocytes express UCP1 (Uncoupling protein 1) genes that are not expressed in white adipose tissue.
  • UCP1 Uncoupling protein 1
  • Pparg peroxisome proliferator activated receptor gamma
  • the strain culture solution was treated in C3H10T1 / 2 cells, which are mouse mesenchymal stem cells, to confirm the expression of heat generation and specific brown adipocyte factors Ucp1, Pgc1a , and Prdm16 .
  • C3H10T1 / 2 cells which are mouse mesenchymal stem cells
  • fibroblast growth factor 21 Fgf21
  • Tbx1, P2RX5, CD137 Tbx1, P2RX5, CD137
  • sheet chromium c-oxidation in 3T3-L1 adipocytes treated with lactic acid bacteria culture medium were examined to confirm the effect of heterozygous conversion to beige adipocytes in 30 white adipocytes.
  • a marked increase in the expression of specific markers of several beige adipocytes such as enzyme subunit II ( Cox2 ) was observed.
  • the cells treated with strain 51 culture medium was found to significantly increase the expression of CD137 and Fgf21 , which are important genes for the expression of beige adipocytes (FIG. 4A).
  • the strain culture solution was treated in C3H10T1 / 2 cells, which are mouse mesenchymal stem cells, to express the beige adipocyte specific genes Fgf21, P2RX5, CD137 and Tbx1 (T-box 1).
  • C3H10T1 / 2 cells which are mouse mesenchymal stem cells
  • Fgf21, P2RX5, CD137 and Tbx1 T-box 1
  • lactic acid bacteria culture medium of the present invention by treating the lactic acid bacteria culture medium in 3T3-L1 cells to confirm the expression level of Atgl, HSL, Plin1, Plin5 genes related to lipolysis, ⁇ of lipid Expression levels of genes related to oxidation ( ⁇ -oxidation), LCAD, MCAD, LCPT, Abhd5 genes were confirmed.
  • the lactic acid bacteria culture medium of the present invention was treated with 3T3-L1 cells and then the degree of activation of PKA signaling was measured.
  • the increase in phosphorylated PKA was confirmed by Western blotting (A of FIG. 6), and the phosphorylated PKA was again confirmed by treating 10 mM of P89 inhibitor H89 (FIG. 6B).
  • the phosphorylated PKA was observed to increase, confirming that there is an effect of activating the PKA signaling process.
  • the Ucp1 and Pgc1a genes which are fever related genes after the treatment of H89, which is the PKA inhibitor, (FIG.
  • the expression of the Ucp1 and Pgc1a genes was further reduced during H89 treatment.
  • the si-PKA cat a1 was used to confirm the expression of genes related to fever genes and adipocyte differentiation and expression of these proteins.
  • the expression of Ucp1, Pgc1a, Pparg, and Ceba genes was suppressed and the Ucp1, Pparg, and Pgc1a proteins were inhibited.
  • the lactic acid bacteria culture medium of the present invention induces an increase in the expression level of the exothermic genes through PKA activation (D to F of FIG. 6).
  • the G5 and G8 groups confirmed that the total cholesterol and LDL levels were significantly reduced compared to the negative control group (FIG. 10), and the strain and the culture solution of the present invention were administered to the animals together. In the case of cholesterol and LDL component was confirmed that the effect is reduced.
  • the expression levels of the genes Ucp1, Pgc1a, and Prdm16 which are genes related to fever or lipolytic enzymes in each adipose tissue, were found to be markedly increased in the group treated with the strain or culture solution of the present invention in four adipose tissues of mice. It could be confirmed (FIG. 11).
  • KCTC13505BP and KCTC13504BP were Genome analysis showed that Bifidobacterium longgum DS0956 and Lactobacillus rhamnosus DS0508 had genome sizes of 2.43Mbp and 3.01 Mbp on one chromosome, respectively, and had no plasmid.

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Abstract

La présente invention concerne une nouvelle souche de Bifidobacterium longum ou de Lactobacillus rhamnosus ayant pour effet de prévenir ou de traiter l'obésité, et une utilisation correspondante. Un traitement par chacune des souches de bactéries lactiques Bifidobacterium longum et Lactobacillus rhamnosus de la présente invention provoque une évolution du phénotype des adipocytes blancs vers celui des adipocytes bruns et, en particulier, il a été confirmé que l'expression génique spécifique des adipocytes beiges et des adipocytes bruns augmente considérablement en comparaison avec celle d'un groupe témoin non traité. En outre, une expérimentation sur des souris obèses, dont l'obésité était induite par un régime riche en graisses, a montré que chaque souche présentait un effet inhibiteur sur la prise de poids plus considérable que celui du groupe servant de contrôle négatif, et conduisait à une augmentation de l'expression d'un gène spécifique de la thermogenèse dans les adipocytes blancs des souris. Par conséquent, chacune des souches de bactéries lactiques Bifidobacterium Longum et Lactobacillus rhamnosus présente un effet anti-obésité qui leur permet d'être efficacement utilisables comme aliment à destination des humains, médicament ou aliment à destination des animaux destinés à prévenir ou traiter l'obésité, ce qui les rend très utiles pour les industries apparentées.
PCT/KR2019/004395 2018-04-11 2019-04-11 Nouvelle souche de bifidobacterium longum ou de lactobacillus rhamnosus ayant pour effet de prévenir ou de traiter l'obésité, et utilisation correspondante Ceased WO2019199094A1 (fr)

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KR102720937B1 (ko) * 2023-05-22 2024-10-25 한동대학교 산학협력단 프로바이오틱스 균주를 포함하는 비만 예방 및 체력 증진용 사료 조성물
KR20250084366A (ko) 2023-12-01 2025-06-11 순천향대학교 산학협력단 신규한 락토바실러스 애시도필러스 균주 및 이의 용도
KR20250084367A (ko) 2023-12-01 2025-06-11 순천향대학교 산학협력단 신규한 락티카제이바실러스 파라카제이 균주 및 이의 용도
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CN111801413A (zh) * 2017-09-06 2020-10-20 韩国亿诺生物有限公司 鼠李糖乳杆菌lm1019菌株及包含其的用于预防及治疗肥胖或糖尿病的组合物
CN111801413B (zh) * 2017-09-06 2023-11-03 韩国亿诺生物有限公司 鼠李糖乳杆菌lm1019菌株及包含其的用于预防及治疗肥胖或糖尿病的组合物
JP2024521057A (ja) * 2021-05-13 2024-05-28 ビーティージン カンパニー，リミティド 新規なビフィドバクテリウム・ロンガム菌株及びこの用途
JP7691784B2 (ja) 2021-05-13 2025-06-12 ビーティージン カンパニー，リミティド 新規なビフィドバクテリウム・ロンガム菌株及びこの用途
CN115624572A (zh) * 2022-10-26 2023-01-20 江南大学 可干预代谢综合征的短双歧杆菌ccfm683及应用

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