WO2023237038A1 - Akkermansia muciniphila, son utilisation et son procédé de culture - Google Patents

Akkermansia muciniphila, son utilisation et son procédé de culture Download PDF

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WO2023237038A1
WO2023237038A1 PCT/CN2023/099055 CN2023099055W WO2023237038A1 WO 2023237038 A1 WO2023237038 A1 WO 2023237038A1 CN 2023099055 W CN2023099055 W CN 2023099055W WO 2023237038 A1 WO2023237038 A1 WO 2023237038A1
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akkermansia muciniphila
cgmcc
liver
group
application
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PCT/CN2023/099055
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English (en)
Chinese (zh)
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郑丽君
刘洋洋
王薇
梁德宝
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 WO2023237038A1 publication Critical patent/WO2023237038A1/fr

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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
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D13/00—Finished or partly finished bakery products
    • A21D13/06—Products with modified nutritive value, e.g. with modified starch content
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
    • A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the technical field of microorganisms, in particular to Akkermansia muciniphila and its application and culture methods.
  • Non-alcoholic fatty liver disease refers to a liver metabolic disease in which lipids, mainly triglycerides, accumulate in liver cells and become pathological changes caused by other clear liver-damaging factors in addition to long-term heavy drinking.
  • liver fat metabolism is impaired, causing a large amount of fatty substances to accumulate in liver cells (simple fatty liver, NAFL), which in turn leads to steatosis, liver cell damage, inflammatory reaction, and liver fibrosis (non-alcoholic fatty liver disease). hepatitis, NASH).
  • NAFLD neurodegenerative disease
  • Metformin, vitamin E, ursodeoxycholic acid, etc. are also used clinically for anti-insulin resistance, anti-oxidative stress and cell protection treatment.
  • Lipid-lowering drugs have also been reported to be used in the treatment of NAFLD, but they are still controversial. Generally, for patients who still have mixed hyperlipidemia after taking weight loss and hypoglycemic drugs or basic treatment for more than 3-6 months, the addition of statins and phenoxyaromatic acid lipid-lowering drugs should be considered, but liver function needs to be monitored.
  • Pioglitazone is an agonist of PPAR ⁇ .
  • pioglitazone can cause side effects such as water and sodium retention, osteoporosis, and weight gain. Its clinical application restricted. For obese patients with non-alcoholic fatty liver disease, if their weight cannot be reduced by more than 5% after 6-12 months of lifestyle changes, they should also use weight-loss drugs such as sibutramine and orlistat with caution to promote fat metabolism and improve fat metabolism. NAFLD symptoms.
  • PPARs are a type of nuclear hormone receptors. Distributed in liver, fat, skeletal muscle and other organs, it regulates lipid metabolism, transport and gluconeogenesis. PPAR ⁇ can promote the oxidative decomposition of fatty acids, and PPAR ⁇ also has anti-inflammatory effects. Elafibranor is a PPAR ⁇ / ⁇ agonist. Phase 2 clinical trials have proven that the drug can maintain blood sugar balance, improve lipid metabolism and reduce liver inflammation. It is a potential drug for the treatment of NAFLD.
  • GLP-1 is a glucagon-like polypeptide secreted by L cells in the small intestine. It can promote insulin secretion, increase the number of pancreatic beta cells, inhibit glucagon secretion, suppress appetite, and delay gastric emptying. Improve insulin sensitivity, etc.
  • Semaglutide is a GLP-1 analog that only needs to be administered once a week, and its clinical trials for the treatment of NASH are ongoing.
  • FXR is a multifunctional nuclear receptor that plays an important role in bile acid metabolism, glucose and lipid metabolism, liver protection, and regulation of intestinal bacterial growth.
  • Obeticholic acid is an FXR agonist that can not only reduce the degree of liver fat degeneration in NAFLD patients, but also improve insulin resistance and inhibit liver inflammation and fibrosis.
  • Obeticholic acid is currently in phase 3 clinical trials, and some subjects have experienced pruritus and increased low-density lipoprotein levels, so the safety of the drug needs to be further clarified.
  • Acetyl-CoA carboxylase ACC is a key enzyme in the de novo synthesis of fatty acids.
  • the ACC inhibitor PF-05221304 can suppress liver fat content in NAFLD patients, but the drug has the potential side effect of causing hypertriglyceridemia.
  • SCD-1 is stearoyl-CoA desaturase, which is the rate-limiting enzyme in the synthesis of unsaturated fatty acids.
  • Aramchol is an inhibitor of SCD-1. Clinical trials have found that the drug can reduce liver fat content in NAFLD patients.
  • Hepatocyte death is an important driving factor in promoting liver inflammation and fibrosis. Therefore, inhibiting liver cell death can help prevent and treat NASH.
  • Emricasan is a pancaspase inhibitor that can inhibit cell apoptosis, thereby alleviating liver inflammation and fibrosis. The drug is currently in Phase 2 clinical trials for the treatment of NASH.
  • Anti-inflammatory drugs Inflammatory cells and pro-inflammatory cytokines play an important role in the occurrence and development of NASH. Apoptosis signaling kinase ASK-1 can promote the activity of JNK, and JNK is an important kinase that promotes inflammation and cell death.
  • a short-term clinical trial found that an ASK-1 inhibitor (BGsertib) can reduce fibrosis in patients with NASH. BGsertib is currently in phase 3 clinical trials, and its efficacy awaits further evaluation.
  • surgical treatment can also be used to control non-alcoholic fatty liver disease.
  • bariatric surgery can help alleviate liver steatosis, fatty hepatitis and liver fibrosis.
  • liver transplantation is the only effective treatment.
  • surgical procedures are mainly targeted, expensive, and difficult to obtain and match liver sources.
  • Akkermansia muciniphila in the preparation of health foods or drugs for the prevention and treatment of non-alcoholic fatty liver disease.
  • the Akkermansia muciniphila is selected from CGMCC No. .22793 Akkermansia muciniphila and Akkermansia muciniphila with deposit number CGMCC No. 22794 or both.
  • the Akkermansia muciniphila deposited as CGMCC No. 22793 and the Akkermansia muciniphila deposited as CGMCC No. 22794 are each independently viable, sterilized One or more types of live bacteria.
  • Akkermansia muciniphila is provided with the deposit number CGMCC No. 22793, which was deposited at the General Microbiology Center of the Chinese Microbial Culture Collection Committee on June 28, 2021.
  • Akkermansia muciniphila is provided with the deposit number CGMCC No. 22794, which was deposited at the General Microbiology Center of the Chinese Microbial Culture Collection Committee on June 28, 2021.
  • a probiotic combination product which includes Akkermansia muciniphila with a deposit number of CGMCC No. 22793 and Akermansia muciniphila with a deposit number of CGMCC No. 22794.
  • Akkermansia species One or both Akkermansia species.
  • a health food comprising: one or both of the Akkermansia muciniphila described in the second aspect and the Akkermansia muciniphila described in the third aspect. , and food accessories.
  • the health food is pastry or drink.
  • a medicine comprising: one or both of the Akkermansia muciniphila described in the second aspect and the Akkermansia muciniphila described in the third aspect, and pharmaceutical excipients.
  • the dosage form of the drug is a pill, tablet, granule, capsule, solution, tube feeding preparation, suspension, cream, spray, ointment or patch.
  • the culture conditions include: using mucin as the sole carbon source; or/and, anaerobic environment; or/and, 36.5°C-37.5°C.
  • Figure 1 is a colony characteristic diagram of Akkermansia muciniphila AM02 cultured using the method of Example 2;
  • Figure 2 is a colony characteristic diagram of Akkermansia muciniphila AM06 cultured using the method of Example 2;
  • Figure 3 is a microscopic observation of Akkermansia muciniphila AM02 cultured using the method of Example 2 after Gram staining;
  • Figure 4 is a microscopic observation of Akkermansia muciniphila AM06 cultured using the method of Example 2 after Gram staining;
  • Figure 5 is a PCA analysis diagram of metabolites in the culture supernatant of Akkermansia muciniphila in Example 5;
  • Figure 6 is a fluorescence microscope picture of the effect of Akkermansia muciniphila on the reduction of tight junction protein ZO-1 expression in Caco2 cells induced by TNF- ⁇ and IFN- ⁇ in Example 6.
  • the Akkermansia muciniphila AM02 provided in this application is classified and named Akkermansia muciniphila. It has been deposited in the General Microbiology Center of the China Committee for the Collection of Microbial Cultures on June 28, 2021. Address: Beichen West Road, Chaoyang District, Beijing No. 3, Hospital No. 1, 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.
  • the Akkermansia muciniphila AM06 provided in this application is classified and named Akkermansia muciniphila. It has been deposited in the General Microbiology Center of the China Committee for the Collection of Microbial Cultures on June 28, 2021. Address: Beichen West Road, Chaoyang District, Beijing No. 3, No. 1 Courtyard, 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").
  • first”, “second”, “third” and “fourth” etc. are for descriptive purposes only and shall not be understood as indicating or implying relative importance or quantity, nor shall they be understood as implicitly indicating the importance or quantity of indicated technical features.
  • first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation of quantity.
  • 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.
  • % (w/w) and wt% both represent weight percentage
  • % (v/v) refers to volume percentage
  • % (w/v) refers to mass volume percentage
  • NAFLD non-alcoholic fatty liver disease
  • “Second hit” is a classic hypothesis for the onset of NAFLD proposed in 1998.
  • “First hit” refers to the accumulation of triglycerides in the liver caused by insulin resistance, and the liver's ability to tolerate endogenous damage factors, ischemia, hypoxia, etc. is reduced.
  • “Second hit” means that after triglycerides accumulate in liver cells, the liver cells will eventually be damaged under the action of inflammatory cytokines, oxidative stress, endoplasmic reticulum stress, etc., and pathological changes such as inflammation and fibrosis will occur in liver tissue. , the "second strike” doctrine gradually shifted to the “multiple strike” doctrine.
  • the lipotoxicity theory believes that the accumulation of triglycerides in the liver will not cause insulin resistance and liver cell damage.
  • the core mechanism causing NASH is endoplasmic reticulum stress and oxidation caused by free cholesterol, free fatty acids (FFA) and their metabolites. Stress and inflammatory response.
  • the traditional view is that triglycerides accumulated in hepatocytes promote lipid peroxidation, oxidative stress, inflammation and fibrosis, and are the driving factors for the development of NAFLD; however, this view is increasingly being challenged because triglycerides Esters may antagonize lipotoxicity.
  • palmitic acid C16:0
  • stearic acid C18:0
  • DAG diacylglycerol
  • ceramides ceramides
  • LPCs lysophosphatidic acid choline
  • fructose is mainly metabolized in the liver, which can promote large-scale lipid synthesis, inhibit mitochondrial ⁇ -oxidation, and cause hepatocyte steatosis. Due to its own instability (containing a five-membered furan ring), fructose will promote the generation of reactive oxygen species (ROS) and cause damage to liver cells.
  • ROS reactive oxygen species
  • ATP adenosine diphosphate and hypoxanthine nucleotides
  • uric acid adenosine diphosphate and hypoxanthine nucleotides
  • long-term intake of large amounts of fructose can lead to intestinal flora disorder and increased intestinal wall permeability.
  • Toxic products such as bacterial endotoxins enter the liver through the portal vein and promote liver inflammation.
  • Endotoxin then reaches the liver through the portal circulation, activates liver Kupffer cells, and promotes Kupffer cells to produce cytokines, thereby triggering an inflammatory cascade reaction, damaging liver cells, hindering their secretion, metabolism and other functions, and causing bile secretion disorders.
  • Abnormal bile secretion will affect the normal metabolism of fat, and abnormal accumulation of fat in the liver will lead to steatosis of liver cells and eventually the formation of NAFLD.
  • liver function After liver function is damaged, the liver's ability to process toxicants from the intestinal tract is reduced, and intestinal toxicants may accumulate and damage the intestinal mucosal barrier, leading to intestinal dysfunction; in addition, the reduction of related antibodies, lysozyme and secretions, coupled with The increase in endotoxin makes the environment conducive to the growth of Gram-negative bacteria, but restricts the growth of probiotics and reduces the local resistance of the intestinal wall. These factors can aggravate the intestinal flora imbalance in NAFLD patients.
  • the present application provides the application of Akkermansia muciniphila in the preparation of health foods or drugs for preventing and treating non-alcoholic fatty liver disease.
  • the Akkermansia muciniphila is selected from the group consisting of Akkermansia muciniphila deposited as CGMCC No. 22793.
  • Akkermansia and accession number CGMCC One or two species of Akkermansia muciniphila No. 22794.
  • the Akkermansia muciniphila described in this application can be a living cell, or it can be a biologically active Akkermansia muciniphila that has been inactivated, genetically recombined, transformed or modified, attenuated, chemically treated, or physically treated. , it may also be a bacterial lysate, a culture (such as a supernatant), or a component extracted from the supernatant.
  • the Akkermansia muciniphila deposited as CGMCC No. 22793 and the Akkermansia muciniphila deposited as CGMCC No. 22794 are each independently a live bacterium or an inactivated bacterium (which may be in the form One or more of the inactivated bacteria with complete structure or incomplete morphological structure).
  • Non-alcoholic fatty liver disease refers to a clinical syndrome characterized by hepatocellular steatosis, excluding excessive drinking and other clear liver damage factors, including simple fatty liver, non-alcoholic fatty liver disease and non-alcoholic fatty liver disease. Hepatitis and related cirrhosis and hepatocellular carcinoma.
  • prevention and treatment includes prevention, treatment, auxiliary treatment, etc.
  • preventing, treating,” or “treating” means alleviating, delaying progression, attenuating, preventing, or maintaining 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.
  • the drugs described in this application may be human drugs or animal drugs.
  • drug includes any agent, compound, composition or mixture that provides a physiological and/or pharmacological effect in vivo or in vitro, often providing a beneficial effect.
  • the scope of physiological and/or 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.
  • This application provides Akkermansia muciniphila with the deposit number CGMCC No. 22793.
  • This strain is isolated from breast milk. Its colony culture characteristics include: round protrusions, neat edges, opaque, white, and uneven sizes. ; The 16S RNA sequence of this strain is shown in SEQ ID NO: 2; Compared with ATCC BAA-835, artificial gastric juice and artificial intestinal juice are better tolerated. The non-targeted metabolic difference analysis of the supernatant is shown in Figure 5 and Table 7. The effect of improving non-alcoholic fatty liver disease is more obvious, so BAA-835 can be identified as a new strain compared to ATCC.
  • This application provides Akkermansia muciniphila with the deposit number CGMCC No. 22794.
  • This strain is a strain isolated from feces. Its colony culture characteristics include: round protrusions, neat edges, opaque, white, and uneven sizes. ; The 16S RNA sequence of this strain is shown in SEQ ID NO: 1; Compared with ATCC BAA-835, artificial gastric juice and artificial intestinal juice are better tolerated. The non-targeted metabolic difference analysis of the supernatant is shown in Figure 5 and Table 7. The effect of improving non-alcoholic fatty liver disease is more obvious, so BAA-835 can be identified as a new strain compared to ATCC.
  • This application provides a probiotic combination product, which includes one of Akkermansia muciniphila deposited as CGMCC No. 22793 and Akkermansia muciniphila deposited as CGMCC No. 22794. Or both.
  • the present application provides a health food, comprising: one or both of the Akkermansia muciniphila described in the second aspect and the Akkermansia muciniphila described in the third aspect, and food accessories.
  • the health food is pastries or drinks.
  • “Nutraceutical” refers to an edible composition. It should be understood that in addition to the aforementioned Akkermansia muciniphila, the food composition is also allowed to contain any suitable other edible substances. In some embodiments, other edible substances 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 brand management regulations. Unless otherwise specified, health product management regulations refer to the current regulations at the time of production.
  • food additives also belong to edible excipients.
  • edible excipients include sugar, fructose, honey, glucose, starch, vitamins, beneficial trace elements and medium elements including calcium powder, soybean powder, mung bean powder, maltodextrin, milk powder, vegetable juice, fruit juice, spices or flavors , the edible excipients of this application can be used singly or in combination.
  • the present application provides a pharmaceutical composition, comprising: one or both of the Akkermansia muciniphila described in the second aspect and the Akkermansia muciniphila described in the third aspect, and pharmaceutical excipients. .
  • the dosage form of the medicament is pills, tablets, granules, capsules, solutions, tube feeding preparations, suspensions, creams, sprays, ointments or patches.
  • pharmaceutical composition refers to a composition that has preventive and therapeutic effects and can be used as a medicine.
  • excipients include but are not limited to mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA Sodium, 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, maltodextrin, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, Tween 80.
  • Agar Agar,
  • pharmaceutically acceptable refers to those ligands, materials, compositions and/or dosage forms that are, within the scope of reasonable medical judgment, suitable for administration to a patient and proportionate to a reasonable benefit/risk ratio.
  • 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 and absorbent agents that are compatible with the administration of the drug. Delay agents and the like. Each entity must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients in the formulation and not harmful 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 glycerin, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Bu
  • the composition for preventing and treating alcoholic fatty liver disease is a pharmaceutical composition. Further, the composition for preventing and treating alcoholic fatty liver disease contains a therapeutically effective amount of Akkermansia muciniphila.
  • a "therapeutically effective amount” refers to an amount of a pharmaceutically active ingredient that will elicit a biological or medical response in an individual in response to a disease, disorder, and/or symptom, such as a physiological and/or pharmacological positive effect in the individual.
  • the amount of the compound of the present application, the physiological and/or pharmacological positive effects include but are not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression or preventing diseases, etc.
  • the present application provides a method for cultivating the Akkermansia muciniphila described in the second aspect or/and the Akkermansia muciniphila described in the third aspect.
  • the culture conditions include: using mucin as the sole carbon source. ; Or/and, anaerobic environment; or/and, 36.5°C-37.5°C.
  • the culture conditions are not particularly limited in this application, and a medium containing animal-derived components or a medium that does not contain animal-derived components can also be used, such as CN114350571A.
  • the temperature in the culture conditions is, for example, 36.5°C, 36.6°C, 36.7°C, 36.8°C, 36.9°C, 37°C, 37.1°C, 37.2°C, 37.3°C, 37.4°C, and 37.5°C.
  • 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.
  • the 16S sequence alignment result of SEQ ID NO:1 and ATCC BAA-835 shows that the Per.Ident value is 99.43%.
  • 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 ), dilute the sample to 10 -6 according to the dilution method of 1:10, 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.
  • the 16S sequence alignment result of SEQ ID NO:2 and ATCC BAA-835 shows that the Per.Ident value is 99.22%.
  • 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%
  • ATCC BAA-835, AM02, and AM06 strains are well tolerated by artificial intestinal fluid.
  • 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.
  • Example 6 Effect of Akkermansia muciniphila on the expression of tight junction protein ZO-1 in Caco2 cells induced by TNF- ⁇ and IFN- ⁇
  • Caco2 cells were seeded into a 96-well plate and cultured until the confluence was 80%-90%. Caco2 cells were induced with 100ng/mL TNF- ⁇ +100ng/mLIFN- ⁇ for 24 hours, and then AM02, AM06, and BAA-835 were added respectively to continue with The cells were incubated for 24 hours, and the experimental groups were as shown in Table 8. Five duplicate wells were made in each group. Immunofluorescence method was used to observe the effects of BAA-835, AM06 and AM02 on the expression of tight junction protein ZO-1 in Caco2 cells induced by TNF- ⁇ and IFN- ⁇ .
  • the livers of 8-week-old C57BL/6 mice were cut into 250 ⁇ m-thick slices using a microtome.
  • the liver slices were placed in a 6-well plate and cultured using slice culture medium with a culture volume of 3 ml/well.
  • the 6-well plate was cultured overnight at 95% oxygen, 5% carbon dioxide, 37 degrees Celsius and shaking at 70 rpm.
  • inflammation was induced by adding 2 ⁇ g/mL LPS to liver slices.
  • the experimental groups are as shown in Table 10, with 3 duplicate holes in each group.
  • an appropriate amount of culture medium, LPS, AM02, AM06 and BAA-835 were added to the 6-well plate according to the grouping, and the culture was continued for 48 hours, and the medium was changed every 24 hours.
  • liver sections were taken and QPCR method was used to detect the expression levels of IL-6 and IL-1 ⁇ genes in the liver sections.
  • test substance and inducer are added at the same time.
  • LPS could significantly induce the upregulation of IL-6 and IL-1 ⁇ gene expression levels in liver slices (P ⁇ 0.01).
  • the AM06 group, AM02 group, and BAA-835 group could significantly reduce the upregulation of IL-6 and IL-1 ⁇ gene expression levels in LPS-induced liver slices (P ⁇ 0.01).
  • the expression levels of IL-6 and IL-1 ⁇ genes in the AM06 group and AM02 group were significantly lower than those in the BAA-835 group. (P ⁇ 0.05).
  • ** indicates that compared with the inflammation model group, the difference is extremely significant at P ⁇ 0.01; a indicates that compared with the BAA-835 group, the difference is extremely significant at p ⁇ 0.05.
  • Experimental design 110 male C57BL/6 mice, 5 weeks old.
  • Experimental groups blank group, model group, positive drug group (obeticholic acid OCA, 3mg/mL), AM06 low dose (10 6 CFU/mL), AM06 medium dose (10 8 CFU/mL), AM06 high dose ( 10 10 CFU/mL) group, AM02 (10 8 CFU/mL) group, ATCC BAA-835 (10 8 CFU/mL) group, and the inactivated bacteria group of AM06, AM02 and BAA-835 (the dosage of each group Both are 10 8 CFU/mL). 10 animals per group. After a one-week adaptation period, the blank group was fed with ordinary feed, and the other groups except the blank group were fed with high-fat feed and given corresponding drugs at the same time.
  • mice After 10 weeks of administration, the mice were fasted for 6 hours and then euthanized with CO2 . Blood samples are collected by cardiac puncture. Separate serum to detect relevant indicators. Terminal body weight and liver weight were recorded. The liver tissue was removed and fixed in formalin for histopathological examination.
  • a means that compared with the BAA-835 medium-dose group, the difference is significant at p ⁇ 0.05, aa means that compared with the BAA-835 medium-dose group, the difference is extremely significant at p ⁇ 0.01;
  • b means that compared with the BAA-835 medium-dose group, the difference is significant at p ⁇ 0.05; bb means that compared with the BAA-835 medium-dose group, the difference is extremely significant at p ⁇ 0.01;
  • the weight of the mice in the model group increased significantly (p ⁇ 0.01), while the liver weight tended to increase, but there was no significant difference.
  • the AM06 medium-dose group and the AM06 inactivated bacteria group can significantly reduce body weight (p ⁇ 0.05).
  • the other administration groups have a tendency to reduce the body weight and liver weight of mice, but there is no significant difference.
  • HE staining of liver pathology was performed on mice in each group, and the scores were scored based on the degree of steatosis of the sections, the degree of ballooning degeneration of hepatocytes, and the degree of inflammation in the lobules, and the non-alcoholic fatty liver NAS score was calculated.
  • the results are shown in Table 7.
  • the NAS score of the model group increased significantly (p ⁇ 0.05), indicating that the animals developed non-alcoholic fatty liver disease.
  • each administration group can reduce NAS points to varying degrees
  • AM06 mid- and low-dose groups and inactivated strains can significantly reduce NAS points (p ⁇ 0.05).
  • the NAS scores of live bacteria of AM02 and AM06 are significantly lower than those of BAA-835 live bacteria (p ⁇ 0.05), and the NAS scores of inactivated bacteria of AM02 and AM06 tend to be lower than those of BAA-835 inactivated bacteria. , indicating that the live and inactivated bacteria of AM02 and AM06 are more effective than BAA-835 live and inactivated bacteria in preventing non-alcoholic fatty liver disease.
  • ALT and AST serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of mice were detected.
  • the results are shown in Table 7.
  • the ALT and AST of the mice in the model group were significantly increased (p ⁇ 0.01), indicating that the liver Functionality is compromised.
  • Each administration group can reduce the levels of ALT and AST in serum to varying degrees.
  • the positive drug group, AM06 low and high dose group, AM06 inactivated bacteria group and AM02 inactivated bacteria group can significantly reduce ALT (p ⁇ 0.05).
  • the positive drug group, all live bacteria group, AM06 inactivated bacteria group and AM02 inactivated bacteria group can significantly reduce AST (p ⁇ 0.05).
  • the AST content of live bacteria of AM02 and AM06 is slightly lower than that of BAA-835 live bacteria, and the AST content of inactivated bacteria of AM02 and AM06 is slightly lower than that of inactivated BAA-835 bacteria. This shows that AM02 and AM06 have slightly better protective effects on the liver than BAA-835.
  • mice The results of testing the serum LPS content of mice are shown in Table 7.
  • the LPS of mice in the model group increased significantly (p ⁇ 0.01), indicating that the model animals had mild endotoxemia.
  • the positive drug group failed to reduce the LPS in serum, while each Akkermansia muciniphila group could reduce the LPS content to varying degrees, among which the live bacteria medium-dose groups of AM02 and AM06, the live bacteria group of AM02 and AM06
  • the inactivated bacteria group can significantly reduce the LPS content (p ⁇ 0.05).
  • the medium-dose live bacteria group of AM02 and AM06 has a significantly better ability to reduce serum LPS than the BAA-835 live bacteria group (p ⁇ 0.05), while the inactivated bacteria group of AM02 and AM06 is slightly better than the BAA-835 inactivated bacteria group. , but there is no significant difference.
  • Akkermansia muciniphila can effectively prevent non-alcoholic fatty liver disease in mice, reduce liver damage and inhibit mild endotoxemia, and the efficacy of each strain is AM06 ⁇ AM02>BAA-835.
  • Example 10 Experiment on the efficacy of Akkermansia muciniphila in treating non-alcoholic steatohepatitis and liver fibrosis in mice
  • Experimental design 110 male C57BL/6 mice, 5 weeks old.
  • Experimental groups blank group, model group, positive drug group (obeticholic acid OCA, 3mg/mL), AM06 low dose (10 6 CFU/mL), AM06 medium dose (10 8 CFU/mL), AM06 high dose ( 10 10 CFU/mL) group, AM02 (10 8 CFU/mL) group, ATCC BAA-835 (10 8 CFU/mL) group, and the inactivated bacteria group of AM06, AM02 and BAA-835 (the dosage of each group Both are 10 8 CFU/mL). 10 animals per group.
  • the blank group was fed with ordinary feed.
  • the remaining groups except the blank group were fed high-fat feed until the 10th week, and then were fed modified high-fat feed (increased cholesterol content) from the 10th to 18th week of the experiment.
  • Each administration group started to receive administration from the 10th week to the 18th week.
  • mice After the administration, the mice were fasted for 6 hours and then euthanized with CO2 . Blood samples are collected by cardiac puncture. Separate serum to detect relevant indicators. Terminal body weight and liver weight were recorded. The liver tissue was removed and fixed in formalin for histopathological examination.
  • a means that compared with the BAA-835 medium-dose group, the difference is significant at p ⁇ 0.05, aa means that compared with the BAA-835 medium-dose group, the difference is extremely significant at p ⁇ 0.01;
  • b means that compared with the BAA-835 medium-dose group, the difference is significant at p ⁇ 0.05; bb means that compared with the BAA-835 medium-dose group, the difference is extremely significant at p ⁇ 0.01;
  • the weight of the mice in the model group increased significantly (p ⁇ 0.01), and the liver weight tended to increase, but there was no significant difference.
  • the AM06 low-dose group and the AM02 inactivated bacteria group could significantly reduce body weight (p ⁇ 0.05).
  • the other administration groups had a tendency to reduce the body weight and liver weight of mice, but there was no significant difference.
  • HE staining of liver pathology was performed on mice in each group, and the scores were scored based on the degree of steatosis of the sections, the degree of ballooning degeneration of hepatocytes, and the degree of inflammation in the lobules, and the non-alcoholic fatty liver NAS score was calculated.
  • the results are shown in Table 8.
  • the NAS score of the model group increased significantly (p ⁇ 0.05), indicating that the animals developed non-alcoholic fatty liver disease.
  • each administration group can reduce NAS points to varying degrees, and the positive drug group, AM06 mid-dose group, AM02 mid-dose group, AM02 and AM06 inactivated strains can significantly reduce NAS points (p ⁇ 0.05 ).
  • the NAS scores of live bacteria of AM02 and AM06 were significantly lower than those of BAA-835 live bacteria (p ⁇ 0.05), and the NAS scores of inactivated bacteria of AM02 and AM06 were significantly lower than those of BAA-835 inactivated bacteria, indicating that AM02 and AM06 are effective in treating Prevent non-alcoholic beverages
  • the efficacy of spermatozoa fatty liver disease is better than BAA-835.
  • mice serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of mice were detected.
  • the results are shown in Table 8.
  • the ALT and AST of the mice in the model group were significantly increased (p ⁇ 0.01), indicating that the liver Functionality is compromised.
  • the ALT levels of all administration groups were significantly reduced (p ⁇ 0.05), and the AST levels of the administration groups except the BAA-835 mid-dose group were significantly decreased (p ⁇ 0.05).
  • the ALT content of live or inactivated bacteria of AM02 and AM06 was significantly lower than that of BAA-835 live or inactivated bacteria (p ⁇ 0.05).
  • the AST content of AM02 live bacteria was significantly lower than that of BAA-835 live bacteria (p ⁇ 0.05), and the AST content of AM06 live bacteria was slightly lower than BAA-835 live bacteria, but there was no significant difference.
  • the AST content of AM02 and AM06 inactivated bacteria was significantly lower than that of BAA-835 inactivated bacteria (p ⁇ 0.05). This shows that AM02 and AM06 have better protective effects on the liver than BAA-835.
  • the liver tissue of mice was taken and QPCR method was used to detect the relative mRNA expression of fibrosis-related gene Col1a1.
  • the results are shown in Table 8.
  • the expression of Col1a1 in the model group mice was significantly increased (p ⁇ 0.01), indicating that liver fibrosis occurred in the liver of the model animals.
  • all administration groups except the BAA-835 mid-dose group could significantly reduce the expression of Col1a1 (p ⁇ 0.05).
  • the BAA-835 mid-dose group had a tendency to reduce the expression of Col1a1, but there was no significance. difference.
  • Akkermansia muciniphila can effectively treat non-alcoholic steatohepatitis in mice, reduce liver damage and inhibit liver fibrosis, and the efficacy of each strain is AM06 ⁇ AM02>BAA-835.
  • Akkermansia muciniphila especially Akkermansia muciniphila AM06 with deposit number CGMCC No. 22793 and Akkermansia muciniphila AM02 with deposit number CGMCC No. 22794 , in in vitro experiments, its tolerance to artificial gastric juice and artificial intestinal juice, its ability to inhibit inflammatory factors from destroying tight junction proteins in intestinal cells, and its ability to inhibit LPS-induced hepatitis in liver slices were all better than the standard strain BAA-835.
  • AM02 and AM06 bacteria can effectively prevent or treat non-alcoholic alcoholic diseases by reducing liver steatosis and hepatitis, improving liver function indicators (such as ALT and AST levels), reducing mild endotoxemia, and inhibiting liver fibrosis.
  • liver function indicators such as ALT and AST levels
  • reducing mild endotoxemia and inhibiting liver fibrosis.
  • the occurrence and development of fatty liver and its deterioration can improve the patient's quality of life.

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Abstract

Des souches d'Akkermansia muciniphila, qui ont respectivement les numéros de conservation CGMCC No. 22793 et CGMCC No. 22794, des produits de combinaison probiotiques comprenant lesdites souches, un aliment de santé ou une composition pharmaceutique, un procédé de culture des souches, et une application des souches dans la préparation d'un aliment de santé ou d'un médicament pour prévenir et traiter une stéatose hépatique non alcoolique. Les souches obtenues par séparation peuvent être utilisées pour prévenir et traiter l'apparition, le développement et l'aggravation de la stéatose hépatique non alcoolique, peuvent réduire la graisse hépatique et l'hépatite, améliorer les indicateurs de fonction hépatique, réduire l'endotoxémie légère et inhiber la fibrose hépatique.
PCT/CN2023/099055 2022-06-08 2023-06-08 Akkermansia muciniphila, son utilisation et son procédé de culture WO2023237038A1 (fr)

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CN114949003A (zh) * 2022-06-08 2022-08-30 广州知易生物科技有限公司 嗜粘蛋白阿克曼菌及其应用和培养方法

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CN108289918A (zh) * 2015-09-10 2018-07-17 卢万天主教大学 经巴氏灭菌的艾克曼菌用于治疗代谢病症的用途
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