WO2023237067A1 - 嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用 - Google Patents

嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用 Download PDF

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WO2023237067A1
WO2023237067A1 PCT/CN2023/099224 CN2023099224W WO2023237067A1 WO 2023237067 A1 WO2023237067 A1 WO 2023237067A1 CN 2023099224 W CN2023099224 W CN 2023099224W WO 2023237067 A1 WO2023237067 A1 WO 2023237067A1
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Prior art keywords
akkermansia muciniphila
metabolic syndrome
composition
optionally
muciniphila
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PCT/CN2023/099224
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English (en)
French (fr)
Inventor
刘洋洋
郑丽君
李平
邝高波
易晓敏
王晔
智发朝
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广州知易生物科技有限公司
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Publication of WO2023237067A1 publication Critical patent/WO2023237067A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C19/00—Cheese; Cheese preparations; Making thereof
    • A23C19/02—Making cheese curd
    • A23C19/032—Making cheese curd characterised by the use of specific microorganisms, or enzymes of microbial origin
    • A23C19/0325—Making cheese curd characterised by the use of specific microorganisms, or enzymes of microbial origin using yeasts, alone or in combination with lactic acid bacteria or with fungi, without using other bacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C19/00—Cheese; Cheese preparations; Making thereof
    • A23C19/06—Treating cheese curd after whey separation; Products obtained thereby
    • A23C19/061—Addition of, or treatment with, microorganisms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G9/00—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor
    • A23G9/32—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds
    • A23G9/36—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A23G9/363—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing microorganisms, enzymes
    • 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
    • A23K10/18—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions of live microorganisms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/14—Yeasts or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L7/00—Cereal-derived products; Malt products; Preparation or treatment thereof
    • A23L7/10—Cereal-derived products
    • A23L7/104—Fermentation of farinaceous cereal or cereal material; Addition of enzymes or microorganisms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; 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
    • 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
    • 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

Definitions

  • This application relates to the technical field of prevention and treatment of glycometabolism syndrome and the technical field of health food, especially the application of Akkermansia muciniphila in the preparation of pharmaceutical compositions or health product compositions for improving metabolic syndrome, and also relates to the application of Akkermansia muciniphila in the preparation of pharmaceutical compositions or health product compositions for improving metabolic syndrome.
  • the application of the Akkermansia composition in preparing or serving as a medicine for preventing and treating metabolic syndrome or in preparing or serving as a health food for improving metabolic syndrome also relates to a composition containing Akkermansia muciniphila.
  • Metabolic syndrome also known as syndrome X, insulin resistance, etc. Metabolic syndrome is not actually a single disease, but a group of cardiovascular disease risk factors with different Organizations define it slightly differently. The three most popular definitions used in surveys and health care plans come from WHO (1999), NCEP (2005), and IDF (2006). In addition, organizations such as AACE and EGIR have also proposed definitions of metabolic syndrome.
  • metabolic syndrome is generally positively correlated with the incidence of obesity and type 2 diabetes (one of the outcomes of MetS).
  • Prevalence estimates of metabolic syndrome vary depending on the criteria used to define MetS, but since MetS is approximately three times more common than diabetes, the global prevalence of diabetes was 8.8% as of 2015, according to the IDF Diabetes Atlas. It is expected to increase to 10.4% by 2040, so the global prevalence is estimated to be approximately one-quarter of the world's population. At this rate, metabolic syndrome now affects more than 1 billion people in the world.
  • Treatment for metabolic syndrome includes lifestyle interventions and symptom-directed medications.
  • Lifestyle intervention includes diet, exercise, etc., but requires precise and personalized plans, and due to individual differences among patients, there are often compliance issues.
  • Symptom-specific drugs include anti-diabetic drugs, anti-hypertensive drugs, anti-hyperlipidemia drugs, etc. Such drug treatments have side effects, cannot take into account other symptoms, and may even lead to abnormalities in other metabolic indicators.
  • the purpose of the invention of the present application includes providing the application of Akkermansia muciniphila in the preparation of pharmaceutical compositions or health care product compositions for improving metabolic syndrome, and also includes providing the application of Akkermansia muciniphila containing
  • the composition is used in the preparation or as a medicine for preventing and treating metabolic syndrome or in the preparation or as a health food for improving metabolic syndrome, and the Akkermansia muciniphila is Akkermansia muciniphila AM06 (deposit number It is CGMCC No. 22793) and Akkermansia muciniphila AM02 (deposit number is CGMCC No. 22794).
  • the application of Akkermansia muciniphila in improving metabolic syndrome is provided, wherein the Akkermansia muciniphila is Akkermansia muciniphila AM06, Akkermansia muciniphila AM06, Akkermansia muciniphila Kermanella AM02 or a combination of both; where,
  • the Akkermansia muciniphila AM06 was deposited in the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021, and the deposit number is CGMCC No. 22793;
  • the Akkermansia muciniphila AM02 was deposited in the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021, and the deposit number is CGMCC No. 22794;
  • the improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome;
  • the Akkermansia muciniphila AM06 and the Akkermansia muciniphila AM02 are each independently a live bacterium, an inactivated bacterium, or a combination thereof.
  • the application of Akkermansia muciniphila in preparing a composition for improving metabolic syndrome is provided, wherein the composition for improving metabolic syndrome is a pharmaceutical composition or a health care product composition, That is to say, the application of Akkermansia muciniphila in preparing pharmaceutical compositions or health care product compositions for improving metabolic syndrome is provided, and the Akkermansia muciniphila is Akkermansia muciniphila AM06, Akkermansia muciniphila AM02 or a combination of both; where,
  • the Akkermansia muciniphila AM06 was deposited in the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021, and the deposit number is CGMCC No. 22793;
  • the Akkermansia muciniphila AM02 was deposited in the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021, and the deposit number is CGMCC No. 22794.
  • the Akkermansia muciniphila AM06 and the Akkermansia muciniphila AM02 are each independently a live bacterium, an inactivated bacterium with an intact morphological structure, an inactivated bacterium, or a combination thereof.
  • the improving metabolic syndrome includes preventing and/or treating metabolic syndrome, that is, the improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • the composition for improving metabolic syndrome is a pharmaceutical composition, which includes the Akkermansia muciniphila and a pharmaceutically acceptable carrier;
  • the pharmaceutical composition is a medicine or pharmaceutical preparation
  • the dosage form of the medicine or the pharmaceutical preparation is a tablet, capsule, granule, pill, ointment, solution, suspension, emulsion, cream, spray, drop, patch or tube. Feeding preparations;
  • the pharmaceutical product or the medicament is suitable for use in humans or other mammals.
  • the composition for improving metabolic syndrome is a health care product composition, which includes the Akkermansia muciniphila and edible raw and auxiliary materials;
  • the health product composition is a health food
  • the dosage form of the health food is pills, tablets, granules, capsules, solutions, suspensions or emulsions;
  • the health food includes one or more of milk powder, cheese, curd, yogurt, ice cream and fermented cereals, or the health food is animal food.
  • the composition containing Akkermansia muciniphila is a pharmaceutical composition or a health product composition.
  • the composition containing Akkermansia muciniphila is a pharmaceutical composition
  • the pharmaceutical composition includes the Akkermansia muciniphila and a pharmaceutically acceptable carrier;
  • the pharmaceutical composition is a medicine or pharmaceutical preparation
  • the dosage form of the medicine or the pharmaceutical preparation is a tablet, capsule, granule, pill, ointment, solution, suspension, emulsion, cream, spray, drop, patch or tube. Feeding preparations;
  • the pharmaceutical product or the medicament is suitable for use in humans or other mammals.
  • the composition containing Akkermansia muciniphila is a health care product composition
  • the health care product composition includes the Akkermansia muciniphila and edible raw and auxiliary materials
  • the health product composition is a health food
  • the dosage form of the health food is pills, tablets, granules, capsules, solutions, suspensions or emulsions;
  • the health food includes one or more of milk powder, cheese, curd, yogurt, ice cream and fermented cereals, or the health food is animal food.
  • the use of a composition containing Akkermansia muciniphila in preparing or serving as a medicine or pharmaceutical preparation for preventing and treating metabolic syndrome, or in preparing or serving as a health food for improving metabolic syndrome wherein, the Akkermansia muciniphila is as defined in the second aspect of this application, and please refer to the following definitions.
  • the application of a composition containing Akkermansia muciniphila in preparing or serving as a medicine or pharmaceutical preparation for preventing and treating metabolic syndrome is provided, wherein the Akkermansia muciniphila is as described in No. 1 of the present application.
  • Akkermansia muciniphila is as described in No. 1 of the present application.
  • the composition containing Akkermansia muciniphila is a pharmaceutical composition
  • the pharmaceutical composition includes the Akkermansia muciniphila and a pharmaceutically acceptable carrier;
  • the dosage form of the medicine or the pharmaceutical preparation is a tablet, capsule, granule, pill, ointment, solution, suspension, emulsion, cream, spray, drop, patch or tube. Feeding preparations;
  • the pharmaceutical product or the pharmaceutical formulation is suitable for use in humans or other mammals.
  • the application of a composition containing Akkermansia muciniphila in preparing or serving as a health food for improving metabolic syndrome is provided, wherein the Akkermansia muciniphila is as described in the second application of the present application.
  • Akkermansia muciniphila is as described in the second application of the present application.
  • the composition containing Akkermansia muciniphila is a health care product composition
  • the health care product composition includes the Akkermansia muciniphila and edible raw and auxiliary materials
  • the dosage form of the health food is pills, tablets, granules, capsules, solutions, suspensions or emulsions;
  • the health food includes one or more of milk powder, cheese, curd, yogurt, ice cream and fermented cereals, or the health food is animal food.
  • the composition containing Akkermansia muciniphila is a complex Probiotics, the compound probiotics also contain probiotics different from the Akkermansia muciniphila;
  • the probiotics different from the Akkermansia muciniphila include Bacteroides fragilis, Saccharomyces boulardii, Christensis, Lactobacillus casei, Lactobacillus rhamnosus, Gaselli Lactobacillus, Lactobacillus plantarum, Lactobacillus curvature, Bifidobacterium infantis Bacillus, one or more of Bifidobacterium longum and Bifidobacterium breve.
  • the composition containing Akkermansia muciniphila further includes a second active ingredient, the second active ingredient being a drug different from the Akkermansia muciniphila;
  • the second active ingredient includes one or more of orlistat, metformin, thiazolidinediones, fibrates, statins, and calcium ion antagonists; wherein, the fibrate
  • the statin drugs include one or more of fenofibrate, bezafibrate and gemfibrozil; the statin drugs include atorvastatin, lovastatin, simvastatin, pravastatin and fluvastatin One or more statins;
  • the second active ingredient includes atorvastatin calcium.
  • Akkermansia muciniphila is provided for improving metabolic syndrome, wherein the Akkermansia muciniphila is as defined in the second aspect of the application, and please also refer to the following definitions .
  • improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • composition for improving metabolic syndrome is provided, wherein the composition for improving metabolic syndrome is a composition containing a trophin as defined in the third aspect of the present application or the fourth aspect of the present application.
  • improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • a composition containing Akkermansia muciniphila is provided.
  • composition containing Akkermansia muciniphila comprising the Akkermansia muciniphila as defined in the second aspect of the application and a second active ingredient;
  • the second active ingredient includes one or more of orlistat, metformin, thiazolidinediones, fibrates, statins, and calcium ion antagonists; wherein, the fibrate
  • the statin drugs include one or more of fenofibrate, bezafibrate and gemfibrozil; the statin drugs include atorvastatin, lovastatin, simvastatin, pravastatin and fluvastatin One or more statins;
  • the second active ingredient includes atorvastatin calcium.
  • a composition containing Akkermansia muciniphila which is a compound probiotic, and the compound probiotic contains the Akkermansia muciniphila described in the second aspect of the application, and further contains Probiotic bacteria other than said Akkermansia muciniphila;
  • the probiotics different from the Akkermansia muciniphila include Bacteroides fragilis, Saccharomyces boulardii, Christersonella, Enterococcus shii, Lactobacillus casei, rhamnosus One or more of Lactobacillus, Lactobacillus gasseri, Lactobacillus plantarum, Lactobacillus curvature, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium breve;
  • composition containing Akkermansia muciniphila further includes a second active ingredient, and the second active ingredient is as defined above.
  • a method for improving metabolic syndrome includes administering Akkermansia muciniphila to a subject, or administering a composition containing Akkermansia muciniphila to the subject, or administering to the subject
  • the subject is given medicine containing Akkermansia muciniphila, or the subject is given health food containing Akkermansia muciniphila; wherein, the Akkermansia muciniphila is as defined in the second aspect of the present application .
  • the method for improving metabolic syndrome includes administering a therapeutically effective amount of Akkermansia muciniphila to a subject, or administering to a subject a therapeutically effective amount of Akkermansia muciniphila containing the Akkermansia muciniphila.
  • the method for improving metabolic syndrome includes administering a health-care effective amount of Akkermansia muciniphila to a subject, or administering a health-care effective amount of Akkermansia muciniphila to a subject.
  • a health care product composition of Akkermansia muciniphila, or a health care effective amount of a health food containing Akkermansia muciniphila is administered to a subject.
  • composition containing Akkermansia muciniphila is as defined in the third aspect of the application or the fourth aspect of the application.
  • the method for improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • strains AM06 deposit number CGMCC No. 22793
  • AM02 deposit number CGMCC No. 22794
  • 16S rRNA analysis morphological analysis, metabolite component analysis, efficacy analysis (such as artificial gastric juice and Comprehensive analysis of the tolerance of artificial intestinal juice, the ability to inhibit inflammatory factors from destroying the tight junction proteins of intestinal cells, and the inhibition of LPS-induced hepatitis in liver slices), etc., both belong to Akkermansia muciniphila, and are identified as different from New strains of Akkermansia muciniphila such as ATCC BAA-835 (standard strain).
  • Akkermansia muciniphila AM06 and/or AM02 (“AM06 and/or AM02" here means AM06, AM02 or a combination of AM06 and AM02) isolated above can be used to improve metabolic syndrome, including using for prevention and control (Prevention and/or treatment, i.e. at least one of prevention and treatment) metabolic syndrome. Therefore, Akkermansia muciniphila AM06 and/or AM02 isolated above can be used to prepare pharmaceutical compositions or health care product compositions, and further can be used to prepare medicines or health food. Akkermansia muciniphila AM06 and/or AM02 isolated above can reduce obesity and insulin resistance in rats, regulate blood pressure, improve blood sugar and blood lipid metabolism, and effectively prevent and treat metabolic syndrome.
  • Figure 1 is a colony characteristic diagram of Akkermansia muciniphila AM02 cultured in an embodiment of the present application
  • Figure 2 is a colony characteristic diagram of Akkermansia muciniphila AM06 obtained in an embodiment of the present application;
  • Figure 3 is a microscopic observation of Akkermansia muciniphila AM02 cultured in an embodiment of the present application after Gram staining;
  • Figure 4 is a microscopic observation picture after Gram staining of Akkermansia muciniphila AM06 cultured in an embodiment of the present application;
  • Figure 5 is a PCA analysis chart of several Akkermansia muciniphila culture supernatant metabolites in an embodiment of the present application;
  • Figure 6 is a fluorescence microscope photograph of the effect of several Akkermansia muciniphila on the reduction of tight junction protein ZO-1 expression in Caco2 cells induced by TNF- ⁇ and IFN- ⁇ in an embodiment of the present application.
  • Akkermansia muciniphila AM06 isolated in this application its classification name is Akkermansia muciniphila, has been deposited in the General Microbiology Center of the China Committee for the Collection of Microbial Cultures on June 28, 2021, address: Beichen, Chaoyang District, Beijing No. 3, Yard No. 1, West Road, the preservation number is CGMCC No. 22793; the strain was received and registered by the preservation center on June 28, 2021, and was detected as a surviving strain by the preservation center on June 28, 2021.
  • the technical solution of "A, and/or, B, and/or, C, and/or, D” includes any one of A, B, C, and D (that is, they are all connected with "logical OR” technical solution), also includes any and all combinations of A, B, C, and D, that is, including combinations of any two or any three of A, B, C, and D, and also includes A, B, C , four combinations of D (that is, technical solutions that are all connected by "logical AND").
  • the technical features described in open format include closed technical solutions composed of the listed features, and also include open technical solutions including the listed features.
  • the temperature parameters in this application are allowed to be treated at a constant temperature, or to vary within a certain temperature range. It should be understood that the thermostatic treatment described allows the temperature to fluctuate within the accuracy of the instrument control. It is allowed to fluctuate within the range of ⁇ 5°C, ⁇ 4°C, ⁇ 3°C, ⁇ 2°C and ⁇ 1°C.
  • room temperature generally refers to 4°C to 35°C, preferably 20°C ⁇ 5°C. In some embodiments of the present application, room temperature refers to 20°C to 30°C.
  • compositions are applicable to the context of this application unless otherwise stated.
  • the "second active ingredient” the modified bacteria of Akkermansia muciniphila described in this application
  • compound probiotics the modified bacteria of Akkermansia muciniphila described in this application
  • second pharmaceutical active ingredient containing Related descriptions of terms such as “compositions of Akkermansia muciniphila”, “other active pharmaceutical ingredients”, etc.
  • any step may include multiple sub-steps or multiple stages. These sub-steps or stages are not necessarily executed at the same time, but may be executed at different times, and the order of execution is not necessarily sequential. It can be performed in turn or alternately with other steps or sub-steps or parts of stages of other steps or simultaneously.
  • strains AM06 deposit number CGMCC No. 22793
  • AM02 deposit number CGMCC No. 22794
  • 16S rRNA analysis morphological analysis, metabolite component analysis, efficacy analysis (such as artificial gastric juice and Comprehensive analysis of the tolerance of artificial intestinal juice, the ability to inhibit inflammatory factors from destroying the tight junction proteins of intestinal cells, and the inhibition of LPS-induced hepatitis in liver slices), etc., both belong to Akkermansia muciniphila, and are identified as different from New strains of Akkermansia muciniphila such as ATCC BAA-835 (standard strain).
  • Akkermansia muciniphila AM06 and/or AM02 (“AM06 and/or AM02" here means AM06, AM02 or a combination of AM06 and AM02) isolated above can be used to improve metabolic syndrome, including using For the prevention and treatment (prevention and/or treatment, that is, at least one of prevention and treatment) of metabolic syndrome. Therefore, Akkermansia muciniphila AM06 and/or AM02 isolated above can be used to prepare pharmaceutical compositions or health care product compositions, and further can be used to prepare medicines or health food. Akkermansia muciniphila AM06 and/or AM02 isolated above can reduce obesity and insulin resistance in rats, regulate blood pressure, improve blood sugar and blood lipid metabolism, and effectively prevent and treat metabolic syndrome.
  • “improving metabolic syndrome” means providing physiological and/or pharmacological beneficial effects on metabolic syndrome.
  • “Improving metabolic syndrome” includes but is not limited to preventing and/or treating metabolic syndrome. That is, improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • Akermansia muciniphila is consistent with the common definition in the art, including but not limited to Akkermansia muciniphila AM06 and AMO2.
  • Akermansia muciniphila can be a living bacterial cell, or it can retain all or part of its original biological activity through inactivation, genetic recombination, transformation or modification, attenuation, chemical treatment, or physical treatment.
  • Akkermansia muciniphila may also be a lysate, a culture (for example, a supernatant) of the bacterial cell, or a component extracted from the supernatant.
  • strains AM06 deposit number CGMCC No. 22793
  • AM02 deposit number CGMCC No. 22794
  • 16S rRNA analysis morphological analysis, metabolite component analysis, efficacy analysis (such as artificial gastric juice and Comprehensive analysis of the tolerance of artificial intestinal juice, the ability to inhibit inflammatory factors from destroying the tight junction proteins of intestinal cells, and the inhibition of LPS-induced hepatitis in liver slices), etc., both belong to Akkermansia muciniphila, and are identified as different from New strains of Akkermansia muciniphila such as ATCC BAA-835 (standard strain).
  • Akkermansia muciniphila belongs to the phylum Verucomicrobia, the family Akkermansiaceae, and the genus Akkermansia.
  • Akkermansia muciniphila is A mucin-degrading bacterium (also noted as AKK or AKK bacterium), which is an anaerobic, non-motile, non-spore-forming, ovoid Gram-negative bacterium, suitable for growth at 20 to 40°C and pH 5.5 to 8.0 (Optimal temperature 37°C, optimal pH 6.5), commonly found in the human intestine. Although it is an anaerobic bacterium, it can also tolerate a certain degree of oxygen.
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • Akermansia muciniphila in this application specifically refers to Akkermansia muciniphila AM06, Akkermansia muciniphila AM02 or a combination of the two, which can be recorded as “AM06 and/or or AM02".
  • AM06 and/or AM02 may also be described as AM06, AM02, or a combination of AM06 and AM02.
  • the colony culture characteristics of Akkermansia muciniphila AM06 include: round protrusions, neat edges, opaque, white, and unevenly sized colonies. Further, the colony size is about 0.08 ⁇ 2.2mm.
  • Akkermansia muciniphila AM06 is isolated from breast milk.
  • Example 1 Akkermansia muciniphila AM02 was deposited at the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021. The deposit number is CGMCC No. 22794. It can be isolated by the method of Example 1, and can also be obtained by including but not One or more methods in Example 2 to Example 5 are used for strain identification.
  • the colony culture characteristics of Akkermansia muciniphila AM02 of CGMCC No. 22794 include: round protrusions, neat edges, opaque, white, and unevenly sized colonies. Further, the colonies The size is approximately 0.08 ⁇ 2.2mm.
  • the applicant also conducted tolerance testing of artificial gastric juice and artificial intestinal juice.
  • the number of viable bacteria after anaerobic incubation at 37 ⁇ 2°C for 0.9wt% NaCl solution group, pH3 artificial gastric juice group and pH2 artificial gastric juice group for 0h, 1.5h and 3h Statistical analysis was performed, and the results showed that the artificial gastric juice tolerance of the mucinophilic Akermann strain was AM02>AM06>standard strain ATCC BAA-835.
  • the artificial intestinal fluid tolerance test statistical analysis was conducted on the number of viable bacteria after anaerobic incubation at 37 ⁇ 2°C for 0h, 4h, and 8h. The artificial intestinal fluid tolerance was better than AM06>AM02>ATCC BAA-835.
  • Akkermansia muciniphila AM06 and AMO2 can each independently be living cells or inactivated Akkermansia muciniphila (i.e., sterilized Live bacteria (which may be completely or partially inactivated), may also be lysates, cultures (for example, supernatants) of bacterial cells, or components extracted from the supernatants.
  • Akkermansia muciniphila i.e., sterilized Live bacteria (which may be completely or partially inactivated
  • Akkermansia muciniphila AM06 and Akkermansia muciniphila AM02 are each independently a live bacterium, an inactivated bacterium, or a combination thereof (i.e., a live bacterium and an inactivated bacterium). combination of bacteria).
  • the inactivated bacteria can be inactivated bacteria with complete morphological structure, inactivated bacteria with incomplete morphological structure, or a combination thereof.
  • Akkermansia muciniphila AM06 and Akkermansia muciniphila AM02 are independently viable bacteria, inactivated bacteria with complete morphological structure, or incomplete morphological structure. One or more types of sterilized bacteria.
  • the Akkermansia muciniphila described in the present application is selected from viable cells of Akkermansia muciniphila.
  • the Akkermansia muciniphila described in the application is selected from the group consisting of inactivated Akkermansia muciniphila.
  • morphologically intact may include, but is not limited to, Akkermansia muciniphila that has been completely or partially inactivated through an inactivation treatment.
  • incomplete morphological structure may include, but is not limited to, bacterial lysate, culture (such as supernatant), or components extracted from the supernatant.
  • Akkermansia muciniphila in improving metabolic syndrome that is, a method of applying Akkermansia muciniphila in improving metabolic syndrome is provided, wherein the Akkermansia muciniphila is Akkermansia mucini AM06, Akkermansia muciniphila AM02, or a combination of the two; among which,
  • improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • Akkermansia muciniphila AM06 and Akkermansia muciniphila AM02 are each independently a live bacterium, a killed bacterium, or a combination thereof.
  • the application of Akkermansia muciniphila in preparing a composition for improving metabolic syndrome is provided, wherein the composition for improving metabolic syndrome is a pharmaceutical composition or a health care product composition, That is to provide the application of Akkermansia muciniphila in preparing pharmaceutical compositions or health care product compositions for improving metabolic syndrome (including preventing and treating metabolic syndrome), and the Akkermansia muciniphila is a muciniphila Kermanella AM06, Akkermansia muciniphila AM02, or a combination of the two; wherein,
  • the Akkermansia muciniphila AM06 was deposited in the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021, and the deposit number is CGMCC No. 22793;
  • the Akkermansia muciniphila AM02 was deposited in the General Microbiology Center of the China Microbial Culture Collection Committee on June 28, 2021, and the deposit number is CGMCC No. 22794.
  • Akkermansia muciniphila AM06 and/or AM02 (“AM06 and/or AM02" here means AM06, AM02 or a combination of AM06 and AM02) isolated above can be used to improve metabolic syndrome. , including being used to prevent and treat (prevention and/or treatment, that is, at least one of prevention and treatment) metabolic syndrome.
  • the Akkermansia muciniphila AM06 and/or AM02 isolated above can be used to prepare pharmaceutical compositions or health care product compositions, and further can be used to prepare medicines or health food.
  • Akkermansia muciniphila AM06 and/or AM02 isolated above can reduce obesity and pancreatic islets in rats. It can reduce hormone resistance, regulate blood pressure, improve blood sugar and blood lipid metabolism, and effectively prevent and treat metabolic syndrome. It is speculated that Akkermansia muciniphila AM06 and/or AM02 act as promoters of organism metabolism.
  • the Akkermansia muciniphila AM06 and the Akkermansia muciniphila AM02 are each independently a live bacterium, an inactivated bacterium with an intact morphological structure, an inactivated bacterium, or a combination thereof.
  • “improving metabolic syndrome” means providing physiological and/or pharmacological beneficial effects on metabolic syndrome.
  • “Improving metabolic syndrome” includes but is not limited to preventing and/or treating metabolic syndrome. That is, improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • the composition for improving metabolic syndrome is a pharmaceutical composition.
  • the pharmaceutical composition includes the Akkermansia muciniphila and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a pharmaceutical or pharmaceutical preparation.
  • the dosage form of the medicine or the pharmaceutical preparation may be, but is not limited to, tablets, capsules, granules, pills, ointments, solutions, suspensions, emulsions, creams, sprays, drops, patches or tubes. Feeding preparations.
  • the pharmaceutical product or the medicament may be suitable for use in humans or other mammals.
  • the composition for improving metabolic syndrome is a health care composition.
  • the health product composition includes the Akkermansia muciniphila and edible raw and auxiliary materials.
  • the health product composition is a health food.
  • the dosage form of the health food may be, but is not limited to, pills, tablets, granules, capsules, solutions, suspensions or emulsions.
  • the health food may include one or more of milk powder, cheese, curd, yogurt, ice cream and fermented cereals, or the health food may be animal food.
  • prevention and prevention and/or treatment have the same meaning and can be used interchangeably.
  • prevention and treatment includes prevention, treatment (including auxiliary treatment), etc.
  • prevent or “treat” means to reduce, delay the progression, attenuate, prevent, or maintain an existing disease or condition.
  • Prevention and treatment also includes curing, preventing the development of, or alleviating to some extent one or more symptoms of a disease or condition.
  • treating means alleviating, delaying progression, attenuating, or maintaining an existing disease or condition.
  • Treatment also includes curing, preventing the progression of, or reducing one or more symptoms of a disease or condition to a certain level. degree. In this application, "prevention and/or treatment” may also be described as at least one of prevention and treatment.
  • composition can be a combination of multiple substances, and further, it can be used in combination, or it can be a mixture of combinations.
  • drug includes any agent, compound, composition or mixture that provides a pharmacological action, often a beneficial effect, in vivo or in vitro.
  • the scope of the pharmacological effects of a “drug” in the body is not particularly limited. It can have systemic effects or only local effects.
  • the activity of the "drug” is not particularly limited. It can be an active substance that can interact with other substances, or it can be an inert substance that does not interact.
  • pharmaceutical composition refers to a composition that has the effect of preventing and treating diseases or conditions, can be used as a medicine, or can be used to prepare medicines.
  • drug refers to a directly administered pharmaceutical preparation, which usually has a prescribed usage and dosage.
  • a subject such as human, rat, mouse
  • body weight a subject
  • FBG fasting blood glucose
  • Fins serum insulin
  • HOMA-IR insulin resistance index
  • tail artery systolic blood pressure serum lipid indicators (including TC, TG, LDL-c and HDL- c); please refer to Example 6.
  • Lee’s index is decreased.
  • blood pressure is lowered.
  • serum TC, TG, and LDL-c levels are reduced.
  • serum HDL-c levels are increased.
  • a pharmaceutical composition includes Akkermansia muciniphila (AM06 and/or AMO2) described herein and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to any of those ligands, materials, compositions and dosage forms that, within the scope of reasonable medical judgment, are suitable for administration to a patient and are commensurate with a reasonable benefit/risk ratio or any suitable combination.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable carrier includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and Absorption delayers and the like. Each carrier must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted ⁇ -cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Powdered tragacanth; (5) Malt; (6) Gelatin; (7) Talc; (8) Fu excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols Alcohols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters Classes, such as ethyl oleate and ethyl laurate; (13) agar; (1
  • carrier includes but is not limited to mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, ethylenediaminetetraacetic acid diamine Sodium (disodium EDTA), calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or their aqueous solutions, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, Xylitol, maltose, glucose, fructose, fructooligosaccharides, dextran, glycine, starch, sucrose, dextrin (such as maltodextrin), lactose, mannitol, silicon derivatives, cellulose and its derivatives, Alginate, gelatin, polyvinylpyr
  • compositions may also include other pharmaceutically active ingredients.
  • “Other active pharmaceutical ingredients” can be pharmaceutical ingredients that have the effect of preventing and treating metabolic syndrome, or they can also be pharmaceutical ingredients that have the effect of preventing and treating other diseases.
  • other pharmaceutical active ingredients can be appropriately selected from existing drugs for preventing and treating metabolic syndrome.
  • health products and “health food” have the same meaning and can be used interchangeably.
  • health products refer to foods with health care functions, which can regulate the physiological functions of animals (humans or other animals) and often provide beneficial effects.
  • beneficial effects There is no particular limit to the range of beneficial effects that “health products” can produce in the body. They can have systemic effects or only local effects.
  • health product composition refers to a food composition with health care functions.
  • the health care product composition can be consumed directly as a health care product or as a dietary additive.
  • food refers to products that are directly edible.
  • Food composition refers to a composition consisting of edible substances. It should be understood that in addition to the aforementioned Akkermansia muciniphila, the food composition in the present application is also allowed to contain any suitable other edible substances. In some embodiments, other edible substances may be selected from substances that are allowed to be added in food management regulations, and further do not include substances that are prohibited from being added in food management regulations. Unless otherwise specified, food control practices refer to the current practices at the time of production.
  • the health product composition includes Akkermansia muciniphila and edible raw materials and auxiliary materials described in this application.
  • edible raw materials and auxiliary materials refer to edible raw materials, edible auxiliary materials or a combination of both.
  • edible raw materials refer to edible substances that can independently provide health care functions, but are not AM06 and AM02;
  • edible excipients refer to edible substances that do not provide independent health care functions.
  • edible raw materials and auxiliary materials can be selected from substances that are allowed to be added in the health care product management regulations, and further do not include substances that are prohibited from being added in the health care product management regulations. Unless otherwise specified, health product management regulations refer to the current regulations at the time of production.
  • a food composition includes Akkermansia muciniphila (AM06 and/or AMO2) described herein and edible excipients.
  • food additives also belong to edible excipients.
  • edible excipients include sugar, fructose, honey, glucose, starch, vitamins, beneficial trace elements and medium elements (such as calcium powder), soybean powder, mung bean powder, maltodextrin, milk powder, vegetable juice, fruit juice, spices , flavors, etc.
  • the edible excipients of the present application can be used singly or in combination.
  • the health product composition consists of Akkermansia muciniphila (AM06 and/or AMO2) described in the present application and edible excipients.
  • the health care composition may also contain other health care ingredients.
  • the other health care ingredients are health care ingredients different from AM06 and AMO2. Their health care functions may be beneficial improvement of metabolic syndrome, or other health care functions. .
  • the nutraceutical composition also contains other probiotics.
  • Other probiotics may be selected from modified strains of Akkermansia muciniphila (AM06 and/or AMO2) described in this application and probiotics of other species.
  • Other species of probiotics may include Bacteroides fragilis, Saccharomyces boulardii, Christella, Enterococcus shii, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus gasseri, Lactobacillus plantarum, One or more of Lactobacillus curvature, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, etc.
  • the health product composition also contains probiotic bacteria of other species.
  • the pharmaceutical composition is a pharmaceutical or pharmaceutical preparation.
  • drug refers to a pharmaceutical preparation that can be directly administered, usually with a prescribed usage and dosage, consistent with the preceding definition.
  • a "pharmaceutical formulation” may be a liquid formulation or a solid formulation.
  • Liquid preparations refer to preparations containing a liquid phase, Non-limiting examples include solutions, suspensions, emulsions, and the like.
  • Non-limiting examples of solid preparations include tablets, capsules, granules, pills, and the like.
  • pharmaceutical preparations can be oral preparations, injections, drops, patches, tube feeding preparations, etc.
  • the pharmaceutical or pharmaceutical preparation is in the form of a tablet, capsule, granule, pill, ointment, solution, suspension, emulsion, cream, spray, drop, patch or tube feeding preparation .
  • the pharmaceutical product contains a therapeutically effective amount of Akkermansia muciniphila (AM06 and/or AMO2) described in this application.
  • Therapeutically effective amounts can be achieved by single or multiple dose administration. Taking tablets as an example, "a dose" may include one or more tablets.
  • a "therapeutically effective amount” refers to an amount of a pharmaceutically active ingredient that will elicit a biological or medical response in an individual for at least one of the diseases, conditions, and related symptoms, such as a pharmacologically positive effect in the individual.
  • the amount of Akkermansia muciniphila in this application, the pharmacological positive effects include but are not limited to reducing or inhibiting enzyme or protein activity, improving symptoms, alleviating symptoms, slowing or delaying disease progression or preventing diseases, etc.
  • the nutraceutical composition is a nutraceutical.
  • the dosage form of the health food is pills, tablets, granules, capsules, solutions, suspensions or emulsions.
  • non-limiting examples include honey pills, water honey pills, water pills, syrups, syrups, etc.
  • the health food contains a health effective amount of Akkermansia muciniphila (AM06 and/or AMO2) described in this application.
  • the "health-care effective dose” here refers to the amount that can beneficially improve metabolic syndrome and can exert a beneficial effect at the normal dosage of health food.
  • subject refers to a patient who takes a pharmaceutical composition or a consumer who consumes a health product composition.
  • a "subject” is an animal, preferably a mammal, and further preferably a human.
  • Subjects include but are not limited to consumers of health products and patients with at least one of diseases, illnesses and related symptoms. .
  • the subject in this application is preferably a mammal.
  • the term "mammal” mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats (such as rats, mice), pigs, cattle , sheep, horses, humans, etc., primates are preferred, and humans are further preferred.
  • the subject is a mammal.
  • the subject is a human or other mammal.
  • the medicines can also be called “animal medicines” and the health food can be called “animal foods” (such as animal feed).
  • compositions and nutraceutical compositions are each independently suitable for use in humans or other mammals.
  • “other mammals” are not humans.
  • Non-limiting examples of “other mammals” include cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats (such as rats, mice), pigs , cattle, sheep, horses, etc., further such as mice or rats; non-limiting examples of “other mammals” include primates.
  • the subject is a human or rat.
  • patient refers to an animal, which may preferably be a mammal, such as a human or a rat.
  • the application of a composition containing Akkermansia muciniphila in improving metabolic syndrome is provided, wherein the Akkermansia muciniphila is as defined above, and reference may be made to Article 1 of this application.
  • the Akkermansia muciniphila is as defined above, and reference may be made to Article 1 of this application.
  • the definitions in the two aspects please also refer to the definitions below.
  • the composition containing Akkermansia muciniphila may be a pharmaceutical composition or a health product composition.
  • the composition containing Akkermansia muciniphila is a pharmaceutical composition
  • the pharmaceutical composition includes the Akkermansia muciniphila and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be a pharmaceutical or pharmaceutical preparation.
  • the dosage form of the medicine or the pharmaceutical preparation may be, but is not limited to, tablets, capsules, granules, pills, ointments, solutions, suspensions, emulsions, creams, sprays, drops, patches or tubes. Feeding preparations.
  • the medicine or medicament may be suitable for use in humans or other mammals.
  • the composition containing Akkermansia muciniphila is a health care product composition.
  • the health care product composition includes the Akkermansia muciniphila and edible raw and auxiliary materials.
  • the health product composition may be a health food.
  • the dosage form of the health food may be, but is not limited to, pills, tablets, granules, capsules, solutions, suspensions or emulsions.
  • the health food may include, but is not limited to, one or more of milk powder, cheese, curd, yogurt, ice cream and fermented cereals, or the health food may be animal food.
  • a composition containing Akkermansia muciniphila in preparing or serving as a medicine or pharmaceutical preparation for preventing and treating metabolic syndrome, or in preparing or serving as a health food for improving metabolic syndrome,
  • the definition of Akkermansia muciniphila may refer to the previous definition.
  • Akkermansia muciniphila described in this application is Akkermansia muciniphila AM06 (deposit number is CGMCC No. 22793), Akkermansia muciniphila AM02 (deposit number: CGMCC No. 22794), or a combination of the two.
  • the composition containing Akkermansia muciniphila is a pharmaceutical composition or a nutraceutical composition.
  • compositions composition, “prevention and treatment”, “metabolic syndrome”, “improving metabolic syndrome”, “prevention and treatment of metabolic syndrome”, “pharmaceutical composition”, “health product composition”.
  • drug composition composition, “prevention and treatment”, “metabolic syndrome”, “improving metabolic syndrome”, “prevention and treatment of metabolic syndrome”, “pharmaceutical composition”, “health product composition”.
  • the application of a composition containing Akkermansia muciniphila in preparing or serving as a medicine or pharmaceutical preparation for preventing and treating metabolic syndrome is provided, wherein the definition of Akkermansia muciniphila is the same as the above. consistent.
  • the composition containing Akkermansia muciniphila is a pharmaceutical composition
  • the pharmaceutical composition includes the Akkermansia muciniphila and a pharmaceutically acceptable carrier.
  • the dosage form of the medicine or the pharmaceutical preparation may be, but is not limited to, tablets, capsules, granules, pills, ointments, solutions, suspensions, emulsions, creams, sprays, drops, patches or tubes. Feeding preparations.
  • the pharmaceutical product or the pharmaceutical preparation may be suitable for use in humans or other mammals.
  • a composition containing Akkermansia muciniphila is provided for use in preparing or serving as a health food for improving metabolic syndrome, wherein the definition of Akkermansia muciniphila is consistent with the above. .
  • the composition containing Akkermansia muciniphila is a health care product composition.
  • the health care product composition includes the Akkermansia muciniphila and edible raw and auxiliary materials.
  • the dosage form of the health food may be, but is not limited to, pills, tablets, granules, capsules, solutions, suspensions or emulsions.
  • the health food includes one or more of milk powder, cheese, curd, yogurt, ice cream, and fermented cereals.
  • the health food is milk powder, cheese, curd, yogurt, ice cream or fermented cereal, or is animal food.
  • the Akkermansia muciniphila described in the present application may be living cells, or may be inactivated Akkermansia muciniphila (i.e., inactivated bacteria, which may be completely or partially inactivated), or may be It is the lysate, culture (such as supernatant) of bacterial cells, or components extracted from the supernatant.
  • Akkermansia muciniphila i.e., inactivated bacteria, which may be completely or partially inactivated
  • It is the lysate, culture (such as supernatant) of bacterial cells, or components extracted from the supernatant.
  • the composition containing Akkermansia muciniphila further includes a second active ingredient.
  • the "second active ingredient” refers to other active ingredients that have comprehensive metabolism-improving effects in addition to Akkermansia muciniphila (AM06 and/or AMO2) described in this application.
  • the second active ingredient may be a modified strain of Akkermansia muciniphila (AM06 and/or AMO2) described in the present application. Transformation methods include but are not limited to gene editing, chemical processing, physical processing, etc.
  • the modified Akkermansia muciniphila formed a new strain different from AM06 and AM02.
  • the modified bacterium can still have the function of improving alcohol metabolic syndrome, and can also be endowed with at least one other new pharmacological and physiological function.
  • the "modified bacteria of Akkermansia muciniphila described in the present application” can be living cells or inactivated Akkermansia muciniphila (i.e., inactivated bacteria, which can be (to be completely or partially inactivated), it may also be a lysate of bacterial cells, a culture (for example, a supernatant), or a component extracted from the supernatant.
  • inactivated bacteria i.e., inactivated bacteria, which can be (to be completely or partially inactivated
  • it may also be a lysate of bacterial cells, a culture (for example, a supernatant), or a component extracted from the supernatant.
  • the composition containing Akkermansia muciniphila based on any suitable embodiment of the present application is Compound probiotics, in this case, in addition to the Akkermansia muciniphila (AM06 and/or AM02) described in this application, the composition also contains other probiotics that are different from Akkermansia muciniphila described in this application. bacteria.
  • a “complex probiotic” contains at least two probiotics. It should be understood that "compound probiotics containing Akkermansia muciniphila” includes Akkermansia muciniphila described in this application, and also includes other probiotics different from Akkermansia muciniphila described in this application.
  • other probiotics may include modified strains of Akkermansia muciniphila described herein as well as probiotics of other species.
  • Other species of probiotics are probiotics that are different from Akkermansia muciniphila, including probiotics or microorganisms of the genus Saccharomyces spp., Lactobacillus spp. and normal human intestinal flora. one or more of them.
  • the probiotic bacteria of the genus Saccharomyces may include one or more of Saccharomyces boulardii and Saccharomyces cerevisiae.
  • the probiotic bacteria other than Akkermansia muciniphila can be selected from the group consisting of Lactobacillus, Bifidobacterium, Bacteroides fragilis, Christersenia, Enterococcus shii, and Saccharomyces boulardii. of one or more.
  • the probiotic bacteria other than Akkermansia muciniphila can be selected from the group consisting of Bacteroides fragilis, Saccharomyces boulardii, Christensis, Enterococcus shii, Lactobacillus casei, Rhamnosus One or more of Lactobacillus, Lactobacillus gasseri, Lactobacillus plantarum (such as Lactobacillus plantarum KY1032), Lactobacillus curvature (such as Lactobacillus curvature HY7601), Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium breve kind.
  • Lactobacillus and Bifidobacterium have been reported to show consistent resistance to pathogenic Obesity properties, including Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus gasseri, Lactobacillus plantarum, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium breve. It has also been reported in the literature that Lactobacillus rhamnosus, which produces conjugated linoleic acid (CLA), has anti-obesity effects. During an 8-week probiotic feeding study, this strain did not change energy intake. Significantly reduced body weight and white adipose tissue in mice.
  • CLA conjugated linoleic acid
  • mice treated with probiotics composed of Lactobacillus curvature HY7601 and Lactobacillus plantarum KY1032 showed weight gain and reduced fat accumulation, as well as reduced plasma insulin, leptin, total cholesterol and hepatotoxicity biomarkers; in this study, the researchers also observed an upregulation of fatty acid oxidation-related genes in the livers of mice treated with probiotics, along with a downregulation of pro-inflammatory genes in adipose tissue.
  • the probiotic complex includes multiple species of Akkermansia muciniphila.
  • the compound probiotic bacteria consists of at least one of Akkerman muciniphila AM06 and AMO2, and at least one of the modified bacteria of AM06 and the modified bacteria of AMO2.
  • the compound probiotics include Akkermansia muciniphila described in this application, and also include probiotics of other species. Other species of probiotics are as defined above. Furthermore, the modified bacteria of Akkermansia muciniphila described in this application are also included.
  • composition containing Akkermansia muciniphila When used to prepare medicines or pharmaceutical preparations, it is a pharmaceutical composition in which the pharmaceutical active ingredients include Akkermansia muciniphila AM06 and Akkermansia muciniphila AM02. at least one of them.
  • the second active ingredient may be a drug different from the Akkermansia muciniphila.
  • the drugs include therapeutic drugs for weight loss, alleviating insulin resistance, good blood sugar control, improving lipid metabolism disorders, and controlling blood pressure.
  • composition containing Akkermansia muciniphila based on any suitable embodiment of the present application also further Includes a second pharmaceutically active ingredient.
  • the second pharmaceutically active ingredient includes, but is not limited to, orlistat, metformin, thiazolidinediones, fibrates (such as fenofibrate, bezafibrate, gemfibrozil, etc.)
  • fibrates such as fenofibrate, bezafibrate, gemfibrozil, etc.
  • statins such as one or more of atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, etc.
  • calcium ion antagonists etc.
  • statins such as one or more of atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, etc.
  • the "second pharmaceutical active ingredient” refers to other pharmaceutical active ingredients that have the effect of preventing and treating metabolic syndrome in addition to Akkermansia muciniphila (AM06 and/or AMO2) described in this application.
  • the composition containing Akkermansia muciniphila further includes a second pharmaceutically active ingredient.
  • second pharmaceutical active ingredient refers to other pharmaceutical active ingredients with comprehensive metabolic prevention and treatment effects in addition to Akkermansia muciniphila (AM06 and/or AMO2) described in this application. “Second pharmaceutically active ingredient” is included within the scope of "second active ingredient”.
  • the second active ingredient is atorvastatin calcium.
  • each component of the "composition containing Akkermansia muciniphila” may appear at any suitable time. For example, it can be directly prepared into a mixture for immediate use, or it can be packaged separately and then prepared into a mixture when used. It can also be administered to the subject separately and appear simultaneously in a local location in the body to exert a combined effect.
  • the composition containing Akkermansia muciniphila also contains other pharmaceutical active ingredients
  • the combination of Akkermansia muciniphila (AM06 and/or AM02) described in this application and other pharmaceutical active ingredients can also be used in any form.
  • the appropriate time arises; for the definition of "other active pharmaceutical ingredients”, please refer to the second aspect of this application.
  • the "composition containing Akkermansia muciniphila” appearing at any appropriate time is within the scope of the present application.
  • Akkermansia muciniphila is provided for improving metabolic syndrome, wherein the Akkermansia muciniphila is as defined above, and please refer to the following definitions.
  • improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • composition for improving metabolic syndrome is provided, wherein the composition for improving metabolic syndrome is a composition containing Akkermansia muciniphila as defined above, and further See definition below.
  • improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • composition containing Akkermansia muciniphila is provided;
  • composition containing Akkermansia muciniphila can be referred to the previous part of this application, including but not limited to the second aspect and the fourth aspect.
  • the Akkermansia muciniphila-containing compositions of this aspect comprise the Akkermansia muciniphila described herein and a second active ingredient.
  • second active ingredient may be found in the fourth aspect of the application.
  • the second active ingredient includes one or more of orlistat, metformin, thiazolidinediones, fibrates (such as fenofibrate, bezafibrate, gemfibrozil ), statins (such as one or more of atorvastatin, lovastatin, simvastatin, pravastatin and fluvastatin), one or more of calcium ion antagonists.
  • orlistat metformin, thiazolidinediones
  • fibrates such as fenofibrate, bezafibrate, gemfibrozil
  • statins such as one or more of atorvastatin, lovastatin, simvastatin, pravastatin and fluvastatin
  • calcium ion antagonists such as calcium ion antagonists.
  • the second active ingredient includes atorvastatin calcium.
  • the composition containing Akkermansia muciniphila includes the Akkermansia muciniphila described in the present application and atorvastatin calcium.
  • the second active ingredient is atorvastatin calcium.
  • compositions containing Akkermansia muciniphila which are complex probiotics, are provided.
  • complex probiotics is consistent with the above.
  • the compound probiotics contain the Akkermansia muciniphila described in this application, and also contain probiotics different from the Akkermansia muciniphila.
  • the probiotic bacteria different from Akkermansia muciniphila include Bacteroides fragilis, Saccharomyces boulardii, Christensis, Enterococcus shii, Lactobacillus casei, One or more of Lactobacillus lanceus, Lactobacillus gasseri, Lactobacillus plantarum, Lactobacillus curvature, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium breve.
  • a composition containing Akkermansia muciniphila is provided, which is a complex probiotic, and further includes a second active ingredient, the second active ingredient being as defined above.
  • a method for improving metabolic syndrome includes administering Akkermansia muciniphila to a subject, or administering a composition containing Akkermansia muciniphila to the subject, or administering to the subject
  • the subject is given medicine containing Akkermansia muciniphila, or the subject is given health food containing Akkermansia muciniphila; wherein the Akkermansia muciniphila is as defined above.
  • the method for improving metabolic syndrome includes at least one of preventing metabolic syndrome and treating metabolic syndrome.
  • a method for improving metabolic syndrome comprising administering to a subject Akkermansia muciniphila described in this application, a composition containing Akkermansia muciniphila described in this application,
  • the medicine of Akkermansia muciniphila described in this application or the health food containing Akkermansia muciniphila described in this application; further, the composition containing Akkermansia muciniphila described in this application can be Pharmaceutical compositions or health care product compositions.
  • a method for improving metabolic syndrome including prevention and treatment methods, including administering to a subject a therapeutically effective dose of Akkermansia muciniphila (i.e., administering to the subject a therapeutically effective amount of Akkermansia muciniphila).
  • the patient administers a therapeutically effective amount of Akkermansia muciniphila described herein).
  • a method for improving metabolic syndrome includes administering to a subject a therapeutically effective amount of a pharmaceutical composition containing Akkermansia muciniphila described in the present application.
  • a method for improving metabolic syndrome includes administering to a subject a therapeutically effective amount of a pharmaceutical preparation containing Akkermansia muciniphila described in the present application.
  • a method for improving metabolic syndrome includes administering to a subject a therapeutically effective amount of a medicine containing Akkermansia muciniphila described in the present application.
  • a method for improving metabolic syndrome includes administering to a subject a health-care effective dose of Akkermansia muciniphila described in the present application, or administering to the subject a health-care effective dose of a drug containing
  • the health care product composition of Akkermansia muciniphila described in the present application, or the health care food containing the Akkermansia muciniphila described in the present application is administered to a subject in a therapeutic and health-care effective amount.
  • the Akkermansia muciniphila described in the present application can be used in combination with other pharmaceutical active ingredients to improve metabolic syndrome.
  • other pharmaceutical active ingredients can be referred to the foregoing part of this application, including but not limited to the second aspect and the fourth aspect.
  • other pharmaceutical active ingredients can be pharmaceutical ingredients that have the effect of improving metabolic syndrome, or they can also be pharmaceutical ingredients that have the effect of preventing and treating other diseases.
  • the other pharmaceutical active ingredients are the second active ingredients described above.
  • the Akkermansia muciniphila described in the application the pharmaceutical composition containing the Akkermansia muciniphila described in the application, the pharmaceutical preparation containing the Akkermansia muciniphila described in the application, Drugs containing Akkermansia muciniphila described in this application all fall into the category of "drugs" defined in this application.
  • modes of administration of the drug include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration, inhalation.
  • the drug may be administered orally, enema, or parenterally.
  • the administration period of the drug may be intermittent administration, periodic administration, continuous administration or long-term administration.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl Cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, for example, glycerin; (d) disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, algae Acids, certain complex silicates, and sodium carbonate; (e) reluctants, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and monostearic
  • the dosage form may also contain buffering agents.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredients or compounds in such compositions may be in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active ingredient can also be in the form of microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, further for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • the suspension may contain suspending agents, further for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalants. It consists of mixing the active ingredient under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the “active ingredients” in the above-mentioned pharmaceutical preparations in this aspect refer to the ingredients in the pharmaceutical composition that can play the role of "medicine”. It can be understood that the medicines in the embodiments of the present application can be prepared into appropriate clinical dosage forms by adding different pharmaceutically acceptable excipients. These clinical dosage forms include but are not limited to the dosage forms mentioned above.
  • the measurement parameters of raw material components are involved. Unless otherwise specified, there may be slight deviations within the range of weighing accuracy. Temperature and time parameters are involved, allowing for acceptable deviations due to instrument testing accuracy or operating accuracy.
  • Freshly collected breast milk samples (from adult healthy women) were immediately injected into 5 mL anaerobic cillin bottles for storage, and then the samples were transferred to an anaerobic workstation at 37°C (85% N 2 , 10% H 2 , 5% CO 2 , volume percentage), dilute the sample to 10 -6 according to 10-fold gradient dilution, take 1 mL of each dilution solution and inoculate it into 9 mL of basal medium with mucin as the only carbon source, and culture it anaerobically for about 1 month.
  • Akkermansia muciniphila AM02 its classification name is Akkermansia muciniphila, has been deposited in the General Microbiology Center of the China Committee for the Collection of Microbial Cultures on June 28, 2021, address: Courtyard 3, No. 1, Beichen West Road, Chaoyang District, Beijing No., the preservation number is CGMCC No. 22794; the strain was received and registered by the preservation center on June 28, 2021, and was detected as a surviving strain by the preservation center on June 28, 2021.
  • Akkermansia muciniphila AM06 whose classification name is Akkermansia muciniphila, has been deposited in the General Microbiology Center of the China Committee for the Collection of Microbial Cultures on June 28, 2021. Address: Courtyard 3, No. 1, Beichen West Road, Chaoyang District, Beijing No., the preservation number is CGMCC No. 22793; the strain was received and registered by the preservation center on June 28, 2021, and was detected as a surviving strain by the preservation center on June 28, 2021.
  • Colony characteristics After culturing Akkermansia muciniphila AM02 and AM06 on the above-mentioned medium for 3 days, they both showed round and raised colonies with neat edges, opaque, white, and uneven sizes. The colony size was about 0.08 to 2.2 mm. , see Figure 1 (Akermansia muciniphila AM02) and Figure 2 (Akermansia muciniphila AM06).
  • the colony characteristics of the standard strain ATCC BAA-835 are: round protrusions, neat edges, opaque, white, and unevenly sized colonies. Under the microscope, the morphology is Gram-negative bacteria, oval, single or arranged in chains.
  • PCA is a data dimensionality reduction method, that is, reducing the dimensionality of multiple variables to a new set of comprehensive variables, and then selecting the first few principal components that reflect as much of the original variable information as possible to achieve the purpose of dimensionality reduction.
  • the PCA chart reflects the true distribution of samples and is mainly used to observe the separation trend between sample groups and whether there are abnormal points. It also reflects the variability between and within groups from the original data.
  • Figure 5 contains PCA analysis of quality control samples (QC samples) and all samples. Each QC sample is clustered together in the two principal component analysis diagrams, indicating that the instrument is stable during the detection and the repeatability of the collected data is good. At the same time, the results also showed that the metabolites in the culture supernatant of AM06 were close to the metabolites of the culture supernatant of BAA-835, while the metabolites of the culture supernatants of AM02 and BAA-835 were quite different.
  • 4.1.1.1 Take 1 Akkermansia muciniphila strain, remove the label, wipe and disinfect the outer surface of the glycerol cryopreservation tube with 75% (v/v) alcohol, vortex and mix, and open. Inoculate 100-500 ⁇ L of bacterial solution into 10 mL/tube of BHI broth, shake well, and prepare a total of 3 tubes. At the same time, do not inoculate the bacteria as a negative control, and place it at 37°C for anaerobic culture for 2-4 days to obtain the first-level seed liquid. .
  • the first-level seed liquid undergoes Gram staining microscopy and should be G-bacillus, without spores and miscellaneous bacteria.
  • the first-level seed liquid undergoes Gram staining microscopy and should be G-bacillus, without spores and miscellaneous bacteria.
  • Survival rate number of viable bacteria at each time point/number of corresponding viable bacteria at 0 h ⁇ 100%
  • the high-fat and high-sugar feed formula (quality Percent content, wt%): 66.5% basic feed, 2.5% cholesterol, 20% sucrose, 10% lard, 1% cholate. The remaining 20 animals were fed basic feed.
  • mice After 8 weeks of feeding, 70 rats that were successfully modeled were selected based on body weight, body length, blood pressure, blood lipids, fasting blood sugar and other levels, and were randomly divided into 8 groups of 10 rats each: model group, positive drug group (Ato Vastatin calcium, Pfizer Pharmaceutical Co., Ltd., 15mg/kg), AKK bacteria AM06 live bacteria low-dose (10 6 CFU/only), high-dose (10 10 CFU/only) group, AM02 live bacteria (10 10 CFU/only) Group, AM02 live bacteria (10 10 CFU/bird) combined with atorvastatin calcium (15mg/kg) group, AKK bacteria AM06, AM02 inactivated bacteria group (10 10 cells/bird). Another 10 unmodeled rats were selected as the normal control group.
  • model group positive drug group (Ato Vastatin calcium, Pfizer Pharmaceutical Co., Ltd., 15mg/kg)
  • AKK bacteria AM06 live bacteria low-dose (10 6 CFU/only), high-dose (10 10 CFU/only) group AM02 live bacteria (10 10 CFU/
  • Administration began after grouping (D0): the normal control group and the model group were administered 1 mL of physiological saline once a day; each administration group was administered a corresponding dose of medicine once a day for 8 consecutive weeks.
  • the normal control group was fed basic feed, while the model group and each administration group were fed high-fat and high-sugar feed.
  • Lee's index weight (g) 1/3 ⁇ 1000 ⁇ body length (cm) -1 ; after the last intragastric administration, the rats were fasted and water-free.
  • SBP tail artery systolic blood pressure
  • FBG fasting blood glucose level
  • Lee’s index is an effective index in evaluating the degree of obesity in adult rats.
  • the Lee’s index of adult obese rats is significantly increased compared with normal rats.
  • the Lee’s index of each drug group decreased.
  • the positive drug and AKK bacteria AM06 groups had significant differences. This shows that AKK bacteria can effectively control the weight of rats and reduce obesity symptoms.
  • MS is a group of clinical syndromes characterized by obesity, hyperglycemia, and hypertension. Its common pathological basis is insulin resistance and hyperinsulinemia. Insulin resistance is mainly manifested by continued elevation of FBG, Fins, and HOMA-IR.
  • each administration group significantly reduced the HOMA-IR levels of rats. This shows that AKK bacteria can effectively reduce insulin resistance in rats and regulate blood sugar metabolism in rats.
  • Akkermansia muciniphila especially Akkermansia muciniphila AM06 deposited as CGMCC No. 22793 and Akkermansia muciniphila AM02 deposited as CGMCC No. 22794. Either one or a combination of the two can effectively treat metabolic syndrome in rats.

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Abstract

嗜粘蛋白阿克曼菌或含有嗜粘蛋白阿克曼菌的组合物在制备改善代谢综合征的药物组合物或保健品组合物中的应用。该嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，嗜粘蛋白阿克曼菌AM06的保藏编号为CGMCC No.22793，嗜粘蛋白阿克曼菌AM02的保藏编号为CGMCC No.22794。改善代谢综合征包括预防和/或治疗代谢综合征。

Description

嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用
相关申请
本申请要求于2022年6月8日提交的、申请号为CN2022106424717、名称为“嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用”的中国专利申请的优先权，在此将其全文引入作为参考。
技术领域
本申请涉及糖代谢综合征防治技术领域和保健食品技术领域，特别涉及嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用，还涉及含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或者在制备或作为改善代谢综合征的保健食品中的应用，还涉及含有嗜粘蛋白阿克曼菌的组合物。
背景技术
代谢综合征(Metabolic syndrome，MetS或记为MS)，也被称为X综合征、胰岛素抵抗等，代谢综合征实际上并不是一种单一的疾病，而是一组心血管疾病危险因素，不同组织对它的定义略有不同。用于调查和医疗保健计划的三个最流行的定义分别来自WHO(1999)、NCEP(2005)、IDF(2006)，此外，AACE和EGIR等组织也提出过对代谢综合征的定义。
代谢综合征的发病率通常与肥胖的发病率和2型糖尿病(MetS的结果之一)的发病率正相关。代谢综合征的流行率估计值因用于定义MetS的标准而异，但由于MetS的发病率大约是糖尿病的三倍，根据IDF糖尿病地图集，截至2015年，全球糖尿病患病率为8.8％，预计到2040年将增加到10.4％，因此全球患病率估计约为世界人口的四分之一。按照此比例进行估计，世界上现在有超过10亿人受到代谢综合征的影响。
代谢综合征的治疗包括生活方式干预和针对症状的药物治疗。生活方式干预包括饮食、锻炼等，但需要精准和个性化的方案，且由于患者个体差异，通常存在依从性问题。针对症状的药物包括降糖药、降压药、降血脂药等，这样的药物治疗存在副作用，且无法兼顾其他症状，甚至会导致其他代谢指标异常。
基于此，有必要进一步开发用于防治代谢综合征的新药物。
发明内容
基于此，本申请的发明目的包括提供嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用中的应用，还包括提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或者在制备或作为改善代谢综合征的保健食品中的应用，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06(保藏编号为CGMCC No.22793)、嗜粘蛋白阿克曼菌AM02(保藏编号为CGMCC No.22794)。
在本申请的第一方面，提供嗜粘蛋白阿克曼菌在改善代谢综合征中的应用，其中，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，
所述嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793；
所述嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794；
所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项；
可选地，所述嗜粘蛋白阿克曼菌AM06和所述嗜粘蛋白阿克曼菌AM02各自独立地为活菌、灭活菌或者其组合。
在本申请的第二方面，提供嗜粘蛋白阿克曼菌在制备改善代谢综合征的组合物中的应用，其中，所述改善代谢综合征的组合物为药物组合物或保健品组合物，也即提供嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物的应用中的应用，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，
所述嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793；
所述嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794。
在一些实施方式中，所述嗜粘蛋白阿克曼菌AM06和所述嗜粘蛋白阿克曼菌AM02各自独立地为活菌、形态结构完整的灭活菌、灭活菌或者其组合。
在一些实施方式中，所述改善代谢综合征包括预防和/或治疗代谢综合征，也即，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
在一些实施方式中，所述改善代谢综合征的组合物为药物组合物，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体；
可选地，所述药物组合物为药品或药物制剂；
可选地，所述药品或所述药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂；
可选地，所述药品或所述药物适用于人或其他哺乳动物。
在一些实施方式中，所述改善代谢综合征的组合物为保健品组合物，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料；
可选地，所述保健品组合物为保健食品；
可选地，所述保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂；
可选地，所述保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品为动物食品。
在本申请的第三方面，提供含有嗜粘蛋白阿克曼菌的组合物在改善代谢综合征中的应用，其中，所述嗜粘蛋白阿克曼菌如本申请第二方面中所定义，还可参阅下文定义；
可选地，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物或保健品组合物。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体；
可选地，所述药物组合物为药品或药物制剂；
可选地，所述药品或所述药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂；
可选地，所述药品或所述药物适用于人或其他哺乳动物。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为保健品组合物，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料；
可选地，所述保健品组合物为保健食品；
可选地，所述保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂；
可选地，所述保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品为动物食品。
在本申请的第四方面，提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或药物制剂，或者在制备或作为改善代谢综合征的保健食品中的应用，其中，所述嗜粘蛋白阿克曼菌如本申请第二方面中所定义，还可参阅下文定义。
在一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或药物制剂中的应用，其中，所述嗜粘蛋白阿克曼菌如本申请第二方面中所定义，还可参阅下文定义。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体；
可选地，所述药品或所述药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂；
可选地，所述药品或所述药物制剂适用于人或其他哺乳动物。
在另一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为改善代谢综合征的保健食品中的应用，其中，所述嗜粘蛋白阿克曼菌如本申请第二方面中所定义，还可参阅下文定义。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为保健品组合物，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料；
可选地，所述保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂；
可选地，所述保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品为动物食品。
在一些实施方式中，基于本申请中任一合适的实施方式(包括基于第三方面和第四方面中任一合适的实施方式)，所述含有嗜粘蛋白阿克曼菌的组合物为复合益生菌，所述复合益生菌还含有不同于所述嗜粘蛋白阿克曼菌的益生菌；
可选地，所述不同于所述嗜粘蛋白阿克曼菌的益生菌包括脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、弯曲乳杆菌、婴儿双歧 杆菌、长双歧杆菌和短双歧杆菌中的一种或多种。
在一些实施方式中，基于本申请中任一合适的实施方式(包括基于第三方面和第四方面中任一合适的实施方式)，所述含有嗜粘蛋白阿克曼菌的组合物还包括第二活性成分，所述第二活性成分为不同于所述嗜粘蛋白阿克曼菌的药物；
可选地，所述第二活性成分包括奥利司他、二甲双胍、噻唑烷二酮、贝特类药物、他汀类药物、钙离子拮抗剂中的一种或多种；其中，所述贝特类药物包括非诺贝特、苯扎贝特和吉非罗齐中的一种或多种；所述他汀类药物包括阿妥伐他汀、洛伐他汀、辛伐他汀、普伐他汀和氟伐他汀中的一种或多种；
进一步可选地，所述第二活性成分包括阿托伐他汀钙。
在本申请的第五方面，提供用于改善代谢综合征的嗜粘蛋白阿克曼菌，其中，所述嗜粘蛋白阿克曼菌如本申请第二方面中所定义，还可参阅下文定义。
在一些实施方式中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
在本申请的第六方面，提供用于改善代谢综合征的组合物，其中，所述用于改善代谢综合征的组合物为本申请第三方面或本申请第四方面中所定义的含有嗜粘蛋白阿克曼菌的组合物，还可参阅下文定义。
在一些实施方式中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
在本申请的第七方面，提供含有嗜粘蛋白阿克曼菌的组合物。
在一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物，其包含本申请的第二方面中定义的所述嗜粘蛋白阿克曼菌和第二活性成分；
可选地，所述第二活性成分包括奥利司他、二甲双胍、噻唑烷二酮、贝特类药物、他汀类药物、钙离子拮抗剂中的一种或多种；其中，所述贝特类药物包括非诺贝特、苯扎贝特和吉非罗齐中的一种或多种；所述他汀类药物包括阿妥伐他汀、洛伐他汀、辛伐他汀、普伐他汀和氟伐他汀中的一种或多种；
进一步可选地，所述第二活性成分包括阿托伐他汀钙。
在另一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物，其为复合益生菌，所述复合益生菌含有本申请第二方面中所述嗜粘蛋白阿克曼菌，还含有不同于所述嗜粘蛋白阿克曼菌的益生菌；
可选地，所述不同于所述嗜粘蛋白阿克曼菌的益生菌包括脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、希氏肠球菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、弯曲乳杆菌、婴儿双歧杆菌、长双歧杆菌和短双歧杆菌中的一种或多种；
进一步可选地，所述含有嗜粘蛋白阿克曼菌的组合物还包括第二活性成分，所述第二活性成分如前述所定义。
在本申请的第八方面，提供一种代谢综合征的改善方法。在一些实施方式中，提供一种代谢综合征的改善方法，其包括给予受试者嗜粘蛋白阿克曼菌，或者给予受试者含有嗜粘蛋白阿克曼菌的组合物，或者给予受试者含有嗜粘蛋白阿克曼菌的药品，或者给予受试者含有嗜粘蛋白阿克曼菌的保健食品；其中，所述嗜粘蛋白阿克曼菌如本申请第二方面中所定义。
在一些实施方式中，所述代谢综合征的改善方法包括给予受试者治疗有效量的所述嗜粘蛋白阿克曼菌，或者给予受试者治疗有效量的含有所述嗜粘蛋白阿克曼菌的药物组合物，或者给予受试者治疗有效量的含有所述嗜粘蛋白阿克曼菌的药品。
在一些实施方式中，所述代谢综合征的改善方法包括给予受试者保健有效量的所述嗜粘蛋白阿克曼菌，或者给予受试者保健有效量的含有所述嗜粘蛋白阿克曼菌的保健品组合物，或者给予受试者保健有效量的含有所述嗜粘蛋白阿克曼菌的保健食品。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物如本申请第三方面或本申请第四方面中所定义。
在一些实施方式中，所述代谢综合征的改善方法包括预防代谢综合征和治疗代谢综合征中至少一项。
本申请的发明人经分离得到了菌株AM06(保藏号CGMCC No.22793)和AM02(保藏号CGMCC No.22794)，根据16S rRNA分析、形态分析、代谢物成分分析、功效分析(如人工胃液和人工肠液的耐受性，抑制炎症因子破坏肠细胞的紧密连接蛋白的能力，抑制LPS诱导肝切片肝炎的作用)等综合分析，两者均属于嗜粘蛋白阿克曼菌，而且鉴定为不同于ATCC BAA-835(标准菌株)等嗜粘蛋白阿克曼菌的新菌种。
发明人发现，上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02(这里的“AM06和/或AM02”表示AM06、AM02或者AM06与AM02的组合)可用于改善代谢综合征，包括用于防治 (预防和/或治疗，即预防和治疗中至少一项)代谢综合征。因此，上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02可用于制备药物组合物或者制备保健品组合物，进一步可制备药品或保健食品。上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02，能够减轻大鼠肥胖程度和胰岛素抵抗，调节血压，改善血糖、血脂代谢，有效防治代谢综合征。
附图说明
为了更清楚地说明本申请实施例中的技术方案、更完整地理解本申请及其有益效果，下面将对实施例描述中所需要使用的附图作简单的介绍。显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对本领域技术人员来说，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本申请一实施例中培养得到的嗜粘蛋白阿克曼菌AM02的菌落特征图；
图2为本申请一实施例中得到的嗜粘蛋白阿克曼菌AM06的菌落特征图；
图3为本申请一实施例中培养得到的嗜粘蛋白阿克曼菌AM02进行革兰氏染色后的显微镜观察图；
图4为本申请一实施例中培养得到的嗜粘蛋白阿克曼菌AM06进行革兰氏染色后的显微镜观察图；
图5为本申请一实施例中几种嗜粘蛋白阿克曼菌培养上清代谢物PCA分析图；
图6为本申请一实施例中几种嗜粘蛋白阿克曼菌对TNF-α和IFN-γ诱导Caco2细胞紧密连接蛋白ZO-1表达降低的影响的荧光显微镜拍摄图。
本申请中分离得到的嗜粘蛋白阿克曼菌AM06，其分类命名为Akkermansia muciniphila，已于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，地址：北京市朝阳区北辰西路1号院3号，保藏编号为CGMCC No.22793；该菌株于2021年06月28日由保藏中心收到并登记入册，经保藏中心于2021年06月28日检测为存活菌株。
本申请中分离得到的嗜粘蛋白阿克曼菌AM02，其分类命名为Akkermansia muciniphila，已于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，地址：北京市朝阳区北辰西路1号院3号，保藏编号为CGMCC No.22794；该菌株于2021年06月28日由保藏中心收到并登记入册，经保藏中心于2021年06月28日检测为存活菌株。
具体实施方式
下面结合附图、实施方式和实施例，对本申请作进一步详细的说明。应理解，这些实施方式和实施例仅用于说明本申请而不用于限制本申请的范围，提供这些实施方式和实施例的目的是使对本申请公开内容理解更加透彻全面。还应理解，本申请可以以许多不同的形式来实现，并不限于本文所描述的实施方式和实施例，本领域技术人员可以在不违背本申请内涵的情况下作各种改动或修改，得到的等价形式同样落于本申请的保护范围。此外，在下文的描述中，给出了大量的细节以便提供对本申请更为充分地理解，应理解，本申请可以无需一个或多个这些细节而得以实施。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述实施方式和实施例的目的，不是旨在于限制本申请。
术语
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：
本申请所使用的术语“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列项目中任一个项目，也包括相关所列项目的任意的和所有的组合，所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明的是，当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时，应当理解，在本申请中，该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案，还毫无疑问地包括均用“逻辑或”连接的技术方案。比如，“A及/或B”包括A、B和“A与B的组合”三种并列方案。又比如，“A，及/或，B，及/或，C，及/或，D”的技术方案，包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案)，也包括A、B、C、D的任意的和所有的组合，也即包括A、B、C、D中任两项或任三项的组合，还包括A、B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。
本申请中涉及“多个”、“多种”、“多次”、“多项”等，如无特别限定，指在数量上大于2或等于2。例如，“一种或多种”表示一种或大于等于两种。
本申请中所使用的“其组合”、“其任意组合”、“其任意组合方式”等中包括所列项目中任两个或任两个以上项目的所有合适的组合方式。
在本申请中，如无其他说明，“一种或多种”表示所列项目中的任一种或者所列项目的任意组合。类似地，“一个或多个”等以其他方式表示“一或多”的情形，如无其他说明，也做相同理解。
本申请中，“合适的组合方式”、“合适的方式”、“任意合适的方式”、“任意合适的组合”等中所述“合适”，以能够实施本申请的技术方案、解决本申请的技术问题、实现本申请预期的技术效果为准。
本申请中，“优选”、“更好”、“更佳”、“为宜”仅为描述效果更好的实施方式或实施例，应当理解，并不构成对本申请保护范围的限制，并不应理解为对前一技术方案的限定，而用来表示在前与在后的不同技术方案在涵盖内容上存在关联。如果一个技术方案中出现多处“优选”，如无特别说明，且无矛盾之处或相互制约关系，则每项“优选”各自独立。
本申请中，“进一步”、“更进一步”、“特别”、“例如”、“如”、“示例”、“举例”等用于描述目的，表示内容上的差异，但并不应理解为对本申请保护范围的限制。在本发明中，如无其他说明，A(如B)，表示B为A中的一种非限制性示例，可以理解A不限于为B。
本申请中，“可选地”、“可选的”、“可选”，指可有可无，也即指选自“有”或“无”两种并列方案中的任一种。如果一个技术方案中出现多处“可选”，如无特别说明，且无矛盾之处或相互制约关系，则每项“可选”各自独立。
本申请中，“第一方面”、“第二方面”、“第三方面”、“第四方面”、“第五方面”、“第六方面”、“第七方面”等中，术语“第一”、“第二”、“第三”、“第四”、“第五”、“第六”、“第七”等仅用于描述目的，不能理解为指示或暗示相对重要性或数量，也不能理解为隐含指明所指示的技术特征的重要性或数量。而且“第一”、“第二”、“第三”等仅起到非穷举式的列举描述目的，应当理解并不构成对数量的封闭式限定。
本申请中，以开放式描述的技术特征中，包括所列举特征组成的封闭式技术方案，也包括包含所列举特征的开放式技术方案。
本发明中所使用的术语“含有”、“包含”和“包括”是同义词，其是包容性或开放式的，不排除额外的、未被引述的成员或时序特征。成员例如材料或组分、结构、元件、仪器等；时序特征的非限制性性举例如动作、动作发生的条件、时机、状态等。
本申请中，涉及到数值区间(也即数值范围)，如无特别说明，该数值区间内可选的数值的分布视为连续，且包括该数值区间的两个数值端点(即最小值及最大值)，以及这两个数值端点之间的每一个数值。如无特别说明，当数值区间仅仅指向该数值区间内的整数时，包括该数值范围的两个端点整数，以及两个端点之间的每一个整数，相当于直接列举了每一个整数。当提供多个数值范围描述特征或特性时，可以合并这些数值范围。换言之，除非另有指明，否则本申请中所公开之数值范围应理解为包括其中所归入的任何及所有的子范围。该数值区间中的“数值”可以为任意的定量值，比如数字、百分比、比例等。“数值区间”允许广义地包括百分比区间、比例区间、比值区间等定量区间。
本申请中的温度参数，如无特别限定，既允许为恒温处理，也允许在一定温度区间内存在变动。应当理解的是，所述的恒温处理允许温度在仪器控制的精度范围内进行波动。允许在如±5℃、±4℃、±3℃、±2℃、±1℃的范围内波动。
本申请中，术语“室温”一般指4℃～35℃，较佳地指20℃±5℃。在本申请的一些实施例中，室温是指20℃～30℃。
在本申请中，涉及数据范围的单位，如果仅在右端点后带有单位，则表示左端点和右端点的单位是相同的。比如，3～5h表示左端点“3”和右端点“5”的单位都是h(小时)。
在本申请提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。除非和本申请的发明目的和/或技术方案相冲突，否则，本申请涉及的引用文献以全部内容、全部目的被引用。本申请中涉及引用文献时，相关技术特征、术语、名词、短语等在引用文献中的定义也一并被引用。本申请中涉及引用文献时，被引用的相关技术特征的举例、优选方式及可选方式也可作为参考纳入本申请中，但以能够实施本申请为限。应当理解，当引用内容与本申请中的描述相冲突时，以本申请为准或者适应性地根据本申请的描述进行修正。
在本申请中，涉及“在本申请中任一方面的一些实施方式中”、任一方面中记载的“在一些实施方式中”、任一方面中记载的“在一些实施例中”，如无其他说明，除非存在矛盾或冲突，否则，前述实施方式或实施例中描述的特征可以结合于本申请中任一方面中可结合的方面，不局限于同一方面中的记载的其他技术方案，前述实施方式或实施例中描述的特征也可以结合于另一方面中的技术方案。
在本申请中，记载于任意位置的“术语”描述，除非另有说明，否则适用于本申请的上下文。 例如本申请第二方面中记载的“组合物”、“药物”、“药物组合物”、“药品”、“药学上可接受的”、“药学上可接受的载体”、“载体”、“保健品”、“保健食品”、“保健品组合物”、“食品”、“改善代谢综合征的保健品组合物”、“可食用原辅料”、“治疗有效量”、“受试者”、“患者”、“其他药物活性成分”等术语的相关描述。还如本申请第四方面中记载的“第二活性成分”、“本申请所述嗜粘蛋白阿克曼菌的改造菌”、“复合益生菌”、“第二药物活性成分”、“含有嗜粘蛋白阿克曼菌的组合物”、“其他药物活性成分”等术语的相关描述。
在本发明中，方法流程中涉及多个步骤的，除非本文中有明确的不同说明，这些步骤的执行并没有严格的顺序限制，其可以以描述以外的其他顺序执行。而且，任一个步骤可以包括多个子步骤或者多个阶段，这些子步骤或者阶段并不必然是在同一时刻执行完成，而是可以在不同的时刻执行，其执行顺序也不必然是依次进行，而是可以与其他步骤或者其他步骤的子步骤或者阶段的一部分轮流或者交替或者同时地执行。
本申请的发明人经分离得到了菌株AM06(保藏号CGMCC No.22793)和AM02(保藏号CGMCC No.22794)，根据16S rRNA分析、形态分析、代谢物成分分析、功效分析(如人工胃液和人工肠液的耐受性，抑制炎症因子破坏肠细胞的紧密连接蛋白的能力，抑制LPS诱导肝切片肝炎的作用)等综合分析，两者均属于嗜粘蛋白阿克曼菌，而且鉴定为不同于ATCC BAA-835(标准菌株)等嗜粘蛋白阿克曼菌的新菌种。
发明人发现，上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02(这里的“AM06和/或AM02”表示AM06、AM02或者AM06与AM02的组合)可用于改善代谢综合征，包括用于防治(预防和/或治疗，即预防和治疗中至少一项)代谢综合征。因此，上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02可用于制备药物组合物或者制备保健品组合物，进一步可制备药品或保健食品。上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02，能够减轻大鼠肥胖程度和胰岛素抵抗，调节血压，改善血糖、血脂代谢，有效防治代谢综合征。
在本申请中，“改善代谢综合征”指针对代谢综合征提供生理和/或药理上的有益作用。“改善代谢综合征”包括但不限于预防和/或治疗代谢综合征，也即，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
在本申请中，“嗜粘蛋白阿克曼菌”与本领域的通常定义一致，包括但不限于嗜粘蛋白阿克曼菌AM06和AM02。
在本申请中，“嗜粘蛋白阿克曼菌”可以是活菌体，也可以经过灭活、基因重组、改造或修饰、减毒、化学处理、物理处理的全部或部分保留原生物活性的嗜黏蛋白阿克曼菌，还可以是菌体的裂解物、培养物(例如上清液)或者从上培养物中提取到的成分。
本申请的发明人经分离得到了菌株AM06(保藏号CGMCC No.22793)和AM02(保藏号CGMCC No.22794)，根据16S rRNA分析、形态分析、代谢物成分分析、功效分析(如人工胃液和人工肠液的耐受性，抑制炎症因子破坏肠细胞的紧密连接蛋白的能力，抑制LPS诱导肝切片肝炎的作用)等综合分析，两者均属于嗜粘蛋白阿克曼菌，而且鉴定为不同于ATCC BAA-835(标准菌株)等嗜粘蛋白阿克曼菌的新菌种。
嗜黏蛋白阿克曼菌(Akkermansia muciniphila，A.muciniphila〉隶属疣微菌门(Verucomicrobia)，阿克曼菌科(Akkermansiaceae)，阿克曼菌属(Akkermansia)。嗜黏蛋白阿克曼菌是一种黏蛋白降解菌(也记为AKK或AKK菌)，为厌氧、无动力、无芽孢的卵圆形革兰氏阴性菌，适合在20～40℃和pH5.5～8.0条件下生长(最适温度37℃，最适pH6.5)，普遍存在于人体肠道内，虽然属于厌氧菌，但也能够耐受一定程度的氧。嗜粘蛋白阿克曼菌可通过降解和利用粘蛋白作为能源，在粘液层和结肠中定植，进一步地，还可通过黏蛋白降解产生短链脂肪酸(SCFA)，这些短链脂肪酸(包括乙酸盐、丙酸盐和丁酸盐)的生产对人类健康具有重要作用。
在本申请中，“本申请所述嗜粘蛋白阿克曼菌”特指嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合，可以记为“AM06和/或AM02”。在本申请中，“AM06和/或AM02”还可以描述为AM06、AM02或AM06与AM02的组合。
嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793，可通过实施例1的方法分离得到，还可通过包括但不限于实施例2至实施例5中的一种或多种方法进行菌种鉴定。
在本申请的一些实施例中，嗜粘蛋白阿克曼菌AM06的菌落培养特征包括：圆形凸起、边缘整齐、不透明、白色、大小不均一的菌落，进一步地，菌落大小约为0.08～2.2mm。
在本申请的一些实施例中，嗜黏蛋白阿克曼菌AM06分离自母乳。
嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794，可通过实施例1的方法分离得到，还可通过包括但不 限于实施例2至实施例5中的一种或多种方法进行菌种鉴定。
在本申请的一些实施例中，CGMCC No.22794的嗜粘蛋白阿克曼菌AM02的菌落培养特征包括：圆形凸起、边缘整齐、不透明、白色、大小不均一的菌落，进一步地，菌落大小约为0.08～2.2mm。
在本申请的一些实施例中，申请人还进行了人工胃液、人工肠液的耐受性考察。其中，人工胃液耐受性考察中，对0.9wt％的NaCl溶液组、pH3人工胃液组和pH2人工胃液组不同组别37±2℃，厌氧孵育0h、1.5h和3h后的活菌数进行统计分析，结果表明，嗜粘蛋白阿克曼菌株的人工胃液耐受性依次为AM02＞AM06＞标准株ATCC BAA-835。其中，人工肠液耐受性考察实验中，对37±2℃厌氧孵育0h、4h、8h后的活菌数进行统计分析，人工肠液耐受性优于AM06>AM02>ATCC BAA-835。
在本申请的一些体外实验中，嗜粘蛋白阿克曼菌AM06和AM02，对人工胃液和人工肠液的耐受性，抑制炎症因子破坏肠细胞的紧密连接蛋白的能力，抑制LPS诱导肝切片肝炎的作用均优于标准株BAA-835。
在本申请中任一方面的一些实施例中，嗜粘蛋白阿克曼菌AM06和AM02各自独立地可以是活菌体，也可以是经过灭活处理的嗜黏蛋白阿克曼菌(即灭活菌，可以为全部或部分地灭活)，还可以是菌体的裂解物、培养物(例如上清液)或者从上培养物中提取到的成分。
在本申请中任一方面的一些实施方式中，嗜粘蛋白阿克曼菌AM06和嗜粘蛋白阿克曼菌AM02各自独立地为活菌、灭活菌或者其组合(即活菌和灭活菌的组合)。灭活菌可以为形态结构完整的灭活菌、形态结构不完整的灭活菌或者其组合。
在本申请中任一方面的一些实施方式中，嗜粘蛋白阿克曼菌AM06和嗜粘蛋白阿克曼菌AM02各自独立地为活菌、形态结构完整的灭活菌、形态结构不完整的灭活菌中的一种或多种。
在本申请中任一方面的一些实施方式中，本申请所述嗜黏蛋白阿克曼菌选自嗜黏蛋白阿克曼菌活菌体。
在本申请中任一方面的一些实施方式中，本申请所述嗜黏蛋白阿克曼菌选自嗜黏蛋白阿克曼菌灭活菌。
在本申请中，“形态结构完整”可以包括但不限于经过灭活处理而被全部或部分地灭活的嗜黏蛋白阿克曼菌。
在本申请中，“形态结构不完整”的情况可以包括但不限于菌体的裂解物、培养物(例如上清液)或者从上培养物中提取到的成分等。
本申请的第一方面
提供嗜粘蛋白阿克曼菌在改善代谢综合征中的应用，也即提供将嗜粘蛋白阿克曼菌应用于改善代谢综合征的方法，其中，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，
嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793；
嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794。
在一些实施方式中，改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
在一些实施方式中，嗜粘蛋白阿克曼菌AM06和嗜粘蛋白阿克曼菌AM02各自独立地为活菌、灭活菌或者其组合。
本申请的第二方面
在本申请的第二方面，提供嗜粘蛋白阿克曼菌在制备改善代谢综合征的组合物中的应用，其中，所述改善代谢综合征的组合物为药物组合物或保健品组合物，也即提供嗜粘蛋白阿克曼菌在制备改善代谢综合征(包括防治代谢综合征)的药物组合物或保健品组合物中的应用，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，
所述嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793；
所述嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794。
发明人经大量实验发现，上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02(这里的“AM06和/或AM02”表示AM06、AM02或者AM06与AM02的组合)可用于改善代谢综合征，包括可用于防治(预防和/或治疗，即预防和治疗中的至少一项)代谢综合征。上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02可用于制备药物组合物或者制备保健品组合物，进一步可制备药品或保健食品。上述分离得到的嗜粘蛋白阿克曼菌AM06和/或AM02，能够减轻大鼠肥胖程度和胰岛 素抵抗，调节血压，改善血糖、血脂代谢，有效防治代谢综合征。推测嗜粘蛋白阿克曼菌AM06和/或AM02作为生物体代谢的促进剂。
在一些实施方式中，所述嗜粘蛋白阿克曼菌AM06和所述嗜粘蛋白阿克曼菌AM02各自独立地为活菌、形态结构完整的灭活菌、灭活菌或者其组合。
如前所定义，“改善代谢综合征”指针对代谢综合征提供生理和/或药理上的有益作用。“改善代谢综合征”包括但不限于预防和/或治疗代谢综合征，也即，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
在一些实施方式中，所述改善代谢综合征的组合物为药物组合物。进一步地，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体。
在一些实施方式中，所述药物组合物为药品或药物制剂。所述药品或所述药物制剂的剂型可以为但不限于片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂。非限制性地，所述药品或所述药物可以适用于人或其他哺乳动物。
在一些实施方式中，所述改善代谢综合征的组合物为保健品组合物。进一步地，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料。
在一些实施方式中，所述保健品组合物为保健食品。所述保健食品的剂型可以为但不限于丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂。非限制性地，所述保健食品可以包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品可以为动物食品。
用于制备药物组合物
在本申请中，“防治”与“预防和/或治疗”具有相同含义，可以互换使用。在本申请中，“防治”包括预防、治疗(含辅助治疗)等方面。如本申请所用，“防治”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症。“防治”还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。其中，如本申请所用，“治疗”是指减轻、延缓进展、衰减，或维持现有疾病或病症，治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。在本申请中，“预防和/或治疗”也可描述为预防和治疗中至少一项。
在本申请中，“组合物”可以为多种物质的组合，进一步地，可以为组合使用，也可以为组合而成的混合物。
在本申请中，“药物”包括在体内或体外提供药理作用的任何药剂、化合物、组合物或混合物，且往往提供的是有益效果。“药物”在体内产生药理作用的范围没有特别限制，可以为全身效果，也可以只在局部产生效果。所述“药物”的活性没有特别限制，可以为能与其它物质发生相互作用的活性物质，也可以为不发生相互作用的惰性物质。
在本申请中，“药物组合物”指具有防治疾病或病症作用、可作为药品使用或者可用于制备药品的组合物。
在本申请中，“药品”指可直接施用的药物制剂，其通常具有规定的用法和用量。
在一些实施例中，向受试者(如人、大鼠、小鼠)给予嗜粘蛋白阿克曼菌AM06或嗜粘蛋白阿克曼菌AM02后，在如下的一个或多个方面有所改善：体质量、Lee’s指数、空腹血糖(FBG)、血清胰岛素(Fins)、胰岛素抵抗指数(HOMA-IR)、尾动脉收缩压、血清脂质指标(包括TC、TG、LDL-c和HDL-c)；可参考实施例6。在一些实施例中，Lee’s指数均有所下降。在一些实施例中，均下调了大鼠的HOMA-IR。在一些实施例中，均下调了血压。在一些实施例中，血清TC、TG、LDL-c水平均有所下降。在一些实施例中，血清HDL-c水平均有所上升。
在一些实施方式中，药物组合物包括本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)以及药学上可接受的载体。
在本申请中，“药学上可接受的”指在合理医学判断范围内适于施用患者且与合理益处/风险比相称的那些配体、材料、组合物和剂型中任一种或者任意合适的组合。
在本申请中，“药学上可接受的载体”指药学上可接受的材料、组合物或媒剂，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。如本申请所用，短语“药学上可接受的载体”包括与药物施用相容的缓冲剂、注射用无菌水、溶剂、分散介质、包衣、抗细菌剂及抗真菌剂、等渗剂及吸收延迟剂及诸如此类。在与配制物中其他成分兼容且对患者无害的意义上，每种载体必须为“药学上可接受的”。合适的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉、马铃薯淀粉及经取代或未经取代的β-环糊精；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯 类，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液；(19)乙醇；(20)磷酸盐缓冲液；及(21)药物配制物中所采用的其他无毒兼容物质。
本申请中，“载体”包括但不限于甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、乙二胺四乙酸二钠(EDTA二钠)、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、低聚果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、糊精(如麦芽糊精)、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁。
在一些实施方式中，药物组合物还可以包括其他药物活性成分。“其他药物活性成分”可以为具有代谢综合征防治作用的药物成分，也可以为具有其他疾病防治效果的药物成分。
在一些实施方式中，其他药物活性成分可以从已有的防治代谢综合征的药物中进行合适的选择。
用于制备保健品组合物
在本申请中，“保健品”与“保健食品”具有相同含义，可互换使用。在本申请中，“保健品”指具有保健功能的食品，其能够调节动物体(人或其它动物)生理机能，且往往提供的是有益效果。“保健品”在体内产生有益作用的范围没有特别限制，可以为全身效果，也可以只在局部产生效果。
在本申请中，“保健品组合物”指具有保健功能的食品组合物。保健品组合物可以作为保健品直接被食用，也可以作为膳食添加剂而被食用。
在本申请中，“食品”指可直接食用的制品。“食品组合物”指由可食用物质组成的组合物。应当理解，本申请中的食品组合物除可以包含前述的嗜粘蛋白阿克曼菌外，还允许包含任意合适的其他可食用物质。在一些实施例中，其他可食用物质可选自食品管理规范中允许添加的物质，进一步地，不包含食品管理规范中禁止添加的物质。如无特别限定，食品管理规范指生产时的现行规范。
在本申请中，“改善代谢综合征的保健品组合物”中的“改善代谢综合征”的定义与上述一致。
在一些实施方式中，保健品组合物包括本申请所述嗜粘蛋白阿克曼菌和可食用原辅料。
在本申请中，“可食用原辅料”指可食用原料、可食用辅料或者两者的组合。其中，“可食用原料”指能够单独提供保健功能的可食用物质，但不是AM06和AM02；“可食用辅料”指不具有单独提供保健功能的可食用物质。应当理解，“可食用原辅料”可以选自保健品管理规范中允许添加的物质，进一步地，不包含保健品管理规范中禁止添加的物质。如无特别限定，保健品管理规范指生产时的现行规范。
在一些实施方式中，食品组合物包括本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)以及可食用辅料。在本申请中，食品添加剂也属于可食用辅料。可食用辅料的举例如食糖，果糖，蜂蜜，葡萄糖，淀粉，维生素，有益微量元素和中量元素(如钙粉)，大豆粉，绿豆粉，麦芽糊精，奶粉，蔬菜汁，水果汁，香料、香精等。本申请的可食用辅料可以单一或复合地使用。
在一些实施方式中，保健品组合物由本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)和可食用辅料组成。
在一些实施方式中，保健品组合物还可以含有其它保健成分，其它保健成分是不同于AM06和AM02的保健成分，其保健功能可以为有益性地改善代谢综合征，也可以为其他的保健功能。
在一些实施方式中，保健品组合物还含有其他益生菌。其他益生菌可以选自本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)的改造菌以及其他种属的益生菌。其他种属的益生菌的可以包括脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、希氏肠球菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、弯曲乳杆菌、婴儿双歧杆菌、长双歧杆菌、短双歧杆菌等中的一种或多种。
在一些实施方式中，保健品组合物还含有其他种属的益生菌。
制剂类型
在一些实施方式中，药物组合物为药品或药物制剂。
在本申请中，“药品”指可直接施用的药物制剂，其通常具有规定的用法和用量，与前述定义一致。
在一些实施方式中，“药物制剂”可以为液体制剂或固体制剂。液体制剂指含有液相的制剂， 非限制性举例如溶液剂、混悬剂、乳剂等。固体制剂的非限制性举例如片剂、胶囊剂、颗粒剂、丸剂等。
在一些实施方式中，根据施用方式的不同，药物制剂可以为口服剂、注射剂、滴剂、贴剂、管饲制剂等。
在一些实施方式中，药品或药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂。
应当理解，药品中含有治疗有效量的本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)。可以通过单剂量或多剂量给药实现治疗有效量。以片剂为例，“一剂量”可以包括一片或多片。
在本申请中，“治疗有效量”是指针对疾病、病症和相关症状中至少一项，将引起个体的生物学或医学响应的药物活性成分的量，例如为个体带来药理上积极效果的本申请嗜粘蛋白阿克曼菌的量，所述药理上积极效果包括但不限于降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等。
在一些实施方式中，保健品组合物为保健食品。
在一些实施方式中，保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂。进一步地，非限制性的举例如蜜丸、水蜜丸、水丸、糖浆、糖浆剂等。
应当理解，保健食品中含有保健有效量的本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)。此处的“保健有效量”指能够有益性改善代谢综合征的量，在正常的保健食品的食用剂量时能够发挥有益性作用。
本申请中，“受试者”指服用药物组合物的患者或食用保健品组合物的食用者。
本申请中，“受试者”是动物，可以优选为哺乳动物，进一步可以优选地为人，受试者包括但不限于保健品的食用者和具有疾病、病症和相关症状中至少一项的患者。本申请中的受试者优选为哺乳动物。术语“哺乳动物”主要是指温血脊椎类哺乳动物，包括但不限于：如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠(如大鼠、小鼠)、猪、牛、羊、马、人等，可以优选灵长类动物，进一步可以优选为人。
在一些实施方式中，受试者为哺乳动物。
在一些实施方式中，受试者为人或其他哺乳动物。受试者为其他哺乳动物时，药品也可称为“动物用药”，保健食品可称为“动物食品”(如动物饲料)。
在一些实施方式中，药物组合物和保健品组合物各自独立地适用于人或其他哺乳动物。本申请中，“其他哺乳动物”不为人，“其他哺乳动物”的非限制性举例如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠(如大鼠、小鼠)、猪、牛、羊、马等，进一步如小鼠或大鼠；“其他哺乳动物”的非限制性举例还如灵长类动物。
在一些实施方式中，受试者为人或者大鼠。
本申请中，“患者”是指一种动物，可以优选为哺乳动物，如人，又如大鼠。
受试者的不同可能会导致前述药物组合物或保健品组合物中的其他成分的选择范围不同。
本申请的第三方面
在本申请的第三方面，提供含有嗜粘蛋白阿克曼菌的组合物在改善代谢综合征中的应用，其中，所述嗜粘蛋白阿克曼菌如前文所定义，可参考本申请第二方面中所定义，还可参阅下文定义。
如前文所描述，所述含有嗜粘蛋白阿克曼菌的组合物可以为药物组合物或保健品组合物。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物，进一步地，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体。非限制性地，所述药物组合物可以为药品或药物制剂。所述药品或所述药物制剂的剂型可以为但不限于片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂。所述药品或所述药物可以适用于人或其他哺乳动物。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为保健品组合物，进一步地，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料。非限制性地，所述保健品组合物可以为保健食品。所述保健食品的剂型可以为但不限于丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂。所述保健食品可以包括但不限于奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品可以为动物食品。
本申请的第四方面
在本申请的第四方面，提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或药物制剂，或者在制备或作为改善代谢综合征的保健食品中的应用，所述嗜粘蛋白阿克曼菌的定义可参考前文定义。
进一步地，本申请所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06(保藏编号为CGMCC No. 22793)、嗜粘蛋白阿克曼菌AM02(保藏编号为CGMCC No.22794)或者两者的组合。
在一些实施方式中，含有嗜粘蛋白阿克曼菌的组合物为药物组合物或保健品组合物。
在本申请的第四方面，“组合物”、“防治”、“代谢综合征”、“改善代谢综合征”、“防治代谢综合征”、“药物组合物”、“保健品组合物”、“药品”、“药物制剂”、“保健食品的定义可参考本申请的前文(不限于第二方面)。“药品”、“药物制剂”、“保健食品”的定义还可参考本申请第八方面。
在一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或药物制剂中的应用，其中，所述嗜粘蛋白阿克曼菌的定义与上述一致。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物，进一步地，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体。所述药品或所述药物制剂的剂型可以为但不限于片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂。所述药品或所述药物制剂可以适用于人或其他哺乳动物。
在另一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物在制备或作为改善代谢综合征的保健食品中的应用，其中，所述嗜粘蛋白阿克曼菌的定义与上述一致。
在一些实施方式中，所述含有嗜粘蛋白阿克曼菌的组合物为保健品组合物，进一步地，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料。所述保健食品的剂型可以为但不限于丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂。
在一些实施方式中，保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种。
在一些实施方式中，保健食品为奶粉、干酪、凝乳、酸奶酪、冰激凌或发酵谷类食品，或者为动物食品。
本申请所述嗜粘蛋白阿克曼菌可以是活菌体，也可以是经过灭活处理的嗜黏蛋白阿克曼菌(即灭活菌，可以为全部或部分地灭活)，还可以是菌体的裂解物、培养物(例如上清液)或者从上培养物中提取到的成分。
在一些实施方式中，含有嗜粘蛋白阿克曼菌的组合物还包括第二活性成分。
在本申请中，“第二活性成分”指除本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)之外，其他具有代谢综合改善作用的活性成分。
在一些实施方式中，第二活性成分可以为本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)的改造菌。改造方式包括但不限于基因编辑、化学处理、物理处理等方式。经改造后的嗜粘蛋白阿克曼菌形成不同于AM06和AM02的新菌种。该改造菌可以仍具有改善酒代谢综合征的功能，还可以被赋予其他的药理和生理上至少一方面的新功能。
在一些实施方式中，“本申请所述嗜粘蛋白阿克曼菌的改造菌”可以是活菌体，也可以是经过灭活处理的嗜黏蛋白阿克曼菌(即灭活菌，可以为全部或部分地灭活)，还可以是菌体的裂解物、培养物(例如上清液)或者从上培养物中提取到的成分。
在一些实施方式中，基于本申请中任一合适的实施方式(包括基于第三、四、六、七、八方面中任一合适的实施方式)含有嗜粘蛋白阿克曼菌的组合物为复合益生菌，此时，该组合物除含有本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)外，还含有不同于本申请所述嗜粘蛋白阿克曼菌的其他益生菌。
在本申请中，“复合益生菌”含有至少两种益生菌。应当理解，“含有嗜粘蛋白阿克曼菌的复合益生菌”包括本申请所述嗜粘蛋白阿克曼菌，还包括不同于本申请所述嗜粘蛋白阿克曼菌的其他益生菌。
在一些实施例中，其他益生菌(不同于本申请所述嗜粘蛋白阿克曼菌)可以包括本申请所述嗜粘蛋白阿克曼菌的改造菌以及其他种属的益生菌。其他种属的益生菌为不同于嗜粘蛋白阿克曼菌的益生菌，包括酵母菌属(Saccharomyces spp.)、乳酸杆菌属(Lactobacillus spp.)及人肠道正常菌群的益生菌或微生物中的一种或多种。所述酵母菌属的益生菌可包括布拉氏酵母(Saccharomyces boulardii)和酿酒酵母(Saccharomyces cerevisiae)中的一种或多种。
在一些实施例中，不同于嗜粘蛋白阿克曼菌的益生菌可选自乳杆菌、双歧杆菌、脆弱拟杆菌、克里斯特森氏菌、希氏肠球菌、布拉氏酵母菌中的一种或多种。
在一些实施方式中，不同于嗜粘蛋白阿克曼菌的益生菌可选自脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、希氏肠球菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌(如植物乳杆菌KY1032)、弯曲乳杆菌(如弯曲乳杆菌HY7601)、婴儿双歧杆菌、长双歧杆菌和短双歧杆菌中的一种或多种。
据报道，在大多数人类和动物研究中，乳杆菌和双歧杆菌的一些特定菌株显示出一致的抗致 肥胖特性，包括干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、婴儿双歧杆菌、长双歧杆菌和短双歧杆菌。另有文献报道，产生共轭亚油酸(CLA)的鼠李糖乳杆菌具有抗肥胖作用，在一项为期8周的益生菌喂养研究过程中，该菌株在不改变能量摄入的情况下显着降低了小鼠的体重和白色脂肪组织。另有文献报道，用由弯曲乳杆菌HY7601和植物乳杆菌KY1032组成的益生菌处理的小鼠显示体重增加和脂肪堆积减少，以及血浆胰岛素、瘦素、总胆固醇和肝毒性生物标志物降低；在这项研究中，研究人员还观察到在接受益生菌治疗的小鼠的肝脏中脂肪酸氧化相关基因的上调，同时脂肪组织中促炎基因下调。
在一些实施例中，复合益生菌包括多种嗜粘蛋白阿克曼菌。
在一些实施例中，复合益生菌由嗜粘蛋白阿克曼AM06和AM02中至少一种，以及AM06的改造菌和AM02的改造菌中至少一种组成。
在一些实施例中，复合益生菌包括本申请所述嗜粘蛋白阿克曼菌，还包括其他种属的益生菌。其他种属的益生菌的定义如上。进一步还包括本申请所述嗜粘蛋白阿克曼菌的改造菌。
含有嗜粘蛋白阿克曼菌的组合物用于制备药品或药物制剂时，是一种药物组合物，其中的药物活性成分包括嗜粘蛋白阿克曼菌AM06和嗜粘蛋白阿克曼菌AM02中至少一种。
第二活性成分可以为不同于所述嗜粘蛋白阿克曼菌的药物。
所述药物包括减轻体重，减轻胰岛素抵抗，良好控制血糖，改善脂代谢紊乱，控制血压等方面的治疗药物。
在一些实施方式中，基于本申请中任一合适的实施方式(包括基于第三、四、六、七、八方面中任一合适的实施方式)含有嗜粘蛋白阿克曼菌的组合物还包括第二药物活性成分。
在一些实施方式中，所述第二药物活性成分包括但不限于奥利司他、二甲双胍、噻唑烷二酮、贝特类(如非诺贝特、苯扎贝特、吉非罗齐等中的一种或多种)、他汀类(如阿妥伐他汀、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀等中的一种或多种)、钙离子拮抗剂等中的一种或多种。
在本申请中，“第二药物活性成分”指除本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)之外，其他具有代谢综合征防治作用的药物活性成分。
在一些实施方式中，含有嗜粘蛋白阿克曼菌的组合物还包括第二药物活性成分。
在本申请中，“第二药物活性成分”指除本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)之外，其他具有代谢综合防治作用的药物活性成分。“第二药物活性成分”包括于“第二活性成分”范围内。
在一些实施例中，第二活性成分为阿托伐他汀钙。
在本申请中，“含有嗜粘蛋白阿克曼菌的组合物”中的各成分可以以任意合适的时机出现。比如，可以直接配制成混合物打开即用，也可以单独包装而在使用时再配制成混合物，还可以分别给予受试者而在体内的局部位置同时出现并发挥组合作用。“含有嗜粘蛋白阿克曼菌的组合物”还含有其他药物活性成分时，本申请所述嗜粘蛋白阿克曼菌(AM06和/或AM02)与其他药物活性成分的组合同样可以以任意合适的时机出现；其中“其他药物活性成分”的定义可参考本申请的第二方面。以任意合适的时机出现的“含有嗜粘蛋白阿克曼菌的组合物”均在本申请的保护范围之内。
本申请的第五方面
在本申请的第五方面，提供用于改善代谢综合征的嗜粘蛋白阿克曼菌，其中，所述嗜粘蛋白阿克曼菌如前文所定义，还可参阅下文定义。
在一些实施方式中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
本申请的第六方面
在本申请的第六方面，提供用于改善代谢综合征的组合物，其中，所述用于改善代谢综合征的组合物为前文所定义的含有嗜粘蛋白阿克曼菌的组合物，还可参阅下文定义。
在一些实施方式中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
本申请的第七方面
在本申请的第七方面，提供含有嗜粘蛋白阿克曼菌的组合物；
其中，“含有嗜粘蛋白阿克曼菌的组合物”的定义可参考本申请的前文，包括但不限于第二方面和第四方面。
在一些实施例中，本方面的含有嗜粘蛋白阿克曼菌的组合物包含本申请所述嗜粘蛋白阿克曼菌和第二活性成分。“第二活性成分”的定义可参考本申请的第四方面。
在一些实施方式中，第二活性成分包括奥利司他、二甲双胍、噻唑烷二酮、贝特类药物(如非诺贝特、苯扎贝特、吉非罗齐中的一种或多种)、他汀类药物(如阿妥伐他汀、洛伐他汀、辛伐他汀、普伐他汀和氟伐他汀中的一种或多种)、钙离子拮抗剂中的一种或多种。
在一些实施例中，第二活性成分包括阿托伐他汀钙。此时，含有嗜粘蛋白阿克曼菌的组合物包含本申请所述嗜粘蛋白阿克曼菌和阿托伐他汀钙。
在一些实施方式中，第二活性成分为阿托伐他汀钙。
在一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物，其为复合益生菌。“复合益生菌”的定义与前述一致。所述复合益生菌含有本申请所述嗜粘蛋白阿克曼菌，还含有不同于所述嗜粘蛋白阿克曼菌的益生菌。
在一些实施方式中，所述不同于所述嗜粘蛋白阿克曼菌的益生菌包括脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、希氏肠球菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、弯曲乳杆菌、婴儿双歧杆菌、长双歧杆菌和短双歧杆菌中的一种或多种。
在一些实施方式中，提供含有嗜粘蛋白阿克曼菌的组合物，其为复合益生菌，还包括第二活性成分，所述第二活性成分如前述所定义。
本申请的第八方面
在本申请的第八方面，提供一种代谢综合征的改善方法。在一些实施方式中，提供一种代谢综合征的改善方法，其包括给予受试者嗜粘蛋白阿克曼菌，或者给予受试者含有嗜粘蛋白阿克曼菌的组合物，或者给予受试者含有嗜粘蛋白阿克曼菌的药品，或者给予受试者含有嗜粘蛋白阿克曼菌的保健食品；其中，所述嗜粘蛋白阿克曼菌如前文所定义。
在一些实施方式中，所述代谢综合征的改善方法包括预防代谢综合征和治疗代谢综合征中至少一项。
在一些实施方式中，提供一种代谢综合征的改善方法，包括给予受试者本申请所述嗜粘蛋白阿克曼菌、含有本申请所述嗜粘蛋白阿克曼菌的组合物、含有本申请所述嗜粘蛋白阿克曼菌的药品或含有本申请所述嗜粘蛋白阿克曼菌的保健食品；进一步地，含有本申请所述嗜粘蛋白阿克曼菌的组合物可以为药物组合物或保健品组合物。
在本申请的第八方面，进一步提供一种代谢综合征的改善方法(包括防治方法)，包括给予受试者治疗有效量的本申请所述嗜粘蛋白阿克曼菌(也即向受试者施用治疗有效量的本申请所述嗜粘蛋白阿克曼菌)。
在一些实施方式中，提供一种代谢综合征的改善方法(包括防治方法)，包括给予受试者治疗有效量的含有本申请所述嗜粘蛋白阿克曼菌的药物组合物。
在一些实施方式中，提供一种代谢综合征的改善方法(包括防治方法)，包括给予受试者治疗有效量的含有本申请所述嗜粘蛋白阿克曼菌的药物制剂。
在一些实施方式中，提供一种代谢综合征的改善方法(包括防治方法)，包括给予受试者治疗有效量的含有本申请所述嗜粘蛋白阿克曼菌的药品。
在本申请的第八方面，还提供一种改善代谢综合征的方法，包括给予受试者保健有效量的本申请所述嗜粘蛋白阿克曼菌，或者给予受试者保健有效量的含有本申请所述嗜粘蛋白阿克曼菌的保健品组合物，或者给予受试者治疗保健有效量的含有本申请所述嗜粘蛋白阿克曼菌的保健食品。
在本申请的第八方面，“嗜粘蛋白阿克曼菌”、“本申请所述嗜粘蛋白阿克曼菌”、“组合物”、“含有嗜粘蛋白阿克曼菌的组合物”、“防治”、“代谢综合征”、“改善代谢综合征”、“防治代谢综合征”、“治疗有效量”、“保健有效量”、“保健品组合物”、“保健食品”的定义可参考前文，包括但不限于第二方面和第四方面。
在本申请的第八方面，本申请所述嗜粘蛋白阿克曼菌可以与其他药物活性成分联用，用于改善代谢综合征。“其他药物活性成分”的定义可参考本申请的前文，包括但不限于第二方面和第四方面。比如，其他药物活性成分可以为具有改善代谢综合征的作用的药物成分，也可以为具有其他疾病防治效果的药物成分。在本申请的一些实施例中，其他药物活性成分为前文所描述的第二活性成分。
在本申请中，本申请所述嗜粘蛋白阿克曼菌，含有本申请所述嗜粘蛋白阿克曼菌的药物组合物，含有本申请所述嗜粘蛋白阿克曼菌的药物制剂，含有本申请所述嗜粘蛋白阿克曼菌的药品，均属于本申请所定义的“药物”范畴。
在一些实施方式中，药物的施用方式包括但不限于：口服、直肠、肠胃外(静脉内、肌肉内或皮下)注射、和局部给药、吸入。
在其中一些实施例中，药物可通过口服、灌肠或肠胃外的形式给药。
在其中一些实施例中，药物的给药周期可为间歇给药、周期性给药、持续给药或长期给药。
用于口服给药的固体剂型可以包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基 纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，进一步例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。如悬浮液可包含悬浮剂，进一步例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水或非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。由活性成分在无菌条件下与药学上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合而成。
本方面的上述药物制剂中的“活性成分”指药物组合物中能够发挥“药物”作用的成分。可以理解的是，本申请实施例的药物可以添加不同的药学上可接受的辅料从而制备成合适的临床剂型，这些临床剂型包括但不限于上文所述剂型。
以下提供一些实施例。
下面将结合实施例对本申请的实施方案进行详细描述。应理解，这些实施例仅用于说明本申请而不用于限制本申请的范围。下列实施例中未注明条件的实验方法，优先参考本申请中给出的指引，还可以按照本领域的实验手册或常规条件，还可以按照制造厂商所建议的条件，或者参考本领域已知的实验方法。
下述的实施例中，涉及原料组分的量度参数，如无特别说明，可能存在称量精度范围内的细微偏差。涉及温度和时间参数，允许仪器测试精度或操作精度导致的可接受的偏差。
实施例1.嗜粘蛋白阿克曼菌的分离及鉴定
1.1.AM02菌株的分离及鉴定
用无菌取样勺，取黄豆粒大小粪便(样本来源于成年健康男性)于10mL离心管中，取样完成后将样本立即转移至37℃厌氧工作站中(85％N2、10％H2、5％CO2，体积百分比)，按10倍梯度稀释将样本稀释至10-9，取各稀释度溶液各1mL接种至9mL以黏蛋白为唯一碳源的基础培养基中，厌氧培养7天。取10-4稀释度接种的培养液1mL，按1：10的梯度稀释方式将培养液稀释至10-6，分别取各稀释度100μL分别于黏蛋白琼脂培养基上涂布，厌氧培养7天，挑取单菌落接种至2mL的BHI肉汤(含N-乙酰-D-氨基葡萄糖培养基)。对培养后的菌液进行16s rRNA测序，将16S rRNA序列于NCBI数据库上进行序列比对。分离得到的菌株鉴定为嗜粘蛋白阿克曼氏菌，16S rRNA测序结果如下所示(SEQ ID No.:1)：

该序列在NCBI上与ATCC BAA-835的16S rRNA序列比对结果显示Per.Ident值为99.43％。
1.2.AM06菌株的分离及鉴定
将新鲜采集的母乳样本(来源于成年健康女性)立即注射于5mL厌氧西林瓶中保存，然后将样本转移至37℃厌氧工作站中(85％N2、10％H2、5％CO2，体积百分比)，按10倍梯度稀释将样本稀释至10-6，取各稀释度溶液各1mL接种至9mL以黏蛋白为唯一碳源的基础培养基中，厌氧培养约1个月。取10-1～10-4稀释度接种的培养液1mL，按1：10的稀释方式将培养液稀释至10-6，分别取各稀释度100μL分别于黏蛋白琼脂培养基上涂布，厌氧培养7天，挑取单菌落接种至2mL的BHI肉汤(含N-乙酰-D-氨基葡萄糖培养基)。对培养后的菌液进行16S rRNA测序鉴定，将16S rRNA序列于NCBI数据库上进行序列比对，结果鉴定为嗜粘蛋白阿克曼氏菌，16S rRNA的测序结果如下所示(SEQ ID No.:2)：
该序列在NCBI上与ATCC BAA-835的16S rRNA序列比对结果显示Per.Ident值为99.22％。
1.3.菌株保藏信息
嗜粘蛋白阿克曼菌AM02，其分类命名为Akkermansia muciniphila，已于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，地址：北京市朝阳区北辰西路1号院3号，保藏编号为CGMCC No.22794；该菌株于2021年06月28日由保藏中心收到并登记入册，经保藏中心于2021年06月28日检测为存活菌株。
嗜粘蛋白阿克曼菌AM06，其分类命名为Akkermansia muciniphila，已于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，地址：北京市朝阳区北辰西路1号院3号，保藏编号为CGMCC No.22793；该菌株于2021年06月28日由保藏中心收到并登记入册，经保藏中心于2021年06月28日检测为存活菌株。
实施例2.嗜粘蛋白阿克曼菌的培养和灭活菌制备
2.1.将嗜粘蛋白阿克曼菌种划线接种于BHA平板，厌氧培养3天。观察菌落形态特征、染色特性、大小、球杆状和分布情况等。
菌落特征：嗜粘蛋白阿克曼菌AM02和AM06在上述培养基上培养3天后，均呈现圆形凸起、边缘整齐、不透明、白色、大小不均一的菌落，菌落大小约为0.08～2.2mm，可参见图1(嗜粘蛋白阿克曼菌AM02)和图2(嗜粘蛋白阿克曼菌AM06)。
显微镜下形态：对嗜粘蛋白阿克曼菌AM02和AM06进行革兰氏染色镜检，为革兰阴性细菌，椭圆形、单个或成链状排列，可参见图3(嗜粘蛋白阿克曼菌AM02)和图4(嗜粘蛋白阿克曼菌AM06)。
标准菌株ATCC BAA-835的菌落特征为：圆形凸起、边缘整齐、不透明、白色、大小不均一的菌落。显微镜下形态为革兰阴性细菌，椭圆形、单个或成链状排列。
2.2.选取单个菌落接种于BHI肉汤中培养48小时(温度为37℃)，所得菌液离心沉淀，转速16000×g，离心30min，去上清，收集沉淀物，即得嗜粘蛋白阿克曼菌菌泥。分别培养得到AM02、AM06、ATCC BAA-835嗜粘蛋白阿克曼菌。
2.3.灭活菌的制备：取适量菌泥，按菌泥:生理盐水(m:v)＝1:10的比例添加生理盐水，使用搅拌器在1000rpm条件下搅拌5～20min，使菌体均匀分散。取100mL分散后菌液置于无菌三口圆底烧瓶内(尽量保证菌液不黏附于烧瓶内壁)。将三口圆底烧瓶置于磁力搅拌器加热盘上，放入无菌搅拌子，并插入温度电极，设置转速300～500rpm，温度70℃，加热30min，得到嗜粘蛋白阿克曼菌的灭活菌。
实施例3.嗜粘蛋白阿克曼菌培养上清非靶向代谢学差异分析
3.1.样本制备
取实施例2中培养结束后的各个嗜粘蛋白阿克曼菌(AM02、AM06、ATCC BAA-835)的培养上清，各取1mL菌液12000rpm离心5min后，上清过0.22μm滤膜后，取滤液作为待测样本，进行非靶向代谢组学分析。每个菌株各制备5份平行的待测样本。
3.2.实验结果
PCA是一种数据降维方法，即把多个变量降维到一组新的综合变量，再从中选取尽可能多地反映原有变量信息的前几个主成分，从而达到降维的目的。PCA图反应样本的真实分布情况，主要用于观察样本组间分离趋势，以及是否有异常点出现，同时从原始数据上反映组间和组内的变异度。
实验结果可参见图5。图5中包含了质控样本(QC样本)和所有样本的PCA分析。其中各个QC样本在两个主成分分析图中均聚集在一起，说明检测期间仪器稳定，采集数据的重复性好。同时结果还显示，AM06培养上清中的代谢物与BAA-835的培养上清代谢物较接近，AM02与BAA-835的培养上清代谢物差异较大。
各菌株之间差异代谢物的数量比较结果可参见表1。可见AM02与标准株BAA-835相比，正离子(pos)模式检测的差异代谢物和负离子(neg)模式检测的差异代谢物分别为205和135个，AM06与标准株BAA-835相比，正离子(pos)模式检测的差异代谢物和负离子(neg)模式检测的差异代谢物分别为111和62个。
表1.差异代谢物统计表
实施例4.嗜粘蛋白阿克曼菌的功效验证
4.1.嗜粘蛋白阿克曼菌对于人工胃液的耐受性
4.1.1.实验方法及分组
表2.实验分组
表3.实验方法
“+”表示需要检测。
4.1.1.1.取嗜粘蛋白阿克曼菌菌种1支，去除标签，75％(v/v)酒精对甘油冻存管外表面进行擦拭消毒，涡旋振荡混匀，开启。吸取100～500μL菌液接种至10mL/管的BHI肉汤中，摇匀，共制备3管，同时不接菌作阴性对照，置于37℃厌氧培养2～4天，得一级种子液。
一级种子液进行革兰氏染色镜检，应为G-杆菌，无芽孢，无杂菌。
4.1.1.2.取上述一级种子液10mL，12000×g、4℃离心10min，弃上清，加入1mL 0.9wt％的NaCl溶液重悬，分别制得菌液，备用。
4.1.1.3.按表2和表3将AM06、AM02及标准菌株的菌液分别加入至0.9wt％NaCl、pH3.0以及pH2.0的人工胃液中，混匀，分装成5mL/管，置于厌氧手套箱37℃孵育0h、1.5h以及3h后取出检测各样品的菌浓度。每个实验组做3个平行。
4.1.1.4.活菌数测定：
取实验样品，按10倍系列梯度稀释为不同的稀释度，取100μL稀释液接种至BHA平板上，涂布均匀，每个稀释度共做2个平皿，一般做2～3个稀释度，同时取稀释液100μL于BHA平板上，作为阴性对照，所有涂布平皿正置，于厌氧条件下培养约3～5天，观察平皿上菌落生长情况，并计数。根据2个平皿菌落数之和按下列公式计算活菌数：
活菌数(CFU/mL)＝2个平皿菌落数之和/2×10×最终稀释度
存活率计算：
4.1.2.实验结果
实验结果可参见表4。不同嗜粘蛋白阿克曼菌株的人工胃液耐受性自高到低依次为AM02＞AM06＞标准株BAA-835。
表4.嗜粘蛋白阿克曼菌人工胃液耐受性存活率结果统计表
4.2.嗜粘蛋白阿克曼菌对于人工肠液的耐受性
4.2.1.实验方法及分组
表5.实验分组
4.2.1.1.一级种子液制备
取嗜粘蛋白阿克曼菌菌种1支去除标签，75％(v/v)酒精对甘油冻存管外表面进行擦拭消毒，涡旋振荡混匀，开启。吸取100μL菌液接种至10mL/管的BHI肉汤中，摇匀，共制备3管，同时不接菌作阴性对照，置于37℃厌氧培养2～4天，得一级种子液。
一级种子液进行革兰氏染色镜检，应为G-杆菌，无芽孢，无杂菌。
4.2.1.2.菌泥制备
分别上述一级种子液分装成1.5mL/管，12000×g、离心10min，弃上清，制得菌泥，AM06、AM02及标准菌株各制备3管菌泥。
4.2.1.3.菌株人工肠液耐受性评价
如表5和表6所示，向制得的菌泥中每管分别加入1.5mL人工肠液，混匀，然后每管溶液按照0.5mL/支进行分装，分装3管，分别于37℃厌氧孵育0、4h和8h，取样检测活菌数。每组各做3个平行。
表6.实验方法
“+”表示需要检测。
4.2.1.4.活菌数测定
分别取孵育后的样品，10倍梯度系列稀释后，取100μL稀释液接种至BHA平板上，涂布均匀，每个稀释度共做2个平皿，一般做2～3个稀释度，同时取100μL稀释液于BHA平板上，作为阴性对照，所有涂布平皿正置，于厌氧条件下培养约3～5天，观察平皿上菌落生长情况，并计数。
活菌数(CFU/mL)＝2个平皿菌落数之和/2×10×最终稀释度
存活率计算：
存活率＝各时间点活菌数/对应0h活菌数×100％
4.2.2.实验结果
结果可参见表7，ATCC BAA-835、AM02、AM06菌株人工肠液耐受性良好，耐受性自高到低依次为AM02＞AM06＞标准株BAA-835。
表7.存活率统计表
5.嗜粘蛋白阿克曼菌对TNF-α和IFN-γ诱导Caco2细胞紧密连接蛋白ZO-1表达的影响
5.1.实验方法和分组
将Caco2细胞接种至96孔板培养至汇合度为80％～90％，使用100ng/mL TNF-α+100ng/mL IFN-γ诱导Caco2细胞24h后，再分别加入AM02、AM06、BAA-835继续与细胞孵育24h，实验分组可参见表8，每组做5个复孔。使用免疫荧光法观察BAA-835、AM06和AM02对TNF-α和IFN-γ诱导Caco2细胞紧密连接蛋白ZO-1表达的影响。
表8.实验分组

5.2.实验结果
对拍摄的图片进行荧光强度统计，结果可参见图6和表9。与空白对照组相比，经过TNF-α和IFN-γ诱导48h后炎症模型组细胞间隙的荧光强度显著减弱，说明ZO-1蛋白表达减少，细胞间的紧密连接被破坏。与炎症模型组相比，给予AM02、AM06、BAA-835干预后细胞的处理组荧光强度显著增加(p<0.05)，且AM02和AM06抑制炎症因子诱导Caco2细胞ZO-1蛋白减少的能力显著优于BAA-825(p<0.05)。
表9.荧光强度统计
注：**表示与模型组比较，差异显著p<0.01；aa表示与BAA-835组相比，差异显著p<0.01。
实施例6.嗜黏蛋白阿克曼菌治疗代谢综合征的药效实验
6.1.实验设计及流程
SPF级雄性SD大鼠100只，体重160～180g，适应性喂养1周后，随机挑选80只，采用高脂高糖饲料喂养8周进行代谢综合征造模，高脂高糖饲料配方(质量百分含量，wt％)：66.5％基础饲料、2.5％胆固醇、20％蔗糖、10％猪油、1％胆酸盐。剩余20只饲喂基础饲料。
喂养8周后，依据体重、体长、血压、血脂、空腹血糖等水平，选择造模成功的大鼠70只，随机分为8组，每组10只：模型组、阳性药组(阿托伐他汀钙，辉瑞制药有限公司，15mg/kg)、AKK菌AM06活菌低剂量(106CFU/只)、高剂量(1010CFU/只)组，AM02活菌(1010CFU/只)组，AM02活菌(1010CFU/只)与阿托伐他汀钙(15mg/kg)联用组，AKK菌AM06、AM02灭活菌组(1010cell/只)。另取10只未造模大鼠作为正常对照组。
分组后开始给药(D0)：正常对照组、模型组每日一次灌胃生理盐水1mL；各给药组每日一次灌胃相应剂量药物，连续灌胃8周。分组给药期间，正常对照组饲喂基础饲料，模型组及各给药组饲喂高脂高糖饲料。
末次灌胃后，记录大鼠体长及体重，计算Lee’s指数，计算公式为：Lee’s指数＝体重(g)1/3×1000×体长(cm)-1；末次灌胃后禁食不禁水12h，无创血压仪测量尾动脉收缩压(SBP)，血糖仪检测空腹血糖水平(FBG)；采用水合氯醛麻痹，腹主动脉取血，分离血清，ELISA测定血清胰岛素水平(Fins)，计算胰岛素抵抗指数(HOMA-IR)，计算公式为：HOMA-IR＝FBG×Fins/22.5；全自动生化分析仪测定血清甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-c)、高密度脂蛋白(HDL-c)。
所有数据采用SPSS 25.0进行统计学分析。p＜0.05视为有统计学差异。
6.2.实验结果
6.2.1.体质量和Lee’s指数
结果可参见表10。
表10.各组大鼠Lee’s指数和体质量(mean±SD)

注：与模型组比较，*表示差异显著p<0.05。
Lee’s指数是在评价成年大鼠肥胖程度方面的有效指数。成年肥胖大鼠较正常大鼠Lee’s指数明显增加。
如表10所示，与正常对照组相比，模型组大鼠体重和Lee’s指数显著上升，造模成功。与模型组相比，各给药组体质量均显著下降。
与模型组相比，各给药组Lee’s指数均有所下降，其中，阳性药及AKK菌AM06各组具有显著性差异。这说明AKK菌能够有效控制大鼠体重，减轻肥胖症状。
6.2.2.空腹血糖、血清胰岛素和胰岛素抵抗指数
表11.各组大鼠空腹血糖、血清胰岛素和胰岛素抵抗指数(mean±SD)
注：与模型组比较，*表示差异显著p<0.05；**表示差异极显著p<0.01。
MS是以肥胖、高血糖、高血压等为主要特征的一组临床症候群，其共同的病理基础为胰岛素抵抗和高胰岛素血症。胰岛素抵抗主要表现为FBG、Fins和HOMA-IR持续升高。
如表11所示，与正常对照组相比，模型组FBG、Fins和HOMA-IR显著升高。与模型组相比，各给药组均下调了大鼠的FBG和Fins水平。
与模型组相比，各给药组均显著下调了大鼠的HOMA-IR水平。这说明AKK菌能够有效减轻大鼠胰岛素抵抗，调节大鼠血糖代谢。
6.2.3.尾动脉收缩压
表12.各组大鼠尾动脉收缩压(mean±SD)

注：与模型组比较，*表示差异显著p<0.05；**表示差异极显著p<0.01。
如表12所示，与正常对照组相比，模型组大鼠SBP显著升高。与模型组相比，各给药组均下调了大鼠血压。AKK菌组内，AM06及其灭活菌效果优于AM02。这说明AKK菌能够有效调节大鼠血压。
6.2.4.血清脂质指标
表13.各组大鼠血清脂质指标(mean±SD)
注：与模型组比较，*表示差异显著p<0.05。
如表13所示，与正常对照组相比，模型组TC、TG、LDL-c水平显著升高，HDL-c水平显著下降，显示出代谢综合征高血脂的症状。与模型组相比，阳性药组大鼠TC、TG、LDL-c水平显著下降，HDL-c水平显著升高。
与模型组相比，AKK菌各组大鼠TC、TG、LDL-c水平均有所下降，其中，TG水平存在显著性差异；AM06及其灭活菌各组大鼠LDL-c水平存在显著性差异。
与模型组相比，AKK菌各组大鼠HDL-c水平均有所上升。这说明AKK菌能够有效调节大鼠血脂代谢。
综上所述，嗜黏蛋白阿克曼菌，尤其是保藏编号为CGMCC No.22793的嗜黏蛋白阿克曼菌AM06和保藏编号为CGMCC No.22794的嗜黏蛋白阿克曼菌AM02中的任一者或二者的组合，能够有效治疗大鼠代谢综合征。
以上各实施方式和实施例的各技术特征可以进行任意合适方式的组合，为使描述简洁，未对上述实施方式和实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为在本说明书记载的范围中。
以上各实施例仅表达了本申请的几种实施方式，便于详细地理解本申请的技术方案，但并不能因此而理解为对本申请保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。此外应理解，在阅读了本申请的上述讲授内容之后，本领域技术人员可以对本申请作各种改动或修改，得到的等价形式同样落于本申请的保护范围。还应当理解，本领域技术人员在本申请提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本申请所附权利要求的保护范围内。因此，本申请专利的保护范围应以所附权利要求的内容为准，说明书及附图可以用于解释权利要求的内容。

Claims (26)

  1. 嗜粘蛋白阿克曼菌在改善代谢综合征中的应用，其中，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，
    所述嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793；
    所述嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794；
    所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项；
    可选地，所述嗜粘蛋白阿克曼菌AM06和所述嗜粘蛋白阿克曼菌AM02各自独立地为活菌、灭活菌或者其组合。
  2. 嗜粘蛋白阿克曼菌在制备改善代谢综合征的组合物中的应用，其中，所述改善代谢综合征的组合物为药物组合物或保健品组合物，所述嗜粘蛋白阿克曼菌为嗜粘蛋白阿克曼菌AM06、嗜粘蛋白阿克曼菌AM02或者两者的组合；其中，
    所述嗜粘蛋白阿克曼菌AM06于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22793；
    所述嗜粘蛋白阿克曼菌AM02于2021年06月28日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22794。
  3. 如权利要求2所述的应用，其中，所述嗜粘蛋白阿克曼菌AM06和所述嗜粘蛋白阿克曼菌AM02各自独立地为活菌、灭活菌或者其组合。
  4. 如权利要求2～3中任一项所述的应用，其中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
  5. 如权利要求2～4中任一项所述的应用，其中，所述改善代谢综合征的组合物为药物组合物，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体；
    可选地，所述药物组合物为药品或药物制剂；
    可选地，所述药品或所述药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂；
    可选地，所述药品或所述药物制剂适用于人或其他哺乳动物。
  6. 如权利要求2～4中任一项所述的应用，其中，所述改善代谢综合征的组合物为保健品组合物，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料；
    可选地，所述保健品组合物为保健食品；
    可选地，所述保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂；
    可选地，所述保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品为动物食品。
  7. 含有嗜粘蛋白阿克曼菌的组合物在改善代谢综合征中的应用，其中，所述嗜粘蛋白阿克曼菌如权利要求2或3中所定义；
    可选地，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物或保健品组合物。
  8. 如权利要求7所述的应用，其中，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体；
    可选地，所述药物组合物为药品或药物制剂；
    可选地，所述药品或所述药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂；
    可选地，所述药品或所述药物制剂适用于人或其他哺乳动物。
  9. 如权利要求7所述的应用，其中，所述含有嗜粘蛋白阿克曼菌的组合物为保健品组合物，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料；
    可选地，所述保健品组合物为保健食品；
    可选地，所述保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂；
    可选地，所述保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品为动物食品。
  10. 含有嗜粘蛋白阿克曼菌的组合物在制备或作为防治代谢综合征的药品或药物制剂中的应用，其中，所述嗜粘蛋白阿克曼菌如权利要求2或3中所定义。
  11. 如权利要求10所述的应用，其中，所述含有嗜粘蛋白阿克曼菌的组合物为药物组合物，所述药物组合物包括所述嗜粘蛋白阿克曼菌和药学上可接受的载体；
    可选地，所述药品或所述药物制剂的剂型为片剂、胶囊剂、颗粒剂、丸剂、膏剂、溶液剂、混悬剂、乳剂、霜剂、喷雾剂、滴剂、贴剂或管饲制剂；
    可选地，所述药品或所述药物制剂适用于人或其他哺乳动物。
  12. 含有嗜粘蛋白阿克曼菌的组合物在制备或作为改善代谢综合征的保健食品中的应用，其中，所述嗜粘蛋白阿克曼菌如权利要求2或3中所定义。
  13. 如权利要求12所述的应用，其中，所述含有嗜粘蛋白阿克曼菌的组合物为保健品组合物，所述保健品组合物包括所述嗜粘蛋白阿克曼菌和可食用原辅料；
    可选地，所述保健食品的剂型为丸剂、片剂、颗粒剂、胶囊、溶液剂、混悬剂或乳剂；
    可选地，所述保健食品包括奶粉、干酪、凝乳、酸奶酪、冰激凌和发酵谷类食品中的一种或多种，或者所述保健食品为动物食品。
  14. 如权利要求7～13中任一项所述的应用，其中，所述含有嗜粘蛋白阿克曼菌的组合物为复合益生菌，所述复合益生菌还含有不同于所述嗜粘蛋白阿克曼菌的益生菌；
    可选地，所述不同于所述嗜粘蛋白阿克曼菌的益生菌包括脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、希氏肠球菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、弯曲乳杆菌、婴儿双歧杆菌、长双歧杆菌和短双歧杆菌中的一种或多种。
  15. 如权利要求7～14中任一项所述的应用，其中，所述含有嗜粘蛋白阿克曼菌的组合物还包括第二活性成分，所述第二活性成分为不同于所述嗜粘蛋白阿克曼菌的药物；
    可选地，所述第二活性成分包括奥利司他、二甲双胍、噻唑烷二酮、贝特类药物、他汀类药物、钙离子拮抗剂中的一种或多种；其中，所述贝特类药物包括非诺贝特、苯扎贝特和吉非罗齐中的一种或多种；所述他汀类药物包括阿妥伐他汀、洛伐他汀、辛伐他汀、普伐他汀和氟伐他汀中的一种或多种；
    进一步可选地，所述第二活性成分包括阿托伐他汀钙。
  16. 用于改善代谢综合征的嗜粘蛋白阿克曼菌，其中，所述嗜粘蛋白阿克曼菌如权利要求2或3中所定义。
  17. 如权利要求16所述的嗜粘蛋白阿克曼菌，其中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
  18. 用于改善代谢综合征的组合物，其中，所述用于改善代谢综合征的组合物为权利要求7～15任一项中所定义的含有嗜粘蛋白阿克曼菌的组合物。
  19. 如权利要求18所述用于改善代谢综合征的组合物，其中，所述改善代谢综合征包括预防代谢综合征和治疗代谢综合征中至少一项。
  20. 含有嗜粘蛋白阿克曼菌的组合物，其中，其包含权利要求2或3中定义的所述嗜粘蛋白阿克曼菌和第二活性成分；
    可选地，所述第二活性成分包括奥利司他、二甲双胍、噻唑烷二酮、贝特类药物、他汀类药物、钙离子拮抗剂中的一种或多种；其中，所述贝特类药物包括非诺贝特、苯扎贝特和吉非罗齐中的一种或多种；所述他汀类药物包括阿妥伐他汀、洛伐他汀、辛伐他汀、普伐他汀和氟伐他汀中的一种或多种；
    进一步可选地，所述第二活性成分包括阿托伐他汀钙。
  21. 含有嗜粘蛋白阿克曼菌的组合物，其为复合益生菌，所述复合益生菌含有权利要求2或3所述嗜粘蛋白阿克曼菌，还含有不同于所述嗜粘蛋白阿克曼菌的益生菌；
    可选地，所述不同于所述嗜粘蛋白阿克曼菌的益生菌包括脆弱拟杆菌、布拉氏酵母菌、克里斯特森氏菌、希氏肠球菌、干酪乳杆菌、鼠李糖乳杆菌、加塞利乳杆菌、植物乳杆菌、弯曲乳杆菌、婴儿双歧杆菌、长双歧杆菌和短双歧杆菌中的一种或多种；
    进一步可选地，所述含有嗜粘蛋白阿克曼菌的组合物还包括第二活性成分，所述第二活性成分如权利要求15中所定义。
  22. 一种代谢综合征的改善方法，其包括给予受试者嗜粘蛋白阿克曼菌，或者给予受试者含有嗜粘蛋白阿克曼菌的组合物，或者给予受试者含有嗜粘蛋白阿克曼菌的药品，或者给予受试者含有嗜粘蛋白阿克曼菌的保健食品；其中，所述嗜粘蛋白阿克曼菌如权利要求2或3中所定义。
  23. 如权利要求22所述的改善方法，其包括给予受试者治疗有效量的所述嗜粘蛋白阿克曼菌，或者给予受试者治疗有效量的含有所述嗜粘蛋白阿克曼菌的药物组合物，或者给予受试者治疗有效量的含有所述嗜粘蛋白阿克曼菌的药品。
  24. 如权利要求22所述的改善方法，其包括给予受试者保健有效量的所述嗜粘蛋白阿克曼菌，或者给予受试者保健有效量的含有所述嗜粘蛋白阿克曼菌的保健品组合物，或者给予受试者保健有效量的含有所述嗜粘蛋白阿克曼菌的保健食品。
  25. 如权利要求22～24中任一项所述的改善方法，其中，所述含有嗜粘蛋白阿克曼菌的组合物如权利要求7～15任一项中所定义。
  26. 如权利要求22～25中任一项所述的改善方法，其中，所述代谢综合征的改善方法包括预防代谢综合征和治疗代谢综合征中至少一项。
PCT/CN2023/099224 2022-06-08 2023-06-08 嗜粘蛋白阿克曼菌在制备改善代谢综合征的药物组合物或保健品组合物中的应用 WO2023237067A1 (zh)

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