WO2017131402A1 - Nouvelle bactérie lactique dérivée d'intestin humain ayant une fonction immunorégulatrice, et son utilisation - Google Patents

Nouvelle bactérie lactique dérivée d'intestin humain ayant une fonction immunorégulatrice, et son utilisation Download PDF

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WO2017131402A1
WO2017131402A1 PCT/KR2017/000792 KR2017000792W WO2017131402A1 WO 2017131402 A1 WO2017131402 A1 WO 2017131402A1 KR 2017000792 W KR2017000792 W KR 2017000792W WO 2017131402 A1 WO2017131402 A1 WO 2017131402A1
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bifidobacterium
lactic acid
adolescentis
acid bacteria
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김동현
한명주
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Kyung Hee University
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    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • 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
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    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
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    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C12R2001/23—Lactobacillus acidophilus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C12R2001/25—Lactobacillus plantarum
    • C—CHEMISTRY; METALLURGY
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    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/46—Streptococcus ; Enterococcus; Lactococcus

Definitions

  • the present invention relates to a novel lactic acid bacteria, and more specifically, derived from the human digestive tract, immunomodulatory effect, immunopotentiation effect, anti-allergic effect, anti-inflammatory effect, colitis improvement effect, arthritis improvement effect, anti-obesity effect, antistress effect
  • the present invention relates to various lactic acid bacteria having various physiological activities such as anti-anxiety effect, antidepressant effect or antipsychotic effect, and various food and pharmaceutical uses of the new lactic acid bacteria.
  • coli such as Kono Stock (Leuconostoc), Peddie OKO Syracuse (Pediococcus), sports as Lactobacillus (Sporolactobacilius) ( E. coli , Veillonella , Clostridium perfringens ) are more dominant than harmful bacteria, and various digestive tract microorganisms can maintain health when the balance.
  • Immune cells in our bodies help to maintain health by controlling externally invading antigens (including microorganisms) and abnormal cells produced internally. More than 70% of these immune cells are located in the digestive tract and control microorganisms already inhabiting the gut or externally invading microbes. Problems with the body's immunomodulatory effects can lead to reduced immune system or immune hypersensitivity, which can lead to viral infections, cancer, inflammatory diseases, enteritis (ulcerative colitis, Crohn's disease, diverticulosis, etc.), allergic diseases, atopy, arthritis, Diseases such as obesity, diabetes and the like can be caused. Therefore, in order to effectively eliminate the occurrence of the diseases, it is necessary to control the disturbance of the intestinal bacterial flora and to make the immune system of the digestive tract operate normally well.
  • salazosulpapyridine which is frequently used as an aminosalicylic acid agent, has been reported to have side effects such as nausea, vomiting, anorexia, rash, headache, liver injury, white blood cell reduction, abnormal red blood cells, proteinuria, and diarrhea.
  • corticosteroids are generally used for oral administration of prednisolone, enemas, suppositories, and intravenous injections, but side effects such as femoral head necrosis due to gastric ulcer and long-term use are strong.
  • these drugs cannot be used continuously.
  • IBS Irritable bowel syndrome
  • allergic patients The complexity of society, the development of industry and civilization increase environmental pollution, stress, and dietary changes, increasing the number of allergic patients every year. In 1980, less than 1% of allergic patients, such as atopy, anaphylaxis, and asthma, increased to more than 5% in the 2000s, and more than 10% of potential patients were estimated.
  • the cause of allergic disease is excessive immune response of the living body resulting from antigen antibody reaction, and allergic disease is generally classified into type 1-4 hypersensitivity reaction according to reaction time and presence of complement involvement.
  • Type 1 hypersensitivity reactions include atopy, anaphylactic shock, bronchial asthma, urticaria, hay fever, and type 2 hypersensitivity reactions include inadequate transfusion, autoimmune hemolytic anemia, hemolytic anemia caused by drugs, granulocytopenia, thrombocytopenic purpura, etc.
  • Type III hypersensitivity reactions include erythema, lymphadenopathy, arthralgia, arthritis, nephritis, acute glomerulonephritis after streptococcal infection, and type 4 hypersensitivity reactions include chronic inflammation. In order to improve allergic diseases, you should take a shower or bath to remove allergens (house dust, mites, etc.) on your skin, and do not eat allergens.
  • drugs such as steroids, antihistamines, and immunosuppressants are used, such as skin atrophy, vasodilation, discoloration, purpura (steroid preparation), drowsiness (antihitamin), and kidney failure ( Side effects such as immunosuppressants) are likely to occur. None of the drugs that have been developed so far can cure allergies, and the symptoms are expected to improve, but side effects are large.
  • Obesity is a metabolic disease caused by an imbalance between calorie intake and consumption and is morphologically caused by hypertrophy or hyperplasia of fat cells in the body. Obesity is not only the most common malnutrition in Western society, but the importance of treatment and prevention has been highlighted in recent years in Korea, as the frequency of obesity is rapidly increasing due to the improvement of dietary life and the westernization of lifestyle. have. Obesity is an important factor that not only psychologically diminishes individuals but also increases the risk of developing various adult diseases.
  • Obesity is known to be directly related to the increased prevalence of various adult diseases, such as type 2 diabetes, hypertension, hyperlipidemia, and heart disease (Cell 87: 377, 1999), and the combination of obesity-related disorders together with metabolic syndrome or insulin resistance It is called syndrome (insulin resistance syndrome), and these have been found to be the cause of atherosclerosis and cardiovascular disease.
  • Known obesity treatments such as Xenical (Roche Pharmaceuticals, Switzerland), Reductil (Eboth, USA), Exolise (Atopama, France), etc.
  • most anti-obesity agents are appetite suppressants that suppress appetite by regulating neurotransmitters associated with the hypothalamus.
  • conventional treatments have low side effects such as heart disease, respiratory disease, and neurological disease, and thus have low sustainability. Therefore, development of an improved obesity treatment agent is needed, and currently developed products have satisfactory treatment effects without side effects. Since there are few therapeutic agents, development of new obesity agents is required.
  • probiotics In the gastrointestinal tract of animals including humans, living organisms that improve the host's intestinal microbial environment and have beneficial effects on the health of the host are collectively called probiotics. To be effective as a probiotic, most of them, when taken orally, should basically have excellent acid resistance, bile resistance and intestinal epithelial cell adhesion. Lactic acid bacteria are used as probiotics because they play a role in breaking down fiber and complex proteins into important nutrients while living in the digestive system of the human body. Lactobacillus has been reported to show the effects of maintaining normal intestinal flora, improving intestinal flora, antidiabetic and antihyperlipidemic effects, inhibiting carcinogenesis, inhibiting colitis, and nonspecific activity of the host's immune system.
  • the strain Lactobacillus is a major member of the normal microbial community in the intestine of the human body, which has long been known to be important for maintaining a healthy digestive system and the vaginal environment, and the US Public Health Service (US Public Health Service). guidelines) are currently classified as 'Bio-safty Level 1', where none of the Lactobacillus strains currently deposited with the American Strain Deposit Organization (ATCC) is known about the potential risk of causing disease in humans or animals. have.
  • ATCC American Strain Deposit Organization
  • kimchi lactic acid bacteria are reported to have the effect of immuno-enhancing, anti-microbial, antioxidant, anti-cancer, anti-obesity, hypertension or constipation as a lactic acid bacteria involved in kimchi fermentation [Hivak P, Odrska J, Ferencik M, Ebringer L, Jahnova E, Mikes Z .: One-year application of Probiotic strain Enterococcus facium M-74 decreases Serum cholesterol levels. Bratisl lek Listy 2005; 106 (2); 67-72; Agerholm-Larsen L. Bell ML. Grunwald GK.
  • Astrup A The effect of a probiotic milk product on plasma cholesterol: a metaanalysis of short-term intervention studies; Eur J Clin Nutr. 2000; 54 (11) 856-860; Renato Sousa, Jaroslava Helper, Jian Zhang, Strephen J Lewis and Wani O Li; Effect of Lactobacillus acidophilus supernants on body weight and leptin expression in rats; BMC complementary and alternative medicine. 2008; 8 (5) 1-8].
  • As various physiological activities of these lactic acid bacteria are known, researches to develop lactic acid bacteria strains which are safe for humans and excellent in function and apply them as pharmaceuticals or functional foods are being actively conducted.
  • Korean Patent Publication No. 10-1486999 discloses Lactobacillus plantarum CJLP133 ( Lactobacillus plantarum CJLP133) KCTC 11403BP useful for the prophylactic treatment of intestinal diseases and immune diseases.
  • Korean Patent Publication No. 10-1500974 discloses Lactobacillus plantarum, which has an effect of improving metabolic disease selected from the group consisting of anti-inflammatory and obesity, diabetes, hyperlipidemia, hypercholesterolemia, arteriosclerosis, fatty liver and cardiovascular disease ( Lactobacillus plantarum ) HAC01 strain (Accession Number: KCTC 12647BP) is disclosed.
  • 01941892 discloses a composition for treating allergies comprising Lactobacillus acidophilus PM-A0002 (Accession No .: M 207038) as an active ingredient.
  • Korean Laid-Open Patent Publication No. 10-2005-0057259 includes Lactobacillus fermentum variant VRI003 (Accession No. NM02 / 31074) as an active ingredient, irritable bowel syndrome, inflammatory bowel Disclosed are compositions for use in treating gastrointestinal diseases such as inflammatory bowel disease.
  • Japanese Patent Laid-Open No. 5273695 discloses Bifidobacterium long gum OLB6001 ( Bifidobacterium).
  • Bifidobacterium long gum OLB6290 Bifidobacterium A composition for preventing or treating allergies comprising longum OLB6290, Accession No .: NITE P-75
  • US Patent Publication No. 20060177424 discloses a method for treating allergic diseases, irritable bowel syndrome, etc. by administering Streptococcus faecalis.
  • the present invention is derived under the conventional technical background, and an object of the present invention is an enterobacterial bacterium, such as immunomodulatory efficacy, immunopotentiation effect, inflammatory response inhibitory effect, colitis improvement effect, arthritis improvement effect, anti-obesity effect or anti-allergic effect, etc. It is to provide a novel lactic acid bacteria having various physiological activities or functions necessary for the control of disturbance and normalization of immunomodulation abnormality. It is also an object of the present invention to provide a novel lactic acid bacteria having antistress efficacy, anti-anxiety efficacy, antidepressant efficacy or antipsychotic effect. Another object of the present invention is to provide various food and pharmaceutical uses of the novel lactic acid bacteria.
  • the inventors of the present invention screen a myriad of lactic acid bacteria from human feces, the specific Lactobacillus strains, certain Bifidobacterium strains, certain Streptococcus strains or specific cholinecell strains have excellent immunomodulation efficacy, immunopotentiation efficacy, After confirming that it has anti-allergic effect, anti-inflammatory effect, colitis improvement effect, arthritis improvement effect, or anti-obesity effect, the present invention was completed.
  • one example of the present invention is Lactobacillus plantarum IM2, Lactobacillus acidophilus IM7, Lactobacillus fermentum IM12 (trusted number: KCCM 11806P), ronggeom Bifidobacterium (Bifidobacterium longum) IM26, Bifidobacterium Adolfo Les sentiseu (Bifidobacterium adolescentis ) Lactic acid bacteria selected from the group consisting of IM38 (Accession No .: KCCM 11807P), Streptococcus faecium IM45 and Collinsella aerofaciens IM50, which are immunomodulatory, immunopotentiating, and anti-allergic It provides lactic acid bacteria having efficacy, anti-inflammatory effect, colitis improvement effect, arthritis improvement effect, anti-obesity effect, anti-stress effect, anti-anxiety effect, anti-depressant effect or anti-
  • one embodiment of the present invention includes Lactobacillus plantarum IM2, its culture, its lysate or extract thereof as an active ingredient, preventing, improving obesity or colitis Or a composition for use for treatment.
  • one embodiment of the present invention includes Lactobacillus acidophilus ( Lactobacillus acidophilus ) IM7 or Bifidobacterium longum (26) Lactobacillus, its culture, its lysate or extract thereof is selected as an active ingredient
  • compositions for use in preventing, ameliorating or treating allergic diseases are provided.
  • one embodiment of the present invention includes Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P), its culture, its lysate or its extract as an active ingredient, allergic disease, colitis, arthritis or obesity
  • Lactobacillus fermentum IM12 accesion Number: KCCM 11806P
  • KCCM 11806P a composition for immunomodulation or anti-inflammatory comprising Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P), its culture, its lysate or extract thereof as an active ingredient.
  • one embodiment of the present invention includes Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract as an active ingredient, allergic diseases, colitis, arthritis Or compositions for use in preventing, ameliorating or treating obesity.
  • Bifidobacterium adolescentis Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P)
  • its culture, its lysate or extracts thereof as an active ingredient comprising an immunomodulatory or anti-inflammatory composition To provide.
  • one embodiment of the present invention provides a stress relief composition comprising Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract as an active ingredient.
  • Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P)
  • Bifidobacterium adolescents ( Bifidobacterium) adolescentis ) IM38 (Accession No .: KCCM 11807P)
  • its culture its lysate or its extract as an active ingredient
  • one embodiment of the present invention is one or more selected from Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract; And bicuculine or N- [2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl] -N-2-pyridinylcyclohexanecarboxamide hydrochloride (WAY-100635 hydrochloride; CAS Registry Number: 146714-97-8) It provides a stress relief composition comprising one or more selected from the active ingredient.
  • one embodiment of the present invention is one or more selected from Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract; And bicuculine or N- [2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl] -N-2-pyridinylcyclohexanecarboxamide hydrochloride (WAY-100635 hydrochloride; CAS Registry Number: 146714-97-8) It provides a composition for use in preventing, improving or treating anxiety disorders, depression or schizophrenia, comprising at least one selected from the group as an active ingredient.
  • one embodiment of the present invention provides a composition for immunomodulation or immunosuppression comprising Streptococcus faecium IM45, its culture, its lysate or extract thereof as an active ingredient.
  • one embodiment of the present invention provides a composition for anti-inflammatory comprising Collinsella aerofaciens IM50, its culture, its lysate or extract thereof as an active ingredient.
  • the specific Lactobacillus strain, the specific Bifidobacterium strain, the specific Streptococcus strain or the specific Cholinella strain according to the present invention are isolated from human feces and have high safety, immunomodulatory efficacy, immune enhancing efficacy, and anti-allergic efficacy. It has various physiological activities such as anti-inflammatory effect, colitis improvement effect, arthritis improvement effect, anti-obesity effect, anti-stress effect, anti-anxiety effect, antidepressant effect or antipsychotic effect.
  • the specific Lactobacillus strain, the specific Bifidobacterium strain, the specific Streptococcus strain or the specific Cholinella strain according to the present invention may be used as a material for immunomodulation, immune augmentation, inhibition of inflammatory response, stress relief, It can also be used as a functional food material useful for preventing, ameliorating or treating allergies, inflammatory diseases, colitis, arthritis, obesity, anxiety disorders, depression or schizophrenia.
  • Figure 1 shows the weight gain when the lactic acid bacteria were administered to mice induced immunity lowering by ⁇ -radiation
  • Figure 2 shows the spleen weight when lactic acid bacteria were administered to mice induced immunity lowering by ⁇ -radiation
  • 3 shows the amount of IFN- ⁇ in serum when lactic acid bacteria were administered to mice in which immunity was induced by ⁇ -radiation
  • FIG. 4 is induced by ⁇ -radiation.
  • the amount of IL-2 in serum when lactic acid bacteria were administered to mice is shown
  • FIG. 5 shows the amount of TNF- ⁇ in serum when lactic acid bacteria are administered to mice whose immunity is induced by ⁇ -radiation. .
  • FIG. 6 shows cytotoxicity against cancer cells of splenocytes of the NK cells extracted after administration of lactic acid bacteria to mice induced with decreased immunity by ⁇ -radiation
  • FIG. 7 shows mice with reduced immunity induced by ⁇ -radiation. Cytotoxic T cells in the spleen extracted after administration of lactic acid bacteria to cytotoxicity against cancer cells.
  • FIG. 8 shows the effect of a given lactic acid bacterium on arthritis-induced arthritis induced by collagen immunogens as an increase in paw volume or myeloperoxidase (MPO) activity
  • FIG. 9 shows arthritis induced by collagen immunogens.
  • the effect of certain lactic acid bacteria on model animals is shown as inflammation-related cytokines
  • Figure 10 shows the effect of certain lactic acid bacteria on art animals induced arthritis by collagen immunogen as inflammatory response indicators.
  • Figure 11 shows the effect of a given lactic acid bacteria on the obesity-induced model animal weight change
  • Figure 12 shows the effect of the predetermined lactic acid bacteria on the obesity-induced model animal appearance score and myeloperoxidase (Myeloperoxidase, MPO) activity
  • FIG. 13 shows the effects of certain lactic acid bacteria on the obesity-induced model animals with inflammation-related cytokines.
  • FIG. 14 shows Bifidobacterium adolescents ( Bifidobacterium) for a model animal in which anxiety symptoms are induced by strap stress. adolescentis ) The effect of IM38 is expressed as the percentage of time spent in the open arm and the number of times the mouse enters the open arm.
  • FIG. 15 shows Bifidobacterium adolescents ( Bifidobacterium) for a model animal in which anxiety symptoms are induced by strapping stress. adolescentis ) The effect of IM38 is expressed by the contents of corticosterone, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF- ⁇ ).
  • IL-6 interleukin-6
  • TNF- ⁇ tumor necrosis factor-alpha
  • FIG. 16 shows Bifidobacterium adolescents ( Bifidobacterium) in a model animal in which anxiety symptoms are induced by strap stress. adolescentis )
  • the effect of flumazenil, bicuculine, or WAY-100635 on the anti-anxiety activity of IM38 is expressed as the percentage of time spent in the open arm and the number of times the mouse enters the open arm.
  • FIG. 18 shows Bifidobacterium adolescents against anxiety behavior of a model animal not subjected to strapping stress. adolescentis )
  • the effect of the combination of IM38 or Bifidobacterium adolescentis IM38 with Flumazenil is expressed as the percentage of time spent in the open arm and the number of times the mouse enters the open arm.
  • IM38 or Bifidobacterium adolescentis
  • the effect of the combination of IM38 and flumazenil is expressed by the contents of corticosterone, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF- ⁇ ).
  • culture means a product obtained by culturing a microorganism in a known liquid medium or a solid medium, and is a concept in which a microorganism is included.
  • pharmaceutically acceptable and “food acceptable” means that they do not significantly stimulate the organism and do not inhibit the biological activity and properties of the administered active substance.
  • prevention means any action that inhibits the symptoms or delays the progression of a particular disease by administration of a composition of the present invention.
  • treatment means any action that improves or beneficially alters the symptoms of a particular disease by administration of a composition of the present invention.
  • the term “improvement” refers to any action that at least reduces or alleviates the parameters associated with the condition being treated, for example, the extent of symptoms.
  • the term "administration" means providing a subject with a composition of the present invention in any suitable manner.
  • the subject refers to all animals, such as humans, monkeys, dogs, goats, pigs or mice having a disease that can improve the symptoms of a particular disease by administering the composition of the present invention.
  • the term "pharmaceutically effective amount” refers to an amount sufficient to treat a disease at a reasonable benefit or risk ratio applicable to medical treatment, which refers to the type of disease, the severity, the activity of the drug, the drug, and the like. Sensitivity, time of administration, route of administration and rate of excretion, duration of treatment, factors including drug used concurrently, and other factors well known in the medical arts.
  • One aspect of the present invention relates to a novel lactic acid bacteria having various physiological activities.
  • the novel lactic acid bacteria is Lactobacillus plantarum IM2, Lactobacillus acidophilus IM7, Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P), ronggeom Bifidobacterium (Bifidobacterium longum) IM26, Bifidobacterium Adolfo Les sentiseu (Bifidobacterium adolescentis ) IM38 (Accession No .: KCCM 11807P), Streptococcus faecium IM45 and Collinsella aerofaciens IM50 selected from the group consisting of immunomodulatory efficacy, immunopotentiation efficacy, anti-allergic efficacy, It has anti-inflammatory effect, colitis improvement effect, arthritis improvement effect, anti-obesity effect, anti-stress effect, anti-anxiety effect, antidepressant effect or antipsychotic effect.
  • the Lactobacillus plantarum IM2 is preferably a carbon source of D-ribose, D-galactose, D-glucose, D-fructose, D-mannose, mannitol, sorbitol, amigdaline, arbutin, and esculin (Esculin ), Salicycin, cellobiose, maltose, lactose, sucrose, trehalose, melezitose and D-turanos.
  • the Lactobacillus acidophilus IM7 is preferably a carbon source of D-galactose, D-glucose, D-fructose, D-mannose, N-acetyl-glucosamine, amigdaline, arbutin, and esculin (Esculin).
  • Esculin esculin
  • Salicycin, cellobiose, maltose, lactose, sucrose, trehalose, raffinose and genthiobioses are used.
  • the Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P) preferably includes the nucleotide sequence of SEQ ID NO: 1 as 16S rDNA, and more preferably uses Esculin.
  • the Bifidobacterium longum IM26 is preferably a carbon source of L-arabinose, D-galactose, D-glucose, D-fructose, mannitol, sorbitol, esculin, maltose, lactose, Melibiose, Melezitose, Raffinose and Genthiobioses are used.
  • the Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P) preferably comprises the nucleotide sequence set forth in SEQ ID NO: 2 as 16S rDNA, more preferably D-xylose, D as a carbon source.
  • the Streptococcus faecium IM45 preferably comprises the nucleotide sequence set forth in SEQ ID NO: 3 as 16S rDNA, more preferably as a carbon source D-ribose, D-fructose, Dulcitol, Sorbitol , Amigdaline, melezitose, starch, glycogen, sodium pyruvate, hippuric acid and esculin ferric citrate are used.
  • the Collinsella aerofaciens IM50 is preferably a carbon source of D-galactose, D-glucose, D-fructose, D-mannose, N-acetyl-glucosamine, maltose, lactose, sucrose and D- Use tagatose.
  • one embodiment of the present invention comprises Lactobacillus plantarum IM2, its culture, its lysate or extract thereof as an active ingredient, for preventing, improving or treating obesity or colitis It provides a composition for use.
  • one example of the present invention is Lactobacillus acidophilus IM7 or Bifidobacterium long gum ( Bifidobacterium) longum ) lactic acid bacteria selected from IM26, its culture, its lysate or extract thereof as an active ingredient, and provides a composition for use in preventing, ameliorating or treating allergic diseases.
  • one embodiment of the present invention includes Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P), its culture, its lysate or its extract as an active ingredient, allergic disease, colitis, arthritis or obesity
  • Lactobacillus fermentum IM12 accesion Number: KCCM 11806P
  • KCCM 11806P a composition for immunomodulation or anti-inflammatory comprising Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P), its culture, its lysate or extract thereof as an active ingredient.
  • one embodiment of the present invention includes Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract as an active ingredient, allergic diseases, colitis, arthritis Or compositions for use in preventing, ameliorating or treating obesity.
  • Bifidobacterium adolescentis Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P)
  • its culture, its lysate or extracts thereof as an active ingredient comprising an immunomodulatory or anti-inflammatory composition To provide.
  • one embodiment of the present invention provides a stress relief composition comprising Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract as an active ingredient.
  • Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P)
  • Bifidobacterium adolescents ( Bifidobacterium) adolescentis ) IM38 (Accession No .: KCCM 11807P)
  • its culture its lysate or its extract as an active ingredient
  • one embodiment of the present invention is one or more selected from Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract; And bicuculine or N- [2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl] -N-2-pyridinylcyclohexanecarboxamide hydrochloride (WAY-100635 hydrochloride; CAS Registry Number: 146714-97-8) It provides a stress relief composition comprising one or more selected from the active ingredient.
  • one embodiment of the present invention is one or more selected from Bifidobacterium adolescentis IM38 (Accession Number: KCCM 11807P), its culture, its lysate or its extract; And bicuculine or N- [2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl] -N-2-pyridinylcyclohexanecarboxamide hydrochloride (WAY-100635 hydrochloride; CAS Registry Number: 146714-97-8) It provides a composition for use in preventing, improving or treating anxiety disorders, depression or schizophrenia, comprising at least one selected from the group as an active ingredient.
  • one embodiment of the present invention provides a composition for immunomodulation or immunosuppression comprising Streptococcus faecium IM45, its culture, its lysate or extract thereof as an active ingredient.
  • one embodiment of the present invention provides a composition for anti-inflammatory comprising Collinsella aerofaciens IM50, its culture, its lysate or extract thereof as an active ingredient.
  • Lactobacillus plantarum IM2 Lactobacillus acidophilus IM7, Lactobacillus fermentum IM12 (Accession Number: KCCM 11806P), Bifidobacterium Technical features of Bifidobacterium longum IM26, Bifidobacterium adolescentis IM38 (Accession No .: KCCM 11807P), Streptococcus faecium IM45 and Collinsella aerofaciens Since is the same as described above, the description is omitted.
  • the allergic disease is not limited in kind as long as it is a disease caused by an excessive immune response of the living body, and is preferably selected from atopic dermatitis, asthma, sore throat or chronic dermatitis.
  • the colitis refers to a condition in which the intestine is inflamed due to bacterial infection or pathological fermentation of the intestinal contents, and is a concept including infective colitis and non-infectious colitis. Specific examples of colitis include inflammatory bowel disease or irritable colitis syndrome. Inflammatory bowel disease also includes ulcerative colitis, Crohn's disease, and the like.
  • the arthritis includes rheumatoid arthritis.
  • the anti-inflammatory composition of the present invention can be used for the purpose of inhibiting an inflammatory response or preventing, improving or treating an inflammatory disease.
  • the inflammatory disease is a disease caused by an inflammatory response, its kind is not particularly limited, and includes all inflammatory diseases caused by bacterial infection and inflammatory diseases caused by viral infection.
  • Culture of the lactic acid bacteria in the present invention is a product obtained by culturing a predetermined strain in a medium
  • the medium may be selected from known liquid medium or solid medium, for example MRS liquid medium, MRS agar medium, BL agar May be a medium.
  • the composition may be embodied as a pharmaceutical composition, a food additive, a food composition (particularly a functional food composition), a feed additive, and the like according to the purpose or aspect of use.
  • the content of lactic acid bacteria and the like as an active ingredient may also be adjusted in various ranges according to the specific form of the composition, purpose of use, and aspects.
  • the content of the novel lactic acid bacterium, its culture, its lysate or its extract is not particularly limited.
  • the pharmaceutical composition according to the present invention may further include an additive such as a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient.
  • Carriers, excipients and diluents that may be included in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention in addition to novel lactic acid bacteria, its culture, its lysate or extract thereof, immunomodulatory effect, immuno-enhancing effect, anti-inflammatory effect, anti-stress effect, allergic disease, inflammatory disease, colitis, arthritis, obesity, anxiety It may further contain one or more known active ingredients having a prophylactic or therapeutic effect for disorders, depression or schizophrenia.
  • the pharmaceutical composition of the present invention may be formulated into a formulation for oral administration or a parenteral administration by a conventional method, and when formulated, such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. Diluents or excipients may be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose in active ingredients. ), Lactose (Lactose) or gelatin can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium styrate talc may also be used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. have.
  • Formulations for parenteral administration may 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.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally to mammals including humans according to a desired method, and parenteral administration methods include external skin, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, muscle Intra-injection or intrathoracic injection;
  • the dosage of the pharmaceutical composition of the present invention is not particularly limited as long as it is a pharmaceutically effective amount, and the range thereof depends on the weight, age, sex, health condition, diet, time of administration, method of administration, excretion rate and severity of the disease. Varies.
  • Typical daily dosages of the pharmaceutical compositions of the present invention are not particularly limited but are preferably 0.1 to 3000 mg / kg, more preferably 1 to 2000 mg / kg, once daily based on the active ingredient. Or divided into several doses.
  • the content of the novel lactic acid bacteria, its culture, its lysate or extract thereof as an active ingredient in the food composition according to the present invention is 0.01 to 99% by weight, preferably 0.1 to 50% by weight, more preferably based on the total weight of the composition. Preferably it is 0.5-25 weight%, but it is not limited to this.
  • the food composition of the present invention includes the form of pills, powders, granules, acupuncture, tablets, capsules, or liquids, and examples of specific foods include meat, sausage, bread, chocolate, candy, snacks, confectionary, pizza, ramen, Other noodles, gums, dairy products, including ice cream, various soups, beverages, tea, functional water, drinks, alcoholic beverages and vitamin complexes, and includes all of the health food in the usual sense.
  • the food composition of the present invention may contain, as an additional component, a food acceptable carrier, various flavors, or natural carbohydrates.
  • the food composition of the present invention is a variety of nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols And carbonation agents used in carbonated beverages.
  • the food composition of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage. These components can be used independently or in combination.
  • the above-mentioned natural carbohydrates are glucose, monosaccharides such as fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol.
  • natural flavoring agents such as taumartin, stevia extract, synthetic flavoring agents such as saccharin, aspartame, etc. may be used.
  • GAM liquid medium GAM broth; Nissui Pharmaceutical, Japan. Subsequently, the supernatant was taken and transplanted into BL agar medium (Nissui Pharmaceutical, Japan), and then anaerobicly cultured at 37 ° C. for about 48 hours, and then colony-forming Lactobacillus sp. ), Bifidobacterium sp. Strain, Streptococcus sp., And Collinsella sp. Were isolated.
  • 16S rDNA was measured by the chemical classification characteristics of Lactobacillus fermentum IM12, and the result was found to have the nucleotide sequence of SEQ ID NO: 1.
  • the 16S rDNA sequence of Lactobacillus fermentum IM12 was identified by BLAST search of Genebank (http://www.ncbi.nlm.nih.gov/). As a result, Lactobacillus fur having the same 16S rDNA sequence was identified. Lactobacillus fermentum strain was not detected and showed 99% homology with the 16S rDNA sequence of Lactobacillus fermentum strain CIP 102980.
  • 16S rDNA was measured by the chemical classification characteristics of Bifidobacterium adolescentis IM38 among the strains described in Table 1, and as a result, it was found to have the nucleotide sequence of SEQ ID NO: 2.
  • 16S rDNA sequence of Bifidobacterium adolescentis IM38 was identified by BLAST search of Genebank (http://www.ncbi.nlm.nih.gov/), and the same 16S rDNA sequence was obtained. Bifidobacterium adolescentis strain was not detected and showed 99% homology with the 16S rDNA sequence of Bifidobacterium adolescentis strain BBMN23.
  • 16S rDNA was measured by the chemical classification characteristics of Streptococcus faecium IM45 among the strains described in Table 1, and as a result it was found to have the nucleotide sequence of SEQ ID NO: 3.
  • 16S rDNA sequencing of Streptococcus faecium IM45 was identified by BLAST search of Genebank (http://www.ncbi.nlm.nih.gov/) and Enterococcus enterococcus faecium ) showed 99% homology with the 16S rDNA sequence of strain Aus0004.
  • Lactobacillus plantarum IM2 Lactobacillus acidophilus IM7, Lactobacillus fermentum IM12, Bifidobacterium long gum ( Bifidobacterium) longum) IM26, Bifidobacterium Adolfo Les sentiseu (Bifidobacterium adolescentis )
  • IM38 Lactobacillus plantarum IM2
  • Lactobacillus acidophilus IM7 Lactobacillus acidophilus IM7
  • Lactobacillus fermentum IM12 Lactobacillus fermentum IM12
  • Bifidobacterium long gum ( Bifidobacterium) longum) IM26 Bifidobacterium Adolfo Les sentiseu
  • Carbon source availability among the physiological characteristics of IM38, Streptococcus faecium IM45 and Collinsella aerofaciens IM50 was determined by API Kit (Model: API 50 CHL; manufacturer: Bio
  • Table 2 shows the results of carbon source availability of Lactobacillus plantarum IM2
  • Table 3 shows the results of carbon source availability of Lactobacillus acidophilus IM7
  • Table 4 It shows the results of the carbon source availability of Lactobacillus fermentum IM12
  • Table 5 below Bifidobacterium long gum ( Bifidobacterium) longum
  • Bifidobacterium shows the carbon source availability results of IM26
  • Table 6 shows the carbon source availability results of Bifidobacterium adolescentis IM38
  • Table 7 below the carbon source of Streptococcus faecium IM45 Usability results are shown
  • Table 8 shows the carbon source availability results of Collinsella aerofaciens IM50 .
  • mannitol was not used as a carbon source, and glycogen and starch were simultaneously used as a carbon source.
  • Conventional Enterococcus faecium strains are known to use mannitol as a carbon source and glycogen and starch at the same time as a carbon source.
  • the inventors of the present invention patented Lactobacillus fermentum IM12 to the Korea Microbiological Conservation Center (Address: 45 Yurim Building, 45, Honggae, Hongje, Seodaemun-gu, Seoul, Korea) on January 20, 2016. You have been assigned an accession number.
  • the inventors of the present invention patent Bifidobacterium adolescentis IM38 to the Korea Microbiological Conservation Center (address: 45 Yurim Building, 45, Honggae, Hongdae, Seodaemun-gu, Seoul, Korea) on January 20, 2016.
  • the deposit was given an accession number of KCCM 11807P.
  • the deposit of lactic acid bacteria was carried out in compliance with the Budapest Treaty on the International Recognition of the Deposit of Microorganism for the Purposes of Patent Procedure.
  • mice Six-week-old C57BL / 6J male mice (20-23 g) were purchased from Roundbio. 2 ml of sterile 4% thioglycolate was injected into the abdominal cavity of the mouse, anesthetized the mouse after 96 hours, and again 8 ml of RPMI 1640 medium was injected into the abdominal cavity of the mouse, and 5 to 10 minutes later, RPMI medium in the mouse abdominal cavity (large Phagocytic cells) were extracted again, centrifuged at 1000 rpm for 10 minutes, and washed twice with RPMI 1640 medium. Macrophages were placed in a 24-well plate at a number of 0.5 ⁇ 10 6 cells per well, incubated for 24 hours, and unattached cells were removed and used.
  • IM2 represents Lactobacillus plantarum IM2
  • IM5 represents Lactobacillus acidophilus IM5
  • IM6 represents Lactobacillus asidophilus ( Lactobacillus acidophilus )
  • IM7 represents Lactobacillus acidophilus IM7
  • IM12 represents Lactobacillus fermentum IM12
  • IM15 represents Lactobacillus fermentum ( Lactobacillus fermentum ) IM15
  • IM18 represents Lactobacillus johnsonii IM18
  • IM20 represents Lactobacillus johnsonii IM20
  • IM23 represents Bifidobacterium longgum ( Bifidobacterium) longum) represents IM23
  • IM26 denotes a ronggeom Bifidobacterium (Bifidobacterium longum) IM26
  • IM27 is ronggeom Bifidobacterium (Bifidobacterium longum
  • Macrophage treatment lactic acid bacteria TNF- ⁇ expression increase rate No treatment - IM2 + IM5 + IM6 + IM7 + IM12 + IM15 ++ IM18 + IM20 + IM23 + IM26 - IM27 - IM30 - IM32 - IM33 + IM36 - IM38 + IM39 + IM42 + IM45 +++ IM46 ++ IM49 ++ IM50 ++
  • the supernatant and cells were obtained after the lactic acid bacteria as a test substance and LPS (lipopolysaccharide) as an inflammatory response-inducing substance were treated for 2 hours or 24 hours in the macrophage culture medium of (1).
  • the lactic acid bacteria treatment concentration was 1 ⁇ 10 4 CFU / ml.
  • the obtained cells were placed in a buffer (Gibco) and homogenized.
  • the expression level of TNF- ⁇ was measured from the obtained supernatant by ELISA kit.
  • the expression levels of p65 (NF-kappa B), p-p65 (phosphor-NF-kappa B) and ⁇ -actin from the obtained cells were measured by immunoblotting.
  • Inhibition ratio -, ⁇ 10%; +, 10-30%; ++, 30-60%; +++,> 60%
  • Anti-CD3, anti-CD28, IL-2 and IL-12 to induce differentiation of T cells into Th1 cells anti-CD3, anti-CD28, to induce differentiation of T cells into Th2 cells IL-2 and IL-4, anti-CD3, anti-CD28, IL-6 and TGF- ⁇ to induce differentiation of T cells into Th17 cells, anti-CD3 to anti-differentiation of T cells into Treg cells
  • the cells were cultured with CD3 and anti-CD28, and lactic acid bacteria were added in an amount of 1 ⁇ 10 5 CFU / mL per well and incubated for 4 days.
  • the differentiation capacity of T cells isolated from the spleen into Th1 cells, Th2 cells, Th17 cells and Treg cells was measured.
  • FACS Fluorescence-activated cell sorting
  • the distribution of cells, Th17 cells and Treg cells were analyzed and the results are shown in Table 11 below.
  • lactic acid bacteria having high inhibition rate of differentiation of T cells into Th1 cells, Th2 cells, and Th17 cells and high rates of differentiation of T cells into Treg cells can effectively inhibit inflammatory responses and effectively improve inflammatory diseases. .
  • Inhibition ratio -, ⁇ 10%; +, 10-30%; ++, 30-60%; +++,> 60%
  • Th1, Th2, Th17 and Treg cells differentiated from splenic T cells were measured.
  • T-bet, IFN- ⁇ and IL-12 were derived from Th1 cell differentiation induction culture, GATA3 and IL-5 from Th2 cell differentiation induction culture, and ROR ⁇ t and IL from Th17 cell differentiation induction culture using qRT-PCR.
  • the expression level of Foxp3 and IL-10 from the Treg cell differentiation induction culture was analyzed, and the results are shown in Table 12 below.
  • Inhibition ratio -, ⁇ 10%; +, 10-30%; ++, 30-60%; +++,> 60%
  • mice induced with reduced immunity by ⁇ -radiation were supplied from Raon Bio Co., Ltd. and bred and purified for 7 days at Korea Hydro & Nuclear Research Institute. Thereafter, one group was divided into eight mice, and mice were divided into six experimental groups. Then, 5 groups of mice except the normal group were treated with ⁇ -radiation at an intensity of 2.5 Gy / 2 min.
  • the lactic acid bacterium a test drug
  • a positive control drug Levamisole hydrochloride
  • only saline was orally administered to mas corresponding to the normal group and the negative control group.
  • all experimental groups were free to eat food and water.
  • mice The weight of the mice before and after oral administration of the test drug lactic acid bacteria for 6 days was measured, and after the sacrifice, the spleen was separated and the weight of the spleen was measured. In addition, blood was separated, and the amounts of IFN- ⁇ , IL-2, TNF- ⁇ , and IL-10 were measured using an ELISA Kit.
  • Figure 1 shows the weight gain when the lactic acid bacteria were administered to mice induced immunity lowering by ⁇ -radiation
  • Figure 2 shows the spleen weight when lactic acid bacteria were administered to mice induced immunity lowering by ⁇ -radiation
  • 3 shows the amount of IFN- ⁇ in serum when lactic acid bacteria were administered to mice in which immunity was induced by ⁇ -radiation
  • FIG. 4 is induced by ⁇ -radiation.
  • the amount of IL-2 in serum when lactic acid bacteria were administered to mice is shown
  • FIG. 5 shows the amount of TNF- ⁇ in serum when lactic acid bacteria are administered to mice whose immunity is induced by ⁇ -radiation. .
  • NOR represents a normal group
  • CON represents a negative control group
  • IM45 represents a Streptococcus faecium IM45 administration group.
  • FIGS. 1 to 5 Streptococcus faecium IM45 improved the weight loss of mice induced with decreased immunity by ⁇ -radiation, such as IFN- ⁇ , IL-2, and TNF- ⁇ .
  • the expression level of immune cytokines was increased, and its effect was superior to that of Levamisole hydrochloride, a commercial immune booster.
  • mice After oral administration of the test drug for 6 days, the mice were sacrificed, disinfected with 70% ethanol aqueous solution, and the spleen was aseptically removed. Thereafter, NK cells were isolated from spleen cells using NK cell Isolation Kit (MACS) and Cytotoxic T cells were isolated using CD8 + T cell Isolation Kit (MACS), and the number of each cell was measured by a flow cytometer.
  • NK cells or Cytotoxic T cells and YAC-1 lymphoma cells (cancer cells) isolated from splenocytes were cultured together, and cytotoxicity of NK cells and Cytotoxic T cells against cancer cells was measured.
  • YAC-1 cells labeled with fluorescence were dispensed using a Vybrant CFDA SE Cell Tracer kit at 0.4 ⁇ 10 5 cells per well in a 96-well plate, and NK cells and cytotoxic T cells isolated therein were 2 ⁇ per well. After dispensing with 10 5 cells, the cells were incubated for 24 hours, and the number of YAC-1 cells was measured by a flow cytometer.
  • FIG. 6 shows cytotoxicity against cancer cells of splenocytes of the NK cells extracted after administration of lactic acid bacteria to mice induced with decreased immunity by ⁇ -radiation
  • FIG. 7 shows mice with reduced immunity induced by ⁇ -radiation.
  • "NOR" represents a normal group
  • CON represents a negative control group
  • "IM45” represents a Streptococcus faecium IM45 administration group.
  • the administration of Streptococcus faecium IM45 to mice with reduced immunity by ⁇ -radiation significantly increased the cancer cell killing effects of NK cells and Cytotoxic T cells in the spleen. .
  • RBL-2H3 cell line (rat mast cell line, Korea Cell Line Bank, Cat. No. 22256) was prepared using DMEM (Dulbeccos' modified Eagle's medium, Sigma, 22256) containing 10% FBS (fetal bovine serum) and L-glutamine. Incubated in a 37 ° C., humidified 5% CO 2 incubator. Cells contained in the culture were suspended using trypsin-EDTA solution, separated and recovered and used for the experiment. The recovered RBL-2H3 cells were aliquoted to a volume of 5 ⁇ 10 5 cells per well in a 24-well plate, and then sensitized with 0.5 ⁇ g / ml of mouse monoclonal IgE and incubated for 12 hours.
  • DMEM Dulbeccos' modified Eagle's medium, Sigma, 22256
  • FBS fetal bovine serum
  • L-glutamine fetal bovine serum
  • the sensitized cells were washed with 0.5 ml of siraganian buffer (119 mM NaCl, 5 mM KCl, 0.4 mM MgCl 2 , 25 mM PIPES, 40 mM NaOH, pH 7.2) and then again with 0.16 ml of Shiraganian buffer (5.6). mM glucose, 1 mM CaCl 2 , 0.1% BSA was added) and incubated at 37 ° C. for 10 minutes. Thereafter, lactic acid bacteria as a test drug were added to the cell culture to a concentration of 1 ⁇ 10 4 CFU / mL, or 0.04 mL of DSCG (disodium cromoglycate), a control drug, was added.
  • siraganian buffer 119 mM NaCl, 5 mM KCl, 0.4 mM MgCl 2 , 25 mM PIPES, 40 mM NaOH, pH 7.2
  • Shiraganian buffer 5.6
  • Cells were activated at 37 ° C. for 10 minutes. Thereafter, the cell culture was centrifuged at 2000 rpm for 10 minutes to obtain a supernatant. 0.025 ml of the supernatant obtained was transferred to a 96-well plate, and 1 mM p-NAG (substrate solution, in which p-nitrophenyl-N-acetyl- ⁇ -D-glucoamide) was dissolved in 0.1 M citrate buffer to pH 4.5). After adding 0.025 ml, the mixture was reacted at 37 ° C. for 60 minutes. Thereafter, 0.2 ml of 0.1 M Na 2 CO 3 / NaHCO 3 was added to the reaction solution to stop the reaction, and the absorbance was measured by an ELISA analyzer at 405 nm.
  • p-NAG substrate solution, in which p-nitrophenyl-N-acetyl- ⁇ -D-glucoamide
  • mice Five groups of BALB / c mice were used as a group, and the test drug lactic acid bacterium was orally administered once a day for 3 days in a quantity of 1 ⁇ 10 9 CFU to the control group except the control group and the control group, or DSCG (disodium cromoglycate) as a control drug.
  • DSCG sodium cromoglycate
  • Azelastine was orally administered once every 3 days in an amount of 0.2 mg / mouse.
  • the mice were left in the observation box (24cm ⁇ 22cm ⁇ 24cm) for 10 minutes to purify the environment, and the hairs on the back of the head (back of the neck) were removed.
  • mice normal mice were injected with saline, and other experimental mice were injected with a pruritic inducer (50 ⁇ g of compound 48/80; Sigma, USA) using a 29 gauge needle. Thereafter, mice were immediately isolated into observation boxes one by one and recorded for 1 hour with an 8-mm video camera (SV-K80, Samsung) under unmanned conditions to observe the behavior. It was admitted that scratching the injection site with the hind paw was not permitted.
  • a pruritic inducer 50 ⁇ g of compound 48/80; Sigma, USA
  • Table 13 shows the results of measuring the degranulation inhibition rate and pruritus inhibition rate of lactic acid bacteria.
  • the lactic acid bacteria selected in the present invention very effectively inhibited the degranulation and pruritus response of basophils can very effectively improve allergy-induced atopic, asthma, sore throat or chronic dermatitis.
  • Treatment medication % Inhibition Degranulation Pruritic reaction none 0 2 IM7 43 42 IM12 47 46 IM26 49 52 IM38 54 49 IM45 48 32 IM50 40 38 DSCo (disodium cromoglycate) 65 25 Azelastine - 68
  • mice Five-week-old C57BL / 6 male mice (24-27 g) were purchased from Orient Bio Co., Ltd., at a humidity of 50 ⁇ 10%, a temperature of 25 ⁇ 2 ° C, and lighting for 12 hours, followed by a 12-hour turn-off period under controlled environmental conditions. After the breeding was used for the experiment. Feed was used as standard experimental feed (Samyang, Korea) and drinking water was freely consumed. In all experiments, one group was 6 animals.
  • TNBS 2,4,6-trinitrobenzenesulfonic acid
  • the animal was lightly anesthetized with ether, and 2.5 g of TNBS (2,4,6-Trinitrobenzene sulfonic acid) solution was mixed with 100 ml of 50% ethanol. Inoculated into the large intestine through 0.1ml and maintained vertically for 30 seconds to cause inflammation.
  • the normal group was orally administered with 0.1 ml of saline solution. Later, the test sample was suspended in physiological saline once a day for 3 days from the next day and orally administered in the amount of 1.5 ⁇ 10 9 CFU.
  • the animal On the day after the administration of the sample, the animal was suffocated and killed with carbon dioxide. The large intestine to the site just before the anus was extracted and used. In addition, only normal saline was administered orally to physiological saline instead of lactic acid bacteria. In addition, the experimental animals of the negative control group was orally administered only saline instead of lactic acid bacteria after induction of colitis caused by TNBS. In addition, the experimental animals of the positive control group were orally administered sulfasalazine (sulfasalazine), a colitis treatment drug, in an amount of 50 mg / kg instead of lactic acid bacteria.
  • sulfasalazine sulfasalazine
  • the length and appearance of the extracted colon were observed and analyzed by appearance according to the criteria of Table 14 (Hollenbach et al., 2005 criteria for colitis degree).
  • the colon tissues were removed from the colon contents, washed in physiological saline, and some were fixed with 4% formaldehyde fixative for use as pathological samples, and the rest were frozen and stored at minus 80 ° C for molecular biological analysis. It was.
  • MPO Myeloperoxidase
  • the supernatant was obtained in the same manner as the myeloperoxidase (MPO) activity measurement experiment. Then, inflammation-related cytokines such as TNF- ⁇ and IL-17 were measured from the supernatant using an ELISA kit.
  • MPO myeloperoxidase
  • Table 15 shows the lactic acid bacteria weight gain, colon length, colonic appearance score, myeloperoxidase (MPO) activity, inflammation-related cytokines when lactobacillus was administered to a model animal induced by acute colitis induced by TNBS. It shows the effect on the content change.
  • Lactobacillus acidophilus IM7, Lactobacillus fermentum IM12, Bifidobacterium adolescents ( Bifidobacterium) adolescentis ) IM38 was more effective in improving colitis than sulfasalazine, a commercial treatment for colitis.
  • a total of 42 8-week-old male DBA / 1J mice were divided into 6 groups (NOR, CIA, IM7, IM12, IM38, and IB), each of which was divided into seven groups.
  • Arthritis was induced using bovine type II collagen as an immunogen for the group, IM7, IM12, IM38, and IB.
  • 100 ⁇ g of collagen immunogen was intradermally injected into the proximal mouse tail, and on the 21st day after the first immunization, the same amount of collagen immunogen was intradermally injected to secondary immunization.
  • the collagen immunogen was used to dissolve the bobbin type 2 collagen (bovine type II collagen) in 0.05M acetic acid and then emulsified by adding the same amount of Freund Complete Adjuvant.
  • NOR and CIA groups were orally administered with vehicle (50 mM sodium bicarbonate buffer containing 1% glucose) for 20 days, and IM7, IM12 and IM38 groups were treated with 2 ⁇ 10 9 CFU /
  • vehicle 50 mM sodium bicarbonate buffer containing 1% glucose
  • IM7, IM12 and IM38 groups were treated with 2 ⁇ 10 9 CFU /
  • the mice were orally administered daily for 20 days.
  • the ibuprofen (ibupropen) was orally administered daily for 20 days at a dose of 50 mg / kg, and the experiment was terminated on the next day of the final administration.
  • Arthritis severity and arthritis incidence of the feet were measured from the arthritis induction stage. Arthritis severity of the feet was assessed by visual observation of the feet and the periphery of the feet and graded macroscopic scores according to the criteria in Table 16 (Arii et al., 2008). The highest macroscopic appearance score that can be awarded to each mouse is 16.
  • step Appearance degree 0 normal One focal slight swelling and / or redness in one digit 2 moderate swelling and erythema 3 marked swelling and erythema of the limb 4 maximal swelling, erythema, deformity, and / or ankylosis
  • MPO Myeloperoxidase
  • the paw joint tissue was collected and immediately stored in -70 °C frozen was used as a sample.
  • Myeloperoxidase (MPO) activity of the foot joint tissues was measured by the same method used to evaluate the efficacy of colitis improvement.
  • the supernatant was obtained using the same method as the myeloperoxidase (MPO) activity measurement experiment from the foot joint tissue, and the inflammatory response indicators such as NO, PGE2 and TNF- ⁇ , IL-17, etc. were obtained using the ELISA kit. Inflammation-related cytokines were measured.
  • FIG. 8 shows the effect of a given lactic acid bacterium on arthritis-induced arthritis induced by collagen immunogens as an increase in paw volume or myeloperoxidase (MPO) activity
  • FIG. 9 shows arthritis induced by collagen immunogens.
  • the effect of certain lactic acid bacteria on model animals is shown as inflammation-related cytokines
  • Figure 10 shows the effect of certain lactic acid bacteria on art animals induced arthritis by collagen immunogen as inflammatory response indicators.
  • Lactobacillus fermentum IM12 effectively improved arthritis.
  • C57BL6 / J mice were purchased from Roundbio, Inc. and a total of 45 mice were acclimated for one week with a chow diet (Purina) under conditions of temperature 20 ⁇ 2 ° C., humidity 50 ⁇ 10%, and 12 hr light / 12 hr dark cycle. Thereafter, nine animals were divided into five groups (LFD, HFD, HFD + IM2, HFD + IM12, and HFD + IM38), and the LFD group was divided into four weeks of normal diet (LFD, 10% of calories from fat; Research, NJ).
  • HFD group HFD + IM2 group
  • HFD + IM12 group HFD + IM38 group
  • HFD + IM38 group HFD + IM38 group
  • HFD + IM2 group, HFD + IM12 group, and HFD + IM38 group were fed a high-fat diet for 4 weeks, while the corresponding lactobacillus Lactobacillus plantarum IM2, Lactobacillus fermentum IM12 and Bifidobacterium adolescents adolescentis ) IM38 was suspended in PBS and orally administered in an amount of 2 ⁇ 10 9 CFU.
  • the anti-obesity effect of lactic acid beef was analyzed by weight change.
  • the anti-inflammatory effect of lactic acid bacteria was analyzed using the same method as measured in a model animal experiment in which acute colitis was induced by TNBS.
  • FIG. 11 shows the effect of a given lactic acid bacteria on the obesity-induced model animal weight change
  • Figure 12 shows the effect of the predetermined lactic acid bacteria on the obesity-induced model animal appearance score and myeloperoxidase (Myeloperoxidase, MPO) activity
  • FIG. 13 shows the effects of certain lactic acid bacteria on the obesity-induced model animals with inflammation-related cytokines.
  • Lactobacillus plantarum IM2 Lactobacillus fermentum IM12
  • Bifidobacterium adolescentis IM38 are obese by high fat diet.
  • mice Male, 19-22 g were acclimated for one week with a chow diet (Purina) under conditions of temperature 20 ⁇ 2 ° C., humidity 50 ⁇ 10%, 12 hr light / 12 hr dark cycle. Thereafter, the experimental animals were divided into several groups, and the normal group was orally administered with saline once every three days for three days, and the rest of the experimental group was once daily for three days with lactic acid bacteria, antispirant buspirone or dexamethason, a corticosteroid. A drug such as (dexamethasone) was administered.
  • a drug such as (dexamethasone) was administered.
  • the lactobacillus was suspended orally in a predetermined amount in saline and administered orally, and in the case of anti-anxiety busspirone (buspirone) and corticosteroid dexamethasone (dexamethasone) was administered intraperitoneally.
  • busspirone buspirone
  • corticosteroid dexamethasone corticosteroid dexamethasone
  • mice in the experimental group except the normal group was subjected to strapping stress to induce anxiety or depressive symptoms.
  • the mouse is placed in a 500 ml falcon tube with a rounded end, and the cotton is inserted into the left, right, top, bottom, and back of the falcon tube to prevent the mouse from moving.
  • the falcon tube was erected to stand and left for 2 hours.
  • flumazenil the antagonist of the benzodiazepine receptor, bicuculine, the antagonist of the GABAA receptor, or WAY-100635, the antagonist of the 5-HT1A receptor
  • flumazenil the antagonist of the benzodiazepine receptor
  • bicuculine the antagonist of the GABAA receptor
  • WAY-100635 the antagonist of the 5-HT1A receptor
  • the elevated plus-maze device consists of two open arms (30 cm long and 7 cm wide) facing each other out of four passages and two closed arms (30 cm long and 30 cm wide) surrounded by a 20 cm high wall. 7 cm), each extending 7 cm in length and 7 cm in length from the central platform.
  • the labyrinth was made of black Plexiglas and set 50 cm above the floor.
  • Video cameras were installed on the central ceiling of the maze to record animal behavior and brightness was adjusted to 20 lux. Mice like to stay in the dark closed arm innately. Thus, when passing through the open arm, there is considerable anxiety.
  • the mouse was placed with its head toward the open arm from the center, and then freely navigated through the maze. Then, the behavior of the mouse was observed for 5 minutes, and the arm entry was assumed to have entered all four feet. At the end of each experiment, 70% alcohol was wiped clean to remove the traces of the previous animals so as not to affect the next experiment. The ratio of time the mouse stayed in the open arm and the number of times the mouse entered the open arm was calculated by the following equation.
  • the decrease in anxiety in the elevated plus-maze test is indicated by an increase in the percentage of time spent in the open arm and an increase in the number of times of entry into the open arm.
  • FIG. 14 shows Bifidobacterium adolescents ( Bifidobacterium) for a model animal in which anxiety symptoms are induced by strap stress. adolescentis ) The effect of IM38 is expressed as the percentage of time spent in the open arm and the number of times the mouse enters the open arm.
  • FIG. 15 shows Bifidobacterium adolescents ( Bifidobacterium) for a model animal in which anxiety symptoms are induced by strapping stress. adolescentis ) The effect of IM38 is expressed by the contents of corticosterone, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF- ⁇ ).
  • IL-6 interleukin-6
  • TNF- ⁇ tumor necrosis factor-alpha
  • NC represents a normal group administered only physiological saline with the drug without applying strap stress
  • IS represents an experimental group administered only physiological saline with the drug with strapping stress
  • SB The experimental group was administered with a dose of 1 mg / kg mouse bw once daily for 3 days with buspyrone as a drug with strap stress
  • SD is 3 days with dexamethasone (dexamethasone) as a drug with strap stress.
  • the experimental group was administered once a day at a dose of 1mg / kg mouse bw
  • "SIL” is Bifidobacterium adolescents with a drug with strapping stress adolescentis
  • SIM Te Solarium Adolfo bipyridinium gambling drug with straps stress
  • LES sentiseu (Bifidobacterium adolescentis ) represents an experimental group administered IM38 at a dose of 1 ⁇ 10 9 CFU / mouse once daily for 3 days
  • SIH refers to the drug Bifidobacterium adolescentis IM38 with strapping stress.
  • Experimental groups administered at a dose of 5 ⁇ 10 9 CFU / mouse once daily for one day are shown.
  • FIG. 16 shows Bifidobacterium adolescents in a model animal in which anxiety symptoms are induced by strap stress ( Bifidobacterium adolescentis The effect of flumazenil, bicuculine, or WAY-100635 on the anti-anxiety activity of IM38 is expressed as the percentage of time spent in the open arm and the number of times the mouse enters the open arm.
  • FIG. 17 shows Bifidobacterium adolescents in a model animal in which anxiety symptoms are induced by strapping stress.
  • Bifidobacterium adolescentis Effects of Flumazenil, Bicuculine, or WAY-100635 on Anti-anxiety Activity of IM38 Cortiosterone, Interleukin-6, IL-6 It is represented by the content of ⁇ (tumor necrosis factor-alpha).
  • ⁇ tumor necrosis factor-alpha
  • FIG. 18 shows Bifidobacterium adolescents against anxiety behavior of a model animal not subjected to strapping stress. adolescentis ) The effect of the combination of IM38 or Bifidobacterium adolescentis IM38 with Flumazenil is expressed as the percentage of time spent in the open arm and the number of times the mouse enters the open arm. 19 shows Bifidobacterium adolescents against anxiety behavior of a model animal not subjected to strapping stress.
  • IM38 or Bifidobacterium adolescentis
  • the effect of the combination of IM38 and flumazenil is expressed by the contents of corticosterone, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF- ⁇ ).
  • NC represents a normal group administered only saline with the drug without applying the strap stress
  • IL is Bifidobacterium Adolescents ( Bifidobacterium) as a drug without applying the strap stress adolescentis ) represents an experimental group administered IM38 at a dose of 2 ⁇ 10 8 CFU / mouse once daily for 3 days
  • IM refers to the drug Bifidobacterium adolescentis IM38 without applying stress to the strap.
  • Adolfo LES sentiseu (for Bifidobacterium adolescentis ) represents an experimental group administered IM38 at a dose of 5 ⁇ 10 9 CFU / mouse once daily for 3 days, and “IM + F” is Bifidobacterium adolescentis as a drug without applying strapping stress.
  • the experimental group was administered IM38 at a dose of 1 ⁇ 10 9 CFU / mouse once daily for 3 days, and flumazenil at a dose of 3 mg / kg mouse bw after the final administration of lactic acid bacteria.
  • Bifidobacterium adolescentis IM38 significantly alleviated anxiety or depressive symptoms of model animals with or without strap stress.
  • Administration of N-2-pyridinylcyclohexanecarboxamide hydrochloride; CAS No. 146714-97-8) resulted in higher anti-anxiety or antidepressant effects.

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Abstract

Selon la présente invention, une souche spécifique de Lactobacillus sp., une souche spécifique de Streptococcus sp. or une souche spécifique de Collinsella sp. est isolé à partir de fèces humaines et possède ainsi une sécurité élevée, et présente différentes activités physiologiques telles qu'un effet immunorégulateur, un effet de renforcement immunitaire, un effet antiallergique, un effet anti-inflammatoire, un effet d'atténuation de la colite, un effet d'atténuation de l'arthrite, un effet anti-obésité, un effet antistress, un effet anti-anxiété, un effet antidépresseur ou un effet anti-schizophrénie. Selon la présente invention, la souche spécifique de Lactobacillus sp., la souche spécifique de Bifidobacterium sp., la souche spécifique de Streptococcus sp. ou la souche spécifique de Collinsella sp. peut être utilisée en tant que matériau d'immunorégulation, de renforcement immunitaire, d'inhibition de réponse inflammatoire, et d'atténuation du stress, et peut également être utilisé en tant qu'aliment fonctionnel et un matériau pharmaceutique utile pour prévenir, atténuer ou traiter des maladies allergiques, des maladies inflammatoires, la colite, l'arthrite, l'obésité, des troubles anxieux, la dépression, la schizophrénie ou similaire.
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CN109362882A (zh) * 2018-12-29 2019-02-22 重庆第二师范学院 发酵乳杆菌cqpc07及其在制备改善溃疡性结肠炎的食品或药品中的应用
CN111902531A (zh) * 2018-12-12 2020-11-06 加图立大学校产学协力团 用于改善、预防或治疗类风湿性关节炎的长双歧杆菌rapo菌株及包含其的组合物
CN112546074A (zh) * 2020-12-24 2021-03-26 江南大学 一株能够抑制IL-23、Th17轴相关炎症因子释放的短双歧杆菌及其应用
CN115245523A (zh) * 2021-01-28 2022-10-28 上海市第六人民医院 青春双歧杆菌在制备脂肪吸收抑制剂中的应用
EP4012019A4 (fr) * 2020-08-24 2023-01-25 Byhealth Co., Ltd. Bifidobacterium breve 207-1 et son utilisation
CN117462564A (zh) * 2023-12-16 2024-01-30 中南大学 甲基α-D-吡喃葡萄糖苷在制备地中海贫血治疗药物中的应用
WO2024067591A1 (fr) * 2022-09-28 2024-04-04 合肥瀚微生物科技有限公司 Collinsella aerofaciens pouvant prévenir et/ou traiter les maladies inflammatoires de l'intestin et son utilisation
CN120310715A (zh) * 2025-06-18 2025-07-15 宁波大学 一株具有改善抑郁功效的益生菌及其微生态制剂和应用
CN120905098A (zh) * 2025-10-11 2025-11-07 武汉微康益生菌研究院有限公司 一株增强免疫调节功能的短双歧杆菌及其应用

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EP3715448A4 (fr) * 2017-09-29 2021-06-30 University - Industry Cooperation Group of Kyung Hee University Nouvelles bactéries d'acide lactique et leur utilisation
KR102668292B1 (ko) * 2021-04-27 2024-05-22 (주) 에이투젠 신규한 락토바실러스 퍼멘텀 atg-v5 균주 또는 이를 포함하는 면역증강용 조성물
KR102686039B1 (ko) 2022-12-30 2024-07-22 주식회사 그린스토어 웨이셀라 시바리아 gskm06 균주 및 그의 용도

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CN111902531B (zh) * 2018-12-12 2022-10-04 比菲德股份有限公司 用于改善、预防或治疗类风湿性关节炎的长双歧杆菌rapo菌株及包含其的组合物
CN111902531A (zh) * 2018-12-12 2020-11-06 加图立大学校产学协力团 用于改善、预防或治疗类风湿性关节炎的长双歧杆菌rapo菌株及包含其的组合物
CN109362882A (zh) * 2018-12-29 2019-02-22 重庆第二师范学院 发酵乳杆菌cqpc07及其在制备改善溃疡性结肠炎的食品或药品中的应用
CN109362882B (zh) * 2018-12-29 2022-04-15 重庆第二师范学院 发酵乳杆菌cqpc07及其在制备食品或改善溃疡性结肠炎的药品中的应用
EP4012019A4 (fr) * 2020-08-24 2023-01-25 Byhealth Co., Ltd. Bifidobacterium breve 207-1 et son utilisation
US11767503B2 (en) 2020-08-24 2023-09-26 BYHEALTH Co., Ltd. Bifidobacterium breve 207-1 and use thereof
AU2021333530B2 (en) * 2020-08-24 2024-05-23 BYHEALTH Co., Ltd. Bifidobacterium breve 207-1 and use thereof
CN112546074A (zh) * 2020-12-24 2021-03-26 江南大学 一株能够抑制IL-23、Th17轴相关炎症因子释放的短双歧杆菌及其应用
CN115245523A (zh) * 2021-01-28 2022-10-28 上海市第六人民医院 青春双歧杆菌在制备脂肪吸收抑制剂中的应用
WO2024067591A1 (fr) * 2022-09-28 2024-04-04 合肥瀚微生物科技有限公司 Collinsella aerofaciens pouvant prévenir et/ou traiter les maladies inflammatoires de l'intestin et son utilisation
CN117462564A (zh) * 2023-12-16 2024-01-30 中南大学 甲基α-D-吡喃葡萄糖苷在制备地中海贫血治疗药物中的应用
CN117462564B (zh) * 2023-12-16 2025-10-03 中南大学 甲基α-D-吡喃葡萄糖苷在制备地中海贫血治疗药物中的应用
CN120310715A (zh) * 2025-06-18 2025-07-15 宁波大学 一株具有改善抑郁功效的益生菌及其微生态制剂和应用
CN120905098A (zh) * 2025-10-11 2025-11-07 武汉微康益生菌研究院有限公司 一株增强免疫调节功能的短双歧杆菌及其应用

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