Bacterial strain, composition, drug combination, and use

Abstract

To provide a drug combination that enhances the effect of a hypoglycemic agent or a lipid-lowering drug.SOLUTION: A drug combination comprises a microorganism and a hypoglycemic agent or a lipid-lowering drug, wherein the microorganism is a bacterial strain of Christensenella sp. species which is Gram-negative, and the hypoglycemic agent or lipid-lowering drug is one or more drugs capable of improving sensitivity to the glucagon-like peptide-1 pathway and complementing and / or enhancing GLP-1 activity, and wherein the bacterial strain has a 16S rRNA gene comprising a base sequence having at least 98.7% identity to the base sequence shown in SEQ ID NO: 1.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This disclosure claims priority to Chinese patent applications bearing application numbers 202110369840.5 (filing date April 6, 2021, entitled "Bacterial Strain and Composition and Use") and 202110370249.1 (filing date April 6, 2021, entitled "Combination Drug Comprising a Microorganism and a Hypoglycemic or Hypolipidemic Drug"), the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to the isolation and application technical field of bacterial strains, specifically to bacterial strains and compositions, drug combinations and uses, the drug combinations including the bacterial strains and hypoglycemic or hypolipidemic drugs. [Background technology]

[0003] At present, liver disease is mainly prevented and treated by administering hepatitis vaccines, reducing alcohol consumption, improving dietary habits and physical training.However, these policies often only serve as a preventative measure, and the benefits are small, and the effectiveness varies depending on individual constitutions.Once liver disease has already occurred, it seems that there is nothing that can be done.Therefore, there is an urgent need to develop countermeasures that can effectively prevent and treat liver disease, and it is necessary to develop methods or drugs that are effective and have few side effects and can prevent and treat liver disease.

[0004] Gastrointestinal mucosal disorders, especially intestinal mucosal disorders, not only affect the digestion and absorption of nutrients, but also have extremely adverse effects on mucosal barrier function and biological immune function. The commonly used Chinese and Western combined drug repair method for gastrointestinal mucosal disorders always has drawbacks such as slow medicinal effect of traditional Chinese medicine, difficulty in complete cure, and prone to recurrence, and Western medicine is prone to irritation and adverse reactions to the digestive system. There is an urgent need to develop drugs that can repair gastrointestinal mucosal disorders with fast medicinal effect, long-lasting efficacy, and no toxic side effects.

[0005] Currently, there is no cure for diabetes, and diabetes is primarily controlled through drug therapy. Current drug therapies for diabetes include oral medications such as sulfonylureas, biguanides, α-glucosidase inhibitors, insulin sensitizers, and insulin injections. While several drugs are available for the treatment of T2D (type 2 diabetes), their therapeutic effects vary from person to person, and they have concerning potential side effects, including (1) gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea; (2) increased pancreatic islet burden, potentially leading to pancreatitis; (3) potential thyroid enlargement and thyroid cancer; (4) several other side effects, such as intestinal, renal, and hypoglycemic effects; and (5) a tendency to cause depression. Therefore, there is an urgent need to develop methods or drugs for treating diabetes that are effective and have minimal side effects.

[0006] Drug treatment of obesity has a long history, and currently commonly used weight loss drugs include liraglutide, orlistat, sibutramine, rimonabant, etc. However, many weight loss drugs are restricted in the market or have been withdrawn from clinical use, because some of them do not achieve the expected effects or some of them cause serious adverse reactions in patients. Therefore, there is an urgent need to develop methods or drugs for treating obesity and its related diseases that are effective and have minimal side effects. Summary of the Invention [Problem to be solved by the invention]

[0007] Objectives of the present disclosure include, for example, providing bacterial strains and compositions, combination drugs and uses to solve the above technical problems, the combination drug including a microorganism and a hypoglycemic or hypolipidemic drug.

[0008] Due to the novel role of gut microbes in obesity and diabetes, utilizing gut microbes to improve diabetes, the interaction between gut microbes and antidiabetic drugs, and their impact on drug function are currently the focus of research. On the one hand, gut microbes can affect host metabolism, immune function, and brain function through pathways such as the secretion of short-chain fatty acids, which have essential effects on human health. On the other hand, the metabolic activity of gut microbes and their metabolites affects drug metabolism and efficacy, and drugs can also manipulate the composition and metabolic capacity of gut microbes.

[0009] The present disclosure provides a Christensenella bacterium (Christensenella sp.) that can treat early steatohepatitis lesions, delay fat accumulation in the liver, and alleviate liver lesions, thereby effectively preventing and treating liver dysfunction and related diseases. At the same time, this strain also has the function of repairing the gastrointestinal mucosal barrier, reducing the body's fasting blood glucose, regulating insulin levels, reducing body weight, and regulating blood lipid levels, thereby having the effect of preventing and treating gastrointestinal mucosal disorders and related diseases, diabetes, obesity, and obesity-related diseases. [Means for solving the problem]

[0010] The present disclosure provides the use of a bacterial strain of the species Christensenella in the manufacture of a drug for treating or preventing at least one disease or condition selected from liver dysfunction and diseases associated with liver dysfunction, gastrointestinal mucosal disorders and diseases associated with gastrointestinal mucosal disorders, diabetes, obesity, and obesity-related diseases.

[0011] The liver dysfunction-related disease includes at least one disease selected from the group consisting of fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and liver cancer; Gastrointestinal mucosal damage refers to increased permeability of the gastrointestinal mucosa and damage to the mucosal barrier function, and diseases associated with gastrointestinal mucosal damage include at least one of leaky intestinal wall, peptic ulcer, gastroenteritis, and inflammatory bowel disease; and Obesity-related diseases include at least one of obesity, metabolic syndrome, cardiovascular disease, hyperlipidemia, hypercholesterolemia, hypertension, insulin resistance syndrome, obesity-related gastroesophageal reflux disease, and steatohepatitis.

[0012] In one or more embodiments of the present disclosure, the bacterial strain has a 16s rRNA sequence that is at least 98.65% identical to SEQ ID NO.1.

[0013] In one or more embodiments of the present disclosure, the bacterial strain has a 16s rRNA sequence that is at least 99% identical to SEQ ID NO.1.

[0014] In one or more embodiments of the present disclosure, the bacterial strain has a 16s rRNA sequence that is 99%, 99.5%, 99.9% or 100% identical to SEQ ID NO.1.

[0015] In one or more embodiments of the present disclosure, the drug is lyophilized.

[0016] In one or more embodiments of the present disclosure, the medicament further comprises one or more pharmaceutically acceptable excipients or carriers.

[0017] In one or more embodiments of the present disclosure, the drug is a vaccine composition.

[0018] In one or more embodiments of the present disclosure, the drug is formulated for oral administration, injection administration, or intragastric administration.

[0019] In one or more embodiments of the present disclosure, diabetes includes at least one of type 1 diabetes, type 2 diabetes, insulin resistance syndrome, glucose intolerance, dyslipidemia, diabetic nephropathy complications, diabetic neuropathy, diabetic eye disease, cardiovascular disease, diabetic foot, and gestational diabetes.

[0020] In one or more embodiments of the present disclosure, the dosage forms of the drug include tablets, pills, powders, suspensions, gels, emulsions, creams, granules, nanoparticles, capsules, suppositories, injections, sprays and injections.

[0021] The present disclosure provides cells of the Christensenella strain deposited under accession number GDMCC No: 61117 or a progeny or subcloned strain thereof.

[0022] The present disclosure provides compositions comprising the above-described Christensenella strain and / or metabolic products of this strain.

[0023] In one or more embodiments of the present disclosure, the composition further comprises a pharmaceutically acceptable excipient or carrier.

[0024] The present disclosure provides the use of a combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug in the manufacture of a drug for treating or preventing at least one disease or symptom selected from liver dysfunction and liver dysfunction-related diseases, diabetes, obesity and obesity-related diseases, wherein the microorganism is a bacterium of the Christensenella sp. species, and the hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 (i.e., GLP-1) pathway sensitivity and complement and / or promote GLP-1 action.

[0025] In one or more embodiments of the present disclosure, the hypoglycemic or hypolipidemic agent is at least one of a GLP-1 receptor agonist (i.e., GLP-1RA) or GLP-1 mimetic, a GIP receptor agonist (i.e., glucose-dependent insulinotropic polypeptide receptor agonist, also known as gastric inhibitory polypeptide), and a dipeptidyl peptidase-4 (i.e., DPP-4) inhibitor.

[0026] The GLP-1 receptor agonist or GLP-1 mimetic is at least one selected from exenatide, liraglutide, semaglutide, oral semaglutide, benaglutide, lixisenatide and weekly exenatide formulations.

[0027] The present disclosure provides a combination drug, the combination drug comprising a hypoglycemic or hypolipidemic drug and a microorganism, wherein the microorganism is a bacterium of the species Christensenella sp. The hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 pathway sensitivity and complement and / or enhance GLP-1 action.

[0028] The present disclosure provides a use of the composition as described above or the combination drug as described above in the manufacture of a drug or a formulation, wherein the drug or formulation comprises: Reducing liver weight; Treating early steatohepatitis lesions; Slowing down fat accumulation in liver cells, Reduce serum AST and ALT levels, Reducing inflammatory lesions in abdominal white fat; Reducing the body weight of a mammal; Reducing food intake in mammals; Delaying the recurrence of obesity after discontinuation, Reducing body fat in a mammal; reducing the level of at least one indicator of total cholesterol level, low density lipoprotein and triglyceride level in the serum of the mammal; Increasing serum high density lipoprotein levels in a mammal; ameliorating oral glucose tolerance impairment in mammals; Reducing fasting blood glucose in a mammal; Reducing the HOMA-IR index in a mammal; Enhance GLP-1 sensitivity and Enhances insulin sensitivity and Avoiding GLP-1RA resistance and associated side effects due to intestinal disorders, and and repairing gastrointestinal mucosal damage.

[0029] The present disclosure provides a composition comprising the above-mentioned Christensenella sp. bacterial strain or the above-mentioned Christensenella strain or its descendant or subcloned strain and / or its metabolic product, and is used to treat or prevent at least one disease or condition selected from liver dysfunction and diseases associated with liver dysfunction, gastrointestinal mucosal disorders and diseases associated with gastrointestinal mucosal disorders, diabetes, obesity and obesity-related diseases.

[0030] In one or more embodiments of the present disclosure, the excipients include antioxidants, chelating agents, emulsifiers, and solvents.

[0031] The present disclosure provides a combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug, wherein the microorganism is a bacterial strain of the Christensenella sp. species described above, or the Christensenella strain or its descendant or subcloned strain and / or a metabolite thereof, and the hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 pathway sensitivity and complement and / or promote GLP-1 action, and is used to treat or prevent at least one disease or condition selected from liver dysfunction and liver dysfunction-related diseases, diabetes, obesity and obesity-related diseases.

[0032] The present disclosure provides a method for treating or preventing a disease or condition, the method comprising administering the composition or the combination drug to a subject in need thereof, wherein the disease or condition is at least one selected from liver dysfunction and liver dysfunction-related diseases, diabetes, obesity, and obesity-related diseases.

[0033] The present disclosure provides a kit, which includes the above-described combination drug. [Effects of the Invention]

[0034] The present disclosure has the following beneficial effects:

[0035] The presently disclosed Christensenella can be used to treat or prevent liver dysfunction and related diseases, gastrointestinal mucosal damage and related diseases, diabetes, obesity, and obesity-related diseases. The applicant's testing has shown that the presently disclosed Christensenella has no toxic side effects on the kidneys, and can reduce liver weight, treat early steatohepatitis lesions, delay fat accumulation in liver cells, reduce serum AST and ALT, and reduce inflammatory lesions in abdominal white fat. Christensenella can reduce fasting blood glucose levels and significantly improve insulin resistance, thereby preventing and treating diabetes. Christensenella can also reduce body fat in mammals and improve metabolic function in obese patients. Christensenella can also repair damaged gastrointestinal mucosa and prevent and treat mucosal damage-related diseases.

[0036] The combination of a hypoglycemic or hypolipidemic drug and a microorganism according to the present disclosure can be used to treat or prevent liver dysfunction and liver dysfunction-related diseases, diabetes, obesity, and obesity-related diseases. The applicant's testing has shown that the combination of a GLP-1 receptor agonist or GLP-1 mimetic and a microorganism according to the present disclosure achieves the technical effect of synergistically enhancing efficacy, and this combination has a superior therapeutic effect to the administration of a microorganism alone or a GLP-1 receptor agonist or a GLP-1 mimetic alone. The microorganism can enhance the slimming effect of the GLP-1 receptor agonist or GLP-1 mimetic, improve impaired glucose tolerance, and reduce fasting blood glucose. Furthermore, the combination can reduce liver weight without causing toxic side effects to the kidney. The combination enhances GLP-1 sensitivity, helping to avoid GLP-1RA resistance and related side effects caused by intestinal disorders. [Brief explanation of the drawings]

[0037] In order to more clearly explain the technical solutions of the embodiments of the present disclosure, the following briefly introduces the drawings that need to be used in the embodiments. It should be understood that the following drawings only illustrate some examples of the present disclosure, and therefore should not be considered as limiting the scope. Those skilled in the art can also obtain other related drawings based on these drawings without exerting creative efforts. [Figure 1] Macromorphology of the isolated strains. [Figure 2] Micromorphology of isolated strains. [Figure 3] FIG. 1 shows a microplate after single colony anaerobic cultivation. [Figure 4] This is a phylogenetic evolutionary tree. [Figure 5] This is a scoring standard for NASH liver damage. [Figure 6] Effect of MNO-863 on liver weight in obese model mice. [Figure 7] FIG. 1 shows the results of HE staining of liver tissue. [Figure 8] FIG. 1 shows the results of Oil Red staining of liver tissue. [Figure 9] NAFLD / NASH liver pathology score. [Figure 10] FIG. 10 is a graph showing the statistical results of the degree of hepatic fatty degeneration. [Figure 11] FIG. 10 is a graph showing the statistical results of hepatic lobule inflammation scores. [Figure 12] FIG. 10 is a graph showing the statistical results of liver ballooning scores. [Figure 13] Serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels. [Figure 14] FIG. 1 shows microscopic images and total area statistics of abdominal white adipose inflammatory lesions in mice. [Figure 15] FIG. 1 shows the results of detecting the contents of creatinine (CREA), urea (UREA) and uric acid (UA) in the blood of mice. [Figure 16]Effect of MNO-863 on oral glucose tolerance in high-fat diet-induced obese mice. [Figure 17] Effect of MNO-863 on fasting blood glucose (mmol / L) in high-fat diet-induced obese mice. [Figure 18] Effect of MNO-863 on the HOMA-IR index in high-fat diet-induced obese mice. [Figure 19] Effect of MNO-863 on body weight (g) in high-fat diet-induced obese mice. [Figure 20] Effect of MNO-863 on body weight (%) in high-fat diet-induced obese mice. [Figure 21] Effect of MNO-863 on food intake (g) in high-fat diet-induced obese mice. [Figure 22] The effects of MNO-863 on TC, TG, LDL, and HDL-C in high-fat diet-induced obese mice. [Figure 23] The effects of MNO-863 on inguinal fat, subcutaneous fat, and epididymal fat in high-fat diet-induced obese mice. [Figure 24] FIG. 1 shows a micrograph of colon tissue from a mouse in the HFD control group. [Figure 25] FIG. 1 shows a micrograph of ileal tissue from a mouse in the HFD control group. [Figure 26] FIG. 1 shows microscopic images of colon tissues from mice treated with MNO-863. [Figure 27] FIG. 1 shows a micrograph of ileal tissue from mice treated with MNO-863. [Figure 28] FIG. 1 shows a micrograph of colon tissue from a mouse in the NCD control group. [Figure 29] FIG. 1 shows a micrograph of ileal tissue from an NCD control mouse. [Figure 30] 1 shows the effects of combined administration of MNO-863 and Liraglutide on absolute body weight and the rate of weight change in obese mice over a 4-week intervention period. [Figure 31] Body weight and percent weight change after 4 weeks of intervention. [Figure 32] Body weight and weight change rate after 4 weeks of intervention and 4 weeks of withdrawal. [Figure 33] This is the inguinal fat weight after 4 weeks of drug discontinuation and recurrence of obesity. [Figure 34] The effect of the MNO-863 strain alone and in combination with Liraglutide on glucose tolerance in obese mice. [Figure 35] The effects of the MNO-863 strain alone and in combination with Liraglutide on glucose hyperglycemia in obese mice. [Figure 36] This shows the effect on hyperglycemia after relapse of obesity in obese mice induced by the MNO-863 strain after 4 weeks of drug withdrawal. [Figure 37] FIG. 10 is a graph showing the effect of the MNO-863 strain alone and the combined use of the strain and Liraglutide on liver weight after a 4-week drug withdrawal and recurrence of obesity. DETAILED DESCRIPTION OF THE INVENTION

[0038] Reference will now be made in detail to embodiments of the present disclosure, one or more examples of which are described below. Each example is provided as an illustration, not a limitation, of the disclosure. In fact, it will be apparent to those skilled in the art that various modifications and variations of the present disclosure can be made without departing from the scope or spirit of the disclosure. For example, features illustrated or described as part of one embodiment can be used with another embodiment to yield still further embodiments.

[0039] The present invention relates to the use of a bacterial strain of the species Christensenella in the manufacture of a drug for treating or preventing at least one disease or condition selected from liver dysfunction and diseases associated with liver dysfunction, gastrointestinal mucosal disorders and diseases associated with gastrointestinal mucosal disorders, diabetes, obesity, and obesity-related diseases.

[0040] Use of a combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug in the manufacture of a drug for treating or preventing at least one disease or symptom selected from liver dysfunction and liver dysfunction-related diseases, diabetes, obesity and obesity-related diseases, wherein the microorganism is a bacterium of the Christensenella sp. species, and the hypoglycemic or hypolipidemic drug is one or more of drugs that can improve pathway sensitivity of glucagon-like peptide-1 (i.e., GLP-1) and complement and / or promote GLP-1 action.

[0041] The liver dysfunction-related disease includes at least one of fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cirrhosis.

[0042] In another embodiment, the liver dysfunction-related diseases further include liver fibrosis and liver cancer.

[0043] Gastrointestinal mucosal damage refers to an increase in permeability of the gastrointestinal mucosa and damage to the mucosal barrier function, and diseases associated with gastrointestinal mucosal damage include at least one of diseases such as leaky intestinal wall, peptic ulcer, gastroenteritis, and inflammatory bowel disease. It should be noted that leaky intestinal wall is expressed as an increase in intestinal permeability.

[0044] Obesity-related diseases include at least one of cardiovascular disease, hyperlipidemia, insulin resistance syndrome, obesity-related gastroesophageal reflux disease, and steatohepatitis.

[0045] In other embodiments, the obesity-related disorders further include obesity, metabolic syndrome, hypercholesterolemia, and hypertension.

[0046] In other embodiments, the "obesity-related disorder" may be selected from overeating, binge eating, starvation, hypertension, diabetes, elevated plasma insulin levels, insulin resistance, hyperlipidemia, metabolic syndrome, insulin resistance syndrome, obesity-related gastroesophageal reflux disease, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, cardiac hypertrophy and left ventricular hypertrophy, lipid metabolism disorders, non-alcoholic steatohepatitis, cardiovascular disease and polycystic ovary syndrome, and those subjects having an obesity-related disorder and including a desire to lose weight.

[0047] The three main types of diabetes are type 1 diabetes (T1D), type 2 diabetes (T2D), and gestational diabetes mellitus (GDM). Type 1 diabetes is caused by autoimmune or idiopathic causes and is characterized by the complete destruction of pancreatic islet function. It is common in children and adolescents and, unless treated with insulin, is unsatisfactory and potentially life-threatening. Type 2 diabetes is a multifactorial syndrome characterized by abnormal carbohydrate and fat metabolism and generally includes hyperglycemia, hypertension, and cholesterol abnormalities. Because type 2 diabetes is caused by the ineffective action of insulin (low receptor binding), not only fasting blood glucose levels but also 2-hour postprandial blood glucose levels should be monitored, with particular emphasis on islet function testing. There are two types of diabetes during pregnancy: one is when diabetes is already diagnosed before pregnancy, which is called "pregnancy with diabetes," and the other is when diabetes appears or is diagnosed during pregnancy in women with normal glucose metabolism or underlying impaired glucose tolerance before pregnancy, also called "gestational diabetes mellitus (GDM)." More than 80% of pregnant women with diabetes have GDM.

[0048] It should be noted that the diabetic applications of the above pharmaceutical uses include, but are not limited to, the treatment or prevention of type 1 diabetes (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM).

[0049] It is further necessary to explain that the above-mentioned use for treating obesity and obesity-related diseases not only includes the combination of the bacterial strain of the present disclosure with a hypoglycemic or hypolipidemic drug, but also includes other active compounds, and the other active compounds may be a combination of two or more other active compounds. For example, in the combination of the above-mentioned combination drug with an anti-obesity compound, the anti-obesity compound may be, for example, fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, a neuropeptide Y5 inhibitor and a β3-adrenergic receptor agonist.

[0050] In addition, in the case of the combined use of the above-mentioned concomitant drug and a cholesterol-lowering agent, the cholesterol-lowering agent may be, for example, (i) an HMG-CoA reductase inhibitor (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, divastatin, pitavastatin, rosuvastatin, and other statin drugs), (ii) a chelating compound (cholestyramine, a dialkylaminoalkyl derivative of colestipol and cross-linked dextran), (iii) a nicotinyl alcohol (iv) PPARα agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) PPARα / γ dual-acting agonists, such as KRP-297, (vi) cholesterol absorption inhibitors, such as β-sitosterol and ezetimibe, (vii) acetyl-CoA cholesterol acyltransferase inhibitors, such as avasimibe, and (viii) antioxidants, such as probucol.

[0051] In other embodiments, it may be used in combination with other anti-inflammatory medications such as aspirin, nonsteroidal anti-inflammatory drugs, glucocorticosteroids, sulfasalazine and cyclooxygenase II selective inhibitors.

[0052] In one or more embodiments of the present disclosure, the bacterial strain has a 16s rRNA sequence that is at least 98.65% identical to SEQ ID NO. 1. For example, the bacterial strain has a 16s rRNA sequence that is 98.7%, 98.75%, 98.8%, 98.85%, 98.9%, 98.95%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100% identical to SEQ ID NO. 1.

[0053] In one or more embodiments of the present disclosure, the Christensenella bacterial strain has a 16s rRNA sequence that is at least 99% identical to SEQ ID NO.1.

[0054] In one or more embodiments of the present disclosure, the Christensenella bacterial strain has a 16s rRNA sequence that is 99%, 99.5%, 99.9% or 100% identical to SEQ ID NO.1.

[0055] In one or more embodiments of the present disclosure, the drug is freeze-dried. Freeze-drying is an effective and convenient technique for producing a stable composition that allows for bacterial delivery. The drug can be powdered or tableted by freeze-drying, making it easy to coat or transport.

[0056] In one or more embodiments of the present disclosure, the medicament further comprises one or more pharmaceutically acceptable excipients or carriers.

[0057] The pharmaceutically acceptable excipients may be antioxidants, chelating agents, emulsifiers, solvents, and the like.

[0058] Drug dosage forms include, but are not limited to, tablets, pills, powders, suspensions, gels, emulsions, creams, granules, nanoparticles, capsules, suppositories, injections, sprays and injections.

[0059] The above-mentioned drugs may further include pharmaceutically acceptable salts, solvates, or stereoisomers thereof. The drug compositions formed with one or more pharmaceutical carriers and / or diluents may be formulated into any clinically or pharmaceutically acceptable dosage form in a manner known in the art and administered to patients in need of such treatment by oral, injection, or intragastric administration. When used for oral administration, the drugs may be prepared into conventional solid preparations such as tablets, capsules, pills, and granules, or into oral liquid preparations such as oral liquids, oral suspensions, and syrups. When prepared into oral preparations, appropriate fillers, adhesives, disintegrants, lubricants, etc. may be added.

[0060] In one or more embodiments of the present disclosure, the drug is a vaccine composition.

[0061] In one or more embodiments of the present disclosure, the drug is formulated for oral administration, injection, or intragastric administration. Results of intragastric administration experiments in mice show that administration of the bacterial strain of the present disclosure exhibits therapeutic effects comparable to those of liraglutide, a diabetes treatment drug.

[0062] In one or more other embodiments, the drug further comprises a pharmaceutically acceptable salt, where a "pharmaceutically acceptable salt" is a salt that is suitable for use, within sound medical judgment, in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit / risk ratio.

[0063] The cells are of the Christensenella strain deposited under accession number GDMCC No: 61117 or its progeny or subcloned strain.

[0064] The Christensenella sp. MNO-863 bacterium disclosed herein was isolated from a fecal sample of a healthy male volunteer of Han Chinese descent from Guangzhou City, Guangdong Province. It was deposited at the Guangdong Provincial Microorganism Depository on August 4, 2020. The deposit number is GDMCC No: 61117, and the deposit address is Guangdong Provincial Institute of Microbiology, 5th Floor, Building 59, Courtyard, No. 100, Xianlie Middle Road, Guangzhou City. The detection result was viable, and the taxonomic name is Christensenella sp.

[0065] Macromorphology: After 72 hours of anaerobically culture at 37°C, colonies were pale yellow, round, moist, translucent, and had regular edges. The cells were short, rod-shaped, non-spore, non-flagellated, and non-motile, measuring 0.3-0.4 μm x 0.6-1.1 μm, arranged singly or in pairs, and Gram-negative. Colony characteristics: MNO-863 was cultured anaerobically on a 104 plate at 37°C for 72 hours. Single colonies exhibited round, microscopic projections, were transparent and white, had a smooth surface, and were approximately 0.46-0.50 mm in diameter.

[0066] The present disclosure further provides a composition, which comprises the above-described Christensenella strain and / or a metabolic product of this strain.

[0067] The above-mentioned Christensenella strain may be obtained by directly culturing the strain deposited under the above-mentioned accession number GDMCC No: 61117, or it may be a strain cultured from a child strain (progeny strain) or the original strain (subcloned strain), for example, an isolated cell.

[0068] It should be noted that the Christensenella strain according to the present disclosure further includes derivatives thereof, which can be modified at the genetic level without eliminating its biological activity, and the derivative strains have therapeutic activity and have activity comparable to that of the Christensenella strain deposited under accession number GDMCC No: 61117.

[0069] In one or more embodiments of the present disclosure, the composition further comprises a pharmaceutically acceptable excipient or carrier.

[0070] Use of the composition as described above in the manufacture of a drug or a pharmaceutical preparation, wherein the drug or pharmaceutical preparation comprises: The composition is used for at least one use selected from the group consisting of reducing liver weight, treating early steatohepatitis lesions, slowing fat accumulation in liver cells, reducing serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase), reducing inflammatory lesions in abdominal white fat, reducing the body weight of a mammal, reducing food intake of a mammal, reducing body fat of a mammal, reducing the level of at least one indicator of total cholesterol level, low-density lipoprotein level, and triglyceride level in the serum of a mammal, improving the serum high-density lipoprotein level of a mammal, improving oral glucose tolerance injury in a mammal, reducing fasting blood glucose in a mammal, reducing the HOMA-IR index in a mammal, and repairing gastrointestinal mucosal damage.

[0071] The following are uses in the treatment of liver damage and its related diseases, namely, reducing liver weight, treating early steatohepatitis lesions, delaying fat accumulation in liver cells, reducing serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels, and reducing inflammatory lesions in abdominal white fat.

[0072] The following are uses in the treatment or prevention of obesity and its related diseases, namely, reducing the body weight of a mammal, reducing food intake of a mammal, reducing body fat of a mammal, reducing the level of at least one indicator of total cholesterol level, low-density lipoprotein and triglyceride level in the serum of a mammal, and increasing the serum high-density lipoprotein level of a mammal.

[0073] The following are applications or uses in the treatment or prevention of diabetes, namely, improving oral glucose tolerance impairment in mammals, reducing fasting blood glucose in mammals, and reducing HOMA-IR index in mammals.

[0074] The repair of gastrointestinal mucosal damage refers to repair of gastrointestinal mucosal damage, typically repair of intestinal mucosal damage, and refers to achieving at least one of the following indicators: restoration of structural integrity of intestinal mucosal tissue, reduction in the degree of intestinal villus atrophy, and reduction in the number of fungal hyphae.

[0075] A combination drug, the combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug, wherein the microorganism is a bacterium of the species Christensenella sp. The hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 pathway sensitivity and complement and / or enhance GLP-1 action.

[0076] The hypoglycemic or hypolipidemic drug is at least one of a GLP-1 receptor agonist (i.e., GLP-1RA) or GLP-1 mimetic, a GIP receptor agonist (i.e., glucose-dependent insulinotropic polypeptide receptor agonist, also known as gastric inhibitory polypeptide), and a dipeptidyl peptidase-4 (i.e., DPP-4) inhibitor. The GLP-1 receptor agonist or GLP-1 mimetic is at least one selected from exenatide, liraglutide, semaglutide, oral semaglutide, benaglutide, lixisenatide, and weekly exenatide formulations.

[0077] Use of the above-mentioned concomitant drug in the manufacture of a drug or a preparation, wherein the drug or the preparation comprises: Reducing liver weight; ameliorating oral glucose tolerance impairment in mammals; Reducing fasting blood glucose in a mammal; Reducing the body weight of a mammal; Reducing food intake in mammals; Delaying the recurrence of obesity after discontinuation, reducing the level of at least one indicator of total cholesterol level, low density lipoprotein cholesterol level, and triglyceride level in the serum of the mammal; Enhance GLP-1 sensitivity and and avoiding resistance to GLP-1RA due to intestinal disorders and associated side effects.

[0078] Aggregation of intestinal flora is likely to lead to ineffectiveness and resistance to GLP-1 drugs, but the inventors' proposal to use probiotics in combination with GLP-1 enhances GLP-1 sensitivity and avoids resistance to GLP-1RAs and related side effects due to intestinal disorders.

[0079] In order to clarify the objectives, technical solutions and advantages of the embodiments of the present disclosure, the following clearly and completely describes the technical solutions in the embodiments of the present disclosure. Unless specific conditions are specified in the examples, they are carried out according to standard conditions or conditions suggested by the manufacturer. Unless the manufacturer is specified, the reagents or equipment used are all standard products that can be purchased commercially.

[0080] The following describes in more detail the features and performance of the present disclosure in conjunction with examples.

[0081] Example 1 This example provides the isolation and identification of Christensenella sp. MNO-863.

[0082] (1) Isolation of MNO-863 The Christensenella sp. MNO-863 described in this disclosure was isolated from a fecal sample of a healthy male Han Chinese volunteer from Guangzhou, Guangdong Province, who had not taken antibiotics for the first three months at the time the sample was collected.

[0083] In a biological safety cabinet, the saline solution was divided into sterile 10 ml centrifuge tubes. 24 h before the start of the experiment, an anaerobic blood plate (Jiangmen Kailin Anaerobic Blood Agar, Yuejian Supplementary Standard 20172400940) and the sterile saline solution were transferred to an anaerobic work bench. Five to seven sterile glass beads were placed on the pre-clotted anaerobic blood plate.

[0084] An appropriate amount of fresh fecal sample from a volunteer was taken and placed in a sample storage tube containing a sterile preservative solution (3% PEG solution, i.e., 30 g of polyethylene glycol 3350 was weighed and dissolved in 1000 mL of saline, and autoclaved at 121°C for 15 min). The sample was mixed uniformly by shaking in a vortex mixer for 10 minutes. Then, 1 mL of the solution was aspirated and diluted with sterile saline in an anaerobic workstation. -6 The bacteria were diluted to the dilution level, and 0.1 mL of the diluted solution was aspirated and spread onto an anaerobic blood agar plate and cultured in an anaerobic workstation at 37°C for 72 hours. Using the streak method, single colonies with different morphologies were selected with a sterile toothpick and streaked onto the anaerobic blood agar plate for isolation and culture. After 72 hours of culture, colonies with good isolation effects were extracted from the streak plate and subcultured.

[0085] (2) Identification of MNO-863 (1) Microbiological characteristics of MNO-863: To observe the microbiological characteristics, MNO-863 was plated and cultured in liquid. The plated strain and the liquid culture solution were 104 medium, the formulation of which for 1 L is shown in Table 1 below.

[0086] Table 1. Recipe for 104 medium. [Table 1]

[0087] Morphological characteristics: Referring to the macromorphology shown in Figure 1, after 72 hours of anaerobically culture at 37°C, the colonies were pale yellow, round, with moist surfaces, translucent, and regular edges.

[0088] Micromorphology: MNO-863 was cultured anaerobically on a 104 medium plate at 37°C for 72 hours, and then Gram staining (upper panel in Figure 2) and spore-staining microscopy (lower panel in Figure 2) were performed on MNO-863. Referring to Figure 2, the bacterial cells are short, rod-shaped, lack spores, no flagella, are non-motile, measure 0.3-0.4 μm x 0.6-1.1 μm, are arranged singly or in pairs, and are Gram-negative.

[0089] Colony characteristics: MNO-863 was cultured anaerobically on a 104 medium plate at 37°C for 72 hours. Single colonies exhibited round, microscopic projections, were transparent and white, had a smooth surface, and were approximately 0.46-0.50 mm in diameter (see Figure 3).

[0090] The physiological and biochemical characteristics of the isolated strain were further characterized. MNO-863 does not grow aerobic, but grows well anaerobic, with the optimal growth temperature being 37°C. Using the API 20A reaction kit, the substrate utilization of MNO-863 and the standard strain Christensenella minuta (DSM 22607) was measured and compared.

[0091] The test results are shown in Table 2. As can be seen from Table 2, the isolated MNO-863 had almost the same physiological and biochemical characteristics as the standard strain DSM 22607, with differences when the substrates were glycerol, gelatin hydrolysis, mannose, mannitol and salicin.

[0092] Table 2. Comparison of substrate utilization by MNO-863 and the standard strain DSM 22607. [Table 2] Explanation of symbols in the above table: "+" is positive, "+w" is weakly positive, and "-" is negative.

[0093] Analysis of cellular fatty acids: The composition and content of phospholipid fatty acids of MNO-863 and the standard strain Christensenella minuta (DSM 22607) after cultivation were compared using gas chromatography. The results of the comparative analysis are shown in Table 3. As can be seen from Table 3, the cellular fatty acid composition of the isolated MNO-863 of the present disclosure is significantly different from that of the standard strain.

[0094] Table 3 Cellular fatty acid analysis results table. [Table 3]

[0095] (2) Analysis and identification of nucleic acids 16srRNA sequencing: The 16S sequence fragment (amplification primer and sequencing primer are 27F: 5'-AGAGTTTGATCCTGGCTCAG-3' and 1492R: 5'-GGTTACCTTGTTACGACTT-3') was measured against the sequence of the MNO-863 strain, and the measurement result of 16s rRNA was as shown in the sequence SEQ ID NO. 1. 1 AGTCGAACGA AGTTGCTCTT TGTGAAGCCC TCGGGTGGAA CTGCGAGTAT 51 ACTTAGTGGC GGACGGGTGA GTAACGCGTG AGCAATCTGC CCTGCAATGG 101 GGGACAACAG TTGGAAACGA CTGCTAATAC CGCATGAGAC CACGAAACCG 151 CATGGTTTTG AGGTAAAAGG ATTTATTCGA TGCAGGATGA GCTCGCGTCC 201 CATTAGATAG TTGGTGAGGT AACGGCCCAC CAAGTCAACG ATGGGTAGCC 251 GACCTGAGAG GGTGATCGGC CACACTGGAA CTGAGACACG GTCCAGACTC 301 CTACGGGAGG CAGCAGTGGG GAATATTGGG CAATGGGGGA AACCCTGACC 351 CAGCAACGCC GCGTGAGGGA AGAAGGTCTT CGGATTGTAA ACCTTTGTCC 401 TATGGGACGA AACAAATGAC GGTACCATAG GAGGAAGCTC CGGCTAACTA 451 CGTGCCAGCA GCCGCGGTAA TACGTAGGGA GCAAGCGTTG TCCGGAATTA 501 CTGGGCGTAA AGGGTGCGTA GGTGGCTATG TAAGTCAGAT GTGAAAGACC 551 GGGGCTTAAC CCCGGGGTTG CATTTGAAAC TGTGTGGCTT GAGTACAGGA 601 GAGGGAAGTG GAATTCCTAG TGTAGCGGTG AAATGCGTAG ATATTAGGAG 651 GAACACCAGT GGCGAAGGCG ACTTTCTGGA CTGTAACTGA CACTGAAGCA 701 CGAAAGCGTG GGGAGCAAAC AGGATTAGAT ACCCTGGTAG TCCACGCCGT 751 AAACGATGGA TACTAGGTGT GGGGCCCGAT AGGGTTCCGT GCCGAAGCTA 801 ACGCATTAAG TATCCCGCCT GGGGAGTACG ATCGCAAGGT TGAAACTCAA 851 AGGAATTGAC GGGGGCCCGC ACAAGCAGCG GAGCATGTGG TTTAATTCGA 901 AGCAACGCGA AGAACCTTAC CAAGGCTTGA CATCCTCTGA CGACTGTAGA 951 GATACAGTTT CCCTTCGGGG CAGAGAGACA GGTGGTGCAT GGTTGTCGTC 1001 AGCTCGTGTC GTGAGATGTT GGGTTAAGTC CCGCAACGAG CGCAACCCTT 1051 ATTGCTAGTT GCCAGCGCGT AAAGGCGGGA ACTCTAGTGA GACTGCCGGG 1101 GACAACTCGG AGGAAGGTGG GGACGACGTC AAATCATCAT GCCCCTTATG 1151 TCTTGGGCTA CACACGTGCT ACAATGGCCG GTACAAAGGG CAGCGAACCC 1201 GTAAGGGGAA GCGAATCTCA AAAAGCCGGT CCCAGTTCGG ATTGTGGGCT 1251 GCAACCCGCC CACATGAAGT CGGAGTTGCT AGTAATCGCG AATCAGCATG 1301 TCGCGGTGAA TGCGTTCCCG GGCCTTGTAC ACACCGCCCG TCACACCACG 1351 GAAGTTGGGA GCACCCGAAG CCAGTGGCTT AACCGTAAGG AGAGAGC

[0096] Evolutionary analysis: Whole genome sequencing was performed on MNO-863, and MEGA 5.0 software was used to generate a phylogenetic tree of 16S rDNA sequences of MNO-863 and related species using a proximity ligation assay. Similarity calculations were performed 1,000 times, and the results were compared with the genome sequences of reference strains of the Christensenellaceae family in NCBI. The phylogenetic tree (Figure 4) showed that MNO-863 and the three reference strains Christensenella minuta (DSM 22607), Christensenella timonensis (Marseille-P2437), and Christensenella massiliensis (Marseille-P2438) were on the same branch, indicating that MNO-863 is a species within the Christensenella genus.

[0097] Based on the above identification using conventional microbial morphological analysis and nucleic acid analysis methods, and comparison with standard strains, MNO-863 may be considered to be a species belonging to the genus Christenella from a taxonomic perspective, and has been named Christensenella sp. MNO-863. It was deposited at the Guangdong Provincial Microorganism Depositary Center on August 4, 2020. The deposit number is GDMCC No: 61117, and the deposit address is Guangdong Provincial Institute of Microbiology, 5th Floor, Building 59, Courtyard, No. 100, Xianlie Middle Road, Guangzhou City. The detection result was viable. The taxonomic name is Christensenella sp.

[0098] Example 2 In this example, an in vivo study of MNO-863 was carried out in a high-fat diet-induced obese mouse model to verify its use in the treatment or prevention of liver dysfunction and its associated diseases.

[0099] Test materials: (1) Experimental animals: Thirty-two C57BL / 6J male mice (purchased from Jiangsu Jisu Yaokang Biotechnology Co., Ltd.) were purchased and maintained in the same environment. They were fed SPF rat and mouse feed (Guangzhou Hancheng Laboratory Equipment Co., Ltd.), and the remaining 24 mice were fed D12492 high-fat feed (Parker). After approximately 8-10 weeks of feeding, they were weighed and reached a standard weight of 38.00±2.00g.

[0100] (2) Test strain: MNO-863 cultured anaerobically. The culture medium was the 10 liquid medium used in Example 1. The culture was performed under anaerobic conditions at 37°C for 48 hours until the bacterial concentration reached approximately 10 11 Only after the bacterial count reached the order of CFU / mL could the experimental group be intragastrically administered. The bacterial solution was stored anaerobically at 4°C.

[0101] (3) PBS phosphate buffered saline: A mixed solution consisting of weak acids and their salts, weak alkalis and their salts, which can offset and reduce the effect of added acids or strong alkalis on the pH of the solution to some extent, thereby maintaining a relatively stable pH value. The formulation of PBS phosphate buffered saline is shown in Table 4 below.

[0102] Table 4. PBS phosphate buffered saline formulation [Table 4]

[0103] Testing process: (1) Test grouping Eight mice fed SPF-grade rat and mouse maintenance diets were randomly divided into two cages, four mice per cage, and designated Group 1. Of the 24 obese mice, 16 mice that reached a body weight of 38.00g ± 2.00g were selected and divided into two groups (Groups 2 and 3), with eight mice per group and four mice per cage. Group 1 was a control group fed a normal diet (NCD-control group), Group 2 was a high-fat diet-induced obese mouse model group (HFD-control group), and Group 3 was a bacterial treatment group (MNO-863). Groups 2 and 3 were fed a high-fat diet. The groupings are shown in Table 5. After grouping, the animals were administered a virtual challenge. One week later, Groups 1 and 2 were intragastrically administered the same volume of PBS phosphate-buffered saline (PBS), while Group 3 received intragastrically administered MNO-863 test strain. The intervention lasted for 4 weeks. The volume of bacterial solution administered intragastrically was 0.2 mL per 10 g of mouse body weight. Data on mouse weight, condition, and food intake were recorded before and after model creation, and every three days before and after the intervention. After administration, animals were dissected and tissues were collected. The use of experimental animals focused on animal welfare and followed the principle of "reduction, replacement, and optimization," and was approved by the institution's Laboratory Animal Ethics Committee. The experimental process was supervised and inspected by the Laboratory Animal Ethics Committee.

[0104] Table 5. Study grouping [Table 5]

[0105] All animals, including those that died during the study, were euthanized, and those sacrificed at the end of the study, underwent a comprehensive autopsy and recorded for gross pathological changes. Livers were weighed, and one lobe of the liver was excised and placed in formalin solution. The remaining tissue was flash-frozen in liquid nitrogen and stored at -80°C. Paraffin-embedded liver sections were then prepared for liver pathology and stained with HE, Masson, and Oil Red. Liver histology and NAS pathology were assessed by scoring micrographs captured at original magnification. Scoring was based on the NASH liver injury scoring system (Kleiner DE, Brunt EM, Van NM, Behling C, Contos MJ, Cummings OW, et al., Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41:1313-21) (Brunt EM. Histopathology of non-alcoholic fatty liver disease. Clin Liver Dis 2009, 13:533-44). The scoring criteria are shown in Figure 5 (0-2 points: non-NASH, 3-4 points: unknown, 5-8 points: NASH).

[0106] Test Results: The effect of MNO-863 on liver weight in obese mice is shown in Figure 6. Compared to the HFD control group, the MNO-863-treated group significantly reduced liver weight in obese mice, restoring it to the same level as the normal NCD control group. The effect data on liver weight in obese mice are shown in Table 6.

[0107] Table 6. Liver weights of mice in different treatment groups [Table 6] NOTE: Results are expressed as mean values, *p<0.05 compared with the HFD-control group.

[0108] (2) Further pathological analysis of liver lesions in obese model mice: The results showed that MNO-863 could treat early steatohepatitis lesions, delay fat accumulation in liver cells, and alleviate liver lesions.

[0109] Specifically, HE staining and Oil Red staining were performed on the liver tissues of mice from each treatment group. The experimental results are shown in Figures 7 and 8. When fed a high-fat diet, MNO-863 was able to treat early steatohepatitis lesions and delay fat accumulation in obese mice.

[0110] The NAFLD / NASH liver pathological scores are shown in Figure 9. As can be seen from the scores, MNO-863 was able to treat early steatohepatitis lesions in obese mice and delay fat accumulation.

[0111] Figure 10 shows the degree of hepatic steatosis. As can be seen from Figure 10, MNO-863 was able to effectively alleviate hepatic steatosis. Figure 11 shows the hepatic lobule inflammation score. As can be seen from Figure 11, compared to the HFD control group, MNO-863 was able to effectively suppress the occurrence of hepatic lobule inflammation. Figure 12 shows the hepatic ballooning score. As can be seen from Figure 12, compared to the HFD control group, the hepatic ballooning score was significantly reduced in MNO-863.

[0112] (3) The applicant further investigated the effects of MNO-863 on serum ALT and AST in obese model mice, and the results showed that MNO-863 could significantly reduce serum ALT and AST indices in obese mice.

[0113] The serum AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels are shown in FIG.

[0114] (4) The applicant further investigated the effect of MNO-863 on abdominal white fat inflammatory lesions in high-fat diet-induced obesity model mice, and the results showed that MNO-863 could significantly reduce abdominal white fat inflammatory lesions in obesity model mice.

[0115] The micrographs and total area statistics of abdominal white adipose inflammatory lesions in mice are shown in FIG.

[0116] (5) The applicant further investigated the effects of MNO-863 on blood creatinine (CREA), blood urea (UREA), and blood uric acid (UA) in high-fat diet-induced obesity model mice, and the results showed that MNO-863 was not toxic to the kidneys.

[0117] The creatinine (CREA) content in mouse blood was measured using an automated biochemical analyzer by the end-point method (creatinine measurement kit, Leisha, S03076) based on the enzymatic detection principle. The urea (UREA) content in blood was measured using an automated biochemical analyzer by the two-point method (urea measurement kit, Leisha Life Sciences Co., Ltd., S03036) based on the urease-glutamate dehydrogenase detection principle. The uric acid (UA) content in blood was measured using an automated biochemical analyzer by the end-point method (uric acid measurement kit, Leisha Life Sciences Co., Ltd., S03035) based on the uric acid enzymatic detection principle.

[0118] The measurement results of blood creatinine (CREA), blood urea (UREA) and blood uric acid (UA) of the mice are shown in FIG.

[0119] Example 3 In this example, an in vivo study was conducted in a high-fat diet-induced obese mouse model to verify the use of MNO-863 in the treatment or prevention of diabetes.

[0120] Test materials: (1) Experimental animals: Forty C57BL / 6J male mice (purchased from Jiangsu Jisu Yaokang Biotechnology Co., Ltd.) were purchased and maintained in the same environment. They were fed SPF rat and mouse feed (Guangzhou Hancheng Laboratory Equipment Co., Ltd.), and 32 were fed D12492 high-fat feed (Parker). After approximately 8-10 weeks of feeding, they were weighed and the standard weight for the diet-induced obesity model was 38.00±2.00g.

[0121] (2) Test strain: MNO-863 cultured anaerobically. The culture medium was a 104 liquid medium. The culture was performed under anaerobic conditions at 37°C for 48 hours until the bacterial concentration reached approximately 10 11 Once the bacterial count reached the order of CFU / mL, it could be administered intragastrically to the experimental group. The bacterial solution was stored anaerobically at 4°C.

[0122] (3) PBS: a mixed solution of weak acids and their salts, weak alkalis and their salts, which can offset and reduce the effects of the added acids or strong alkalis on the pH of the solution to some extent, thereby maintaining a relatively stable pH value. The formulation of PBS is the same as Table 4 in Example 2.

[0123] (4) Liraglutide (positive control): Liraglutide is a human glucagon-like peptide-1 (GLP-1) analog used in the treatment of diabetes. It was purchased from Novo Nordisk and sold under the trade name Victoza. (登録商標) -Novo Nordisk, administered subcutaneously at 15 μg / kg / d.

[0124] Testing process: (1) Test grouping Eight mice fed SPF-grade rat and mouse maintenance diet were randomly divided into two cages (4 mice per cage) and designated Group 1. From the 32 obese mice, 24 mice that reached a body weight of 38.00g ± 2.00g were selected and divided into three groups (Groups 2, 3, and 4), with 8 mice per group and 4 mice per cage. Group 1 was the control group fed a normal diet (NCD-control group), Group 2 was the high-fat diet-induced obese mouse model group (HFD-control group), Group 3 was the bacterial treatment group (MNO-863), and Group 4 was the liraglutide positive control group. Groups 2, 3, and 4 were fed a high-fat diet. The groupings are shown in Table 7. After dividing the animals into groups, the virtual treatment began. Treatment began one week later. Groups 1 and 2 received the same volume of PBS phosphate-buffered saline intragastrically. Group 3 received the MNO-863 test strain intragastrically. The treatment continued for four weeks. The volume of intragastrically administered bacterial solution was 0.2 mL per 10 g of mouse body weight. Data such as mouse weight and condition were recorded before and after model creation and every three days before and after the treatment. The use of experimental animals focused on animal welfare and followed the principle of "reduction, replacement, and optimization," and was approved by our institution's Laboratory Animal Ethics Committee. The study process was supervised and inspected by the Laboratory Animal Ethics Committee.

[0125] Table 7. Study grouping [Table 7]

[0126] Oral glucose tolerance test (OGTT): On day 28 after administration, mice were fasted for 12 h (e.g., from 8:30 PM to 8:30 AM the next day) and then subjected to an OGTT. Mice were weighed for fasting body weight and intragastrically administered glucose at a dose of 2 g / kg (g glucose / kg mouse fasting body weight). Fasting blood glucose levels were measured at 15, 30, 60, 90, and 120 min after glucose administration. Each mouse was carefully timed and blood glucose levels were measured at six precise time points. The oral glucose tolerance test (OGTT) is a type of glucose tolerance test used to understand pancreatic islet β-cell function and the body's ability to regulate blood glucose, and to monitor a patient's glucose tolerance. It is currently the recognized gold standard for diabetic diagnosis.

[0127] After the intervention experiment, mice were fasted overnight for 10–12 h and weighed the following day. After anesthesia with isoflurane (Ruiwot Biotechnology Co., Ltd.), blood was collected from the eyes and fasting blood glucose levels were measured using a Roche ACCU-CHEK blood glucose meter. The blood was then placed in a 4°C refrigerator for 3–4 h. After the blood had coagulated and the clot had shrunk, it was centrifuged at 4°C for 15 min at 4500 rpm. The upper serum layer was collected and serum insulin levels were measured using a mouse insulin (INS) enzyme-linked immunosorbent assay kit (Wuhan Huamei Biotechnology Co., Ltd.). HOMA-IR was calculated based on the fasting blood glucose and insulin levels in the serum. HOMA-IR is an index used to assess an individual's insulin resistance level and is now widely used clinically to evaluate insulin sensitivity, insulin resistance, and pancreatic islet β-cell function in diabetic patients. It is calculated as fasting blood glucose level (FPG, mmol / L) × fasting insulin level (FINS, μU / mL) / 22.5, with the HOMA-IR index in normal individuals being 1. As insulin resistance increases, the HOMA-IR index increases above 1. Insulin resistance occurs when, due to various causes, insulin promotes glucose uptake and its utilization becomes less efficient, leading the body to compensate by secreting excess insulin, producing hyperinsulinemia, thereby maintaining blood glucose stability. Insulin resistance can lead to metabolic syndrome and type 2 diabetes.

[0128] Test Results: (1) Effect of MNO-863 on oral glucose tolerance in obese model mice: The effect of MNO-863 on oral glucose tolerance in high-fat diet-induced obese mice is shown in Table 8 and FIG.

[0129] Table 8. Effect of MNO-863 on oral glucose tolerance in high-fat diet-induced obese mice [Table 8] NOTE: Results are expressed as mean ± standard difference (SD), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 compared with the HFD-control group.

[0130] When glucose metabolism is disturbed, blood glucose levels may rise sharply after a certain amount of glucose is orally administered, or may not rise significantly but fail to fall to fasting levels (or the normal level) within a short period of time. This is called impaired glucose tolerance (IGT) or reduced glucose tolerance. IGT indicates a decrease in the body's ability to metabolize glucose and is commonly seen in type 2 diabetes and obesity.

[0131] As can be seen from the results in Table 8 and Figure 16, after 4 weeks of MNO-863 treatment, the high-fat diet-induced obese mice in the MNO-863-treated group had a significantly lower blood glucose elevation after 15 minutes of intragastric glucose administration than the HFD control group. Subsequent testing showed that the blood glucose levels of the MNO-863-treated mice gradually decreased, and after 120 minutes, the blood glucose levels had recovered to nearly the level of the NCD control group, which was significantly lower than the HFD control group. At the same time, MNO-863 exhibited a therapeutic effect comparable to that of the diabetes treatment drug liraglutide.

[0132] (2) Effect of MNO-863 on fasting blood glucose in obese model mice: The effect of MNO-863 on fasting blood glucose in high-fat diet-induced obese mice is shown in Table 9 and FIG.

[0133] Table 9. Effect of MNO-863 on fasting blood glucose (mmol / L) in high-fat diet-induced obese mice [Table 9] NOTE: Results are expressed as mean values, *p<0.05, ****p<0.0001 compared with the HFD-control group.

[0134] As can be seen from the results in Table 9 and Figure 17, the MNO-863 treatment group significantly reduced blood glucose levels in high-fat diet-induced obese mice compared to the HFD control group, demonstrating a significant difference compared to the HFD control group. Furthermore, the blood glucose control effect of MNO-863 was more pronounced than that of the diabetes treatment drug liraglutide. This indicates that MNO-863 has a clear blood glucose-lowering effect and can ameliorate diabetic symptoms.

[0135] (3) Effect of MNO-863 on HOMA-IR index in high-fat diet-induced obese mouse model: The effect of MNO-863 on HOMA-IR index in high-fat diet-induced obese mice is shown in Table 10 and FIG.

[0136] Table 10. Effect of MNO-863 on HOMA-IR in high-fat diet-induced obese mice [Table 10] NOTE: Results are expressed as mean values.

[0137] Insulin resistance (IR) is a major cause of type 2 diabetes and can promote the onset and progression of complications in type 2 diabetes patients. Biochemical indices related to HOMA-IR are useful for clarifying the causes of IR onset. However, HOMA-IR in diabetic patients is generally significantly higher than that in normal subjects.

[0138] As can be seen from the results in Table 10 and Figure 18, compared to the HFD control group, MNO-863 treatment significantly reduced HOMA-IR in high-fat diet-induced obese mice, demonstrating that MNO-863 can improve in vivo insulin resistance and pancreatic islet β cell function, thereby achieving the goal of preventing and treating diabetes.

[0139] Example 4 This example demonstrates that MNO-863 was tested in vivo in a high-fat diet-induced obese mouse model to evaluate its potential application in the treatment and prevention of obesity and related disorders. The experimental materials (including experimental animals, test strains, PBS phosphate-buffered saline, and positive control) were the same as those used in Example 3.

[0140] Testing process: (1) Test grouping Eight mice fed SPF-grade rat and mouse maintenance diet were randomly divided into two cages (4 mice per cage) and designated Group 1. From the 32 obese mice, 24 mice that reached a body weight of 38.00g ± 2.00g were selected and divided into three groups (Groups 2, 3, and 4), with 8 mice per group and 4 mice per cage. Group 1 was the control group fed a normal diet (control group), Group 2 was the high-fat diet-induced obese mouse model group (model group), Group 3 was the bacterial treatment group, and Group 4 was the liraglutide positive control group. Groups 2, 3, and 4 were fed a high-fat diet. The groupings are shown in Table 11. After dividing the animals into groups, the virtual treatment began. Treatment began one week later. Groups 1 and 2 received the same volume of PBS phosphate-buffered saline (PBS) intragastrically. Group 3 received the MNO-863 test strain intragastrically. The treatment continued for four weeks. The volume of intragastrically administered bacterial solution was 0.2 mL per 10 g of mouse body weight. Data on mouse weight, condition, and food intake were recorded before and after model creation and every three days before and after the treatment. After treatment, animals were dissected and tissues were collected. The use of experimental animals focused on animal welfare and followed the principle of "reduction, replacement, and optimization," and was approved by our institution's Laboratory Animal Ethics Committee. The study process was supervised and inspected by the Laboratory Animal Ethics Committee.

[0141] Table 11. Study Grouping [Table 11]

[0142] After the experiment, the mice were sacrificed, the fat content was recorded, and blood was collected. The blood was centrifuged at 4500 r / min for 15 min at 4°C to collect serum. The serum lipid contents were detected using total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDLC) assay kits (Nanjing Jiancheng Institute of Bioengineering).

[0143] Test Results: (1) Effect of MNO-863 on body weight of obese model mice: As can be seen from the results in Tables 12 and 13 and Figures 19 and 20, compared with the HFD-control group, the MNO-863-intervention group was able to effectively reduce the body weight of high-fat diet-induced obese mice by more than 3 g and the body weight percentage by approximately 10% within 3 weeks. The difference was significant, comparable to the weight-reducing effect of the positive control weight loss drug liraglutide, demonstrating that MNO-863 has a weight-reducing effect on organisms with a high lipid intake.

[0144] Table 12. Effect of MNO-863 on body weight (g) in high-fat diet-induced obese mice [Table 12]

[0145] Table 13. Effect of MNO-863 on body weight (g) of high-fat diet-induced obese mice [Table 13] NOTE: Results are expressed as mean ± standard difference, ****p < 0.0001 compared with the HFD-control group.

[0146] (2) Effect of MNO-863 on food intake in obese model mice: As can be seen from the results in Table 14 and Figure 21, the MNO-863 intervention group was able to reduce food intake in high-fat diet-induced obese mice within 3 weeks compared to the HFD-control group.

[0147] Table 14. Effect of MNO-863 on food intake (g) in high-fat diet-induced obese mice [Table 14] NOTE: Results are expressed as mean values.

[0148] (3) Effect of MNO-863 on blood lipids in high-fat diet-induced obesity model mice: As can be seen from the results in Table 15 and Figure 22, the MNO-863 intervention group had a clear regulatory effect on blood lipid levels in mice on a sustained high-fat diet. It reduced total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDLC), which are indicators related to cardiovascular diseases such as primary hyperlipidemia, and also improved blood high-density lipoprotein (HDL-C) levels. HDL exhibits a negative correlation with the incidence and severity of cardiovascular disease, and significant differences were observed in the results for total cholesterol (TC) and triglycerides (TG).

[0149] Table 15. Effect of MNO-863 on four blood lipid parameters in high-fat diet-induced obese mice [Table 15] NOTE: Results are expressed as mean values, *p<0.05, **p<0.01 compared with the HFD-control group.

[0150] (4) Effect of MNO-863 on body fat in high-fat diet-induced obese mouse models: As can be seen from the results in Table 16 and Figure 23, MNO-863 significantly reduced the weight of inguinal fat, subcutaneous fat, and epididymal fat in high-fat diet-induced obese mice compared to the HFD-control group, demonstrating that MNO-863 has the effect of reducing body fat in mammals.

[0151] Table 16. Effect of MNO-863 on body fat (g) in high-fat diet-induced obese mice [Table 16] NOTE: Results are expressed as mean, *p<0.05, **p<0.01, ****p<0.0001 compared with the HFD-control group.

[0152] Experimental Example 5 In this example, in order to verify the application of MNO-863 in repairing gastrointestinal mucosal damage and in the prevention and treatment of diseases associated with gastrointestinal mucosal damage, an in vivo test of mucosal repair of ileum and colon tissues in a mouse model by MNO-863 was carried out.

[0153] Animal testing process: Eight mice fed SPF-grade rat and mouse maintenance diets were randomly divided into two cages, four mice per cage, and designated Group 1. Sixteen mice that reached a body weight of 38.00g ± 2.00g were selected from 24 obese mice and divided into two groups (Groups 2 and 3), with eight mice per group and four mice per cage. Group 1 was a control group fed a normal diet (NCD-control group), Group 2 was a high-fat diet-induced obese mouse model group (HFD-control group), and Group 3 was a bacterial treatment group (MNO-863). Groups 2 and 3 were fed a high-fat diet. The grouping method was the same as in Table 5 in Example 2. After grouping, the animals were administered a virtual dose of phosphate-buffered saline (PBS) intragastrically. One week later, Groups 1 and 2 were intragastrically administered the same volume of PBS. Group 3 received intragastrically administered MNO-863 test strain. The intervention lasted for four weeks. The volume of bacterial solution administered intragastrically was 0.2 mL per 10 g of mouse body weight. Data on mouse weight, condition, and food intake were recorded before and after model creation, and every three days before and after the intervention. After administration, animals were dissected and tissues were collected. The use of experimental animals focused on animal welfare and followed the principle of "reduction, replacement, and optimization," and was approved by the institution's Laboratory Animal Ethics Committee. The experimental process was supervised and inspected by the Laboratory Animal Ethics Committee.

[0154] Dissection and observation process: All animals, including those that died during the study, those euthanized, and those killed at the end of the study, were required to undergo a general dissection. The ileum and colon of the mice were excised and preserved in formalin solution. Pathological sections were prepared, photographed, and observed at Wuhan Severe Biotechnology Co., Ltd.

[0155] Results: The MNO-863 test strain had a repairing effect on the damaged mucosal layer of mouse ileum and colon tissue (see Table 17). Compared to the HFD-control group, MNO-863 treatment resulted in a clearer layer structure in mouse colon tissue, an intact mucosal epithelium, more abundant and tightly arranged intestinal glands, and no obvious abnormalities (see Figure 26). The ileum tissue also showed a clearer layer structure, more abundant intestinal villi, an intact mucosal epithelium, more abundant and tightly arranged intestinal glands, and no other obvious abnormalities (see Figure 27). On the other hand, microscopic images of the HFD-control group showed numerous mucosal layer damage, mucosal epithelial cell loss, and a small amount of destruction of the intestinal gland structure in the mouse colon tissue, with a large amount of basophilic hyphae in the intestinal lumen (see Figure 24). Also, mucosal layer damage in the mouse ileal tissue, localized intestinal villi and mucosal epithelial defects, loss of intestinal gland structure, a small amount of epithelial cell swelling, and coarse and pale staining of the cysts were observed, with a large amount of basophilic hyphae in the intestinal lumen (see Figure 25).

[0156] Microscopic images of the NCD-control group showed that the layer structure of the mouse colon tissue was clear, the mucosal epithelium was intact, the intestinal glands were abundant and tightly arranged, and no obvious abnormalities were observed (see Figure 28). The layer structure of the mouse ileum tissue was clear, the intestinal villi were abundant, the mucosal epithelium was intact, the intestinal glands were abundant and tightly arranged, and no obvious abnormalities were observed (see Figure 29).

[0157] These results demonstrate that MNO-863 has the ability to repair the ileal and colonic mucosa, and its administration can effectively repair the gastrointestinal mucosa and produce positive effects in the prevention and treatment of diseases associated with gastrointestinal mucosal damage.

[0158] Table 17. Pathological scores for colonic and ileal mucosal damage in MNO-863 mice [Table 17]

[0159] The following describes in more detail the drug combinations according to the present disclosure in conjunction with examples.

[0160] In this example, in vivo testing of the MNO-863 strain and / or the drug Liraglutide was performed in a high-fat diet-induced obese mouse model to verify its use in the treatment or prevention of obesity, diabetes, and liver disease.

[0161] (1) Experimental animals: Fifty C57BL / 6J male mice (purchased from Jiangsu Jisui Yaokang Biotechnology Co., Ltd.) were purchased. All mice were normally raised and 5 weeks old. The mice were kept in the same environment throughout their development. Eight mice were fed SPF rat and mouse maintenance chow (purchased from Guangzhou Hancheng Laboratory Equipment Co., Ltd.), and 42 mice were fed D12492 high-fat chow (purchased from Parker). After approximately 8-10 weeks of feeding, they were weighed. The model formation standard for the diet-induced obesity model was a weight of 38.00 ± 2.00 g.

[0162] (2) Test strain: MNO-863 cultured anaerobically. The culture medium was a 104 liquid medium (the recipe is shown in Table 1 above). The culture was performed under anaerobic conditions at 37°C for 48 hours, and the bacterial concentration reached approximately 10 9 Only after the CFU / mL level is reached can the bacteria be administered intragastrically to the experimental group. The bacterial solution should be stored anaerobically at 4°C.

[0163] (3) PBS phosphate buffered saline: A mixed solution consisting of weak acids and their salts, weak alkalis and their salts, which can offset and reduce the effect of added acids or strong alkalis on the pH of the solution to some extent, thereby maintaining a relatively stable pH value. The formulation of PBS phosphate buffered saline is shown in Table 4 above.

[0164] The test process is as follows:

[0165] (1) The test grouping is as follows:

[0166] Thirty-two obese mice were selected from the 42 mice that reached a body weight of 38.00g ± 2.00g. They were divided into four groups, with eight mice per group and four mice per cage. Group 1 was a control group fed a normal diet (NCD control group), Group 2 was a high-fat diet-induced obese mouse model group (HFD control group), Group 3 was treated with MNO-863 antibiotics, Group 4 was treated with Liraglutide (Lira group), and Group 5 was treated with MNO-863 antibiotics and Liraglutide (Lira + MNO-863). Groups 2, 3, 4, and 5 were fed a high-fat diet. The grouping is shown in Table 18. After grouping, the animals were administered a virtual dose, and treatment began 1 week later. The intervention continued for 4 weeks. The volume of intragastric administration was 0.2 mL per 10 g of mouse body weight.

[0167] Data such as mouse weight, condition, and food intake were recorded before and after model creation, and every three days before and after intervention. After administration, tissues were collected from the animals. The use of experimental animals focused on animal welfare and followed the principle of "reduction, replacement, and optimization," and was approved by the institution's Animal Ethics Committee. The study process was supervised and inspected by the Animal Ethics Committee.

[0168] Table 18. Study Grouping [Table 18]

[0169] (2) The effect of combined therapy with liraglutide and MNO-863 on body weight.

[0170] The effects of MNO-863 and Liraglutide on absolute body weight and weight change rate in obese mice during a 4-week intervention period are shown in Figure 30, the body weight and weight change rate after 4 weeks of intervention are shown in Figure 31, the body weight and weight change rate after 4 weeks of intervention and 4 weeks of withdrawal are shown in Figure 32, and the inguinal fat weight after 4 weeks of withdrawal and obesity relapse are shown in Figure 33. As can be seen from Figures 30, 31, 32, and 33, both MNO-863 and Liraglutide reduced body weight, inhibited weight gain, and reduced inguinal fat in obese mice, but the combined use of MNO-863 and Liraglutide significantly reduced body weight, inhibited weight gain, and reduced inguinal fat compared to the use of MNO-863 or Liraglutide alone, demonstrating that the microbiological preparation enhances the slimming effect of the drug.

[0171] (3) The therapeutic effect of Liraglutide and MNO-863 antibacterial agent in combination therapy for diabetes.

[0172] When glucose metabolism is disturbed, blood glucose levels may rise sharply after a certain amount of glucose is orally administered, or may not rise significantly but fail to fall to fasting levels (or the normal level) within a short period of time. This is called impaired glucose tolerance (IGT) or reduced glucose tolerance. IGT indicates a decrease in the body's ability to metabolize glucose and is commonly seen in type 2 diabetes and obesity.

[0173] The glucose metabolism test allowed us to evaluate the therapeutic effects of drugs and antimicrobial agents on diabetes.

[0174] The effects of the MNO-863 strain alone and in combination with Liraglutide on glucose tolerance in obese mice are shown in Figure 34, the effects of the MNO-863 strain alone and in combination with Liraglutide on glucose hyperglycemia in obese mice are shown in Figure 35, and the effect of the MNO-863 strain on hyperglycemia in obese mice after a 4-week drug withdrawal and relapse of obesity is shown in Figure 36.

[0175] As can be seen from Figures 34, 35 and 36, both MNO-863 bacteria and Liraglutide drug could improve the impaired glucose tolerance of obese mice and reduce fasting blood glucose. The effect of the combined use of bacteria and drug was more significant than that of either the bacteria or drug alone, demonstrating that microbiota agents can play a role in reinforcing the effects of diabetes drug treatment.

[0176] (4) The therapeutic effect of the combination therapy of Liraglutide drug and MNO-863 fungicide on liver diseases.

[0177] Figure 37 shows the effect of the MNO-863 strain alone and in combination with Liraglutide on liver weight after four weeks of drug discontinuation and recurrence of obesity. As can be seen from Figure 37, both the MNO-863 strain and Liraglutide drug were able to reduce liver weight in obese mice, but the effect of the combined use of the strain and drug was more significant than that of either the strain or drug alone, demonstrating that microbiota agents can play a role in reinforcing the effects of drug treatment for liver disease.

[0178] The above is only a typical example of the present disclosure, and is not intended to limit the present disclosure, and those skilled in the art can make various modifications and changes to the present disclosure. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure. [Industrial Applicability]

[0179] The Christensenella bacteria of the present disclosure can be cultivated industrially in large quantities and can be used to treat or prevent liver dysfunction and liver dysfunction-related diseases, gastrointestinal mucosal damage and gastrointestinal mucosal damage-related diseases, diabetes, obesity, and obesity-related diseases. The Christensenella bacteria of the present disclosure also have no toxic side effects on the kidneys, and can reduce liver weight, treat early steatohepatitis lesions, delay fat accumulation in liver cells, reduce serum AST and ALT, and reduce inflammatory lesions in abdominal white fat. The Christensenella bacteria can also repair the gastrointestinal mucosa, restore mucosal barrier function, and prevent and treat diseases such as intestinal fistula and peptic ulcer caused by impaired barrier function. The Christensenella bacteria also have the effects of reducing fasting blood glucose in the body, regulating insulin levels, and reducing body fat in mammals, as well as preventing and treating diabetes and improving metabolic function in obese patients. Christensenella further has the function of repairing damaged gastrointestinal mucosa and preventing and treating diseases associated with mucosal damage. A combination drug comprising Christensenella and a hypoglycemic or hypolipidemic drug according to the present disclosure can be industrially mass-produced, and can be used to treat or prevent liver dysfunction and diseases associated with liver dysfunction, diabetes, obesity, and obesity-related diseases. The combination drug according to the present disclosure achieves the technical effect of synergistically enhancing the effect, i.e., the combination drug has a superior therapeutic effect to administration of Christensenella alone or a hypoglycemic or hypolipidemic drug alone, and the combination drug can reduce liver weight without causing toxic side effects to the kidneys.

Claims

1. Use of a bacterial strain of the Christensenella sp. species in the manufacture of a drug for treating or preventing at least one disease or condition selected from liver dysfunction and diseases associated with liver dysfunction, gastrointestinal mucosal disorders and diseases associated with gastrointestinal mucosal disorders, diabetes, obesity, and obesity-related diseases.

2. The liver dysfunction-related disease includes at least one disease selected from the group consisting of fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and liver cirrhosis; The gastrointestinal mucosal damage refers to an increase in permeability of the gastrointestinal mucosa or an impairment of the mucosal barrier function, and the gastrointestinal mucosal damage-related disease includes at least one disease selected from the group consisting of leaky intestinal wall, peptic ulcer, gastroenteritis, and inflammatory bowel disease; The obesity-related disease includes at least one of cardiovascular disease, hyperlipidemia, insulin resistance syndrome, obesity-related gastroesophageal reflux disease, and steatohepatitis; and The use according to claim 1, characterized in that the diabetes includes at least one disease selected from the group consisting of type 1 diabetes, type 2 diabetes, insulin resistance syndrome, glucose intolerance, dyslipidemia, diabetic nephropathy complications, diabetic neuropathy, diabetic eye disease, cardiovascular disease, diabetic foot, and gestational diabetes.

3. The bacterial strain has a 16s rRNA sequence that is at least 98.65% identical to SEQ ID NO. 1; Preferably, the bacterial strain has a 16s rRNA sequence that is at least 99% identical to SEQ ID NO. 1, and 3. The use according to claim 1 or 2, characterized in that the bacterial strain preferably has a 16s rRNA sequence that is 99%, 99.5%, 99.9% or 100% identical to SEQ ID NO.

1.

4. the drug is lyophilized; Preferably, the medicament further comprises one or more pharmaceutically acceptable excipients or carriers; and The use according to any one of claims 1 to 3, characterized in that the medicament is preferably a vaccine composition.

5. Cells of the Christensenella strain deposited under accession number GDMCC No: 61117 or a progeny or subcloned strain thereof.

6. A composition comprising the Christensenella strain of claim 5 and / or a metabolite thereof, and Preferably, the composition further comprises a pharmaceutically acceptable excipient or carrier.

7. 7. The composition of claim 6, wherein the excipients include antioxidants, chelating agents, emulsifiers, and solvents.

8. Use of a combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug in the manufacture of a drug for treating or preventing at least one disease or symptom selected from liver dysfunction and diseases associated with liver dysfunction, diabetes, obesity and obesity-related diseases, wherein the microorganism is a bacterium of the Christensenella sp. species, and the hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 pathway sensitivity and complement and / or promote GLP-1 action.

9. the hypoglycemic or hypolipidemic agent is at least one of a GLP-1 receptor agonist or GLP-1 mimetic, a GIP receptor agonist, and a dipeptidyl peptidase-4 inhibitor; The use according to claim 8, characterized in that the GLP-1 receptor agonist or GLP-1 mimetic is at least one selected from exenatide, liraglutide, semaglutide, oral semaglutide, benaglutide, lixisenatide and weekly formulations of exenatide.

10. The Christensenella bacterium has a 16s rRNA sequence that is at least 98.65% identical to SEQ ID NO. 1; Preferably, the Christensenella bacterium has a 16s rRNA sequence that is at least 99% identical to SEQ ID NO. 1; and 10. The use according to claim 8 or 9, characterized in that the Christensenella bacterium has a 16s rRNA sequence that is 99%, 99.5%, 99.9% or 100% identical to SEQ ID NO.

1.

11. 11. The use according to any one of claims 8 to 10, characterized in that the microorganism is the Christensenella strain deposited under GDMCC No: 61117 or a descendant thereof.

12. A combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug, wherein the microorganism is a bacterium of the Christensenella sp. species, and the hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 pathway sensitivity and complement and / or enhance GLP-1 action.

13. Use of the composition according to claim 6 or 7 or the combination drug according to claim 12 in the manufacture of a drug or a preparation, wherein the drug or the preparation comprises: Reducing liver weight; Treating early steatohepatitis lesions; Slowing down fat accumulation in liver cells, Reducing serum AST and ALT; Reducing inflammatory lesions in abdominal white fat; Reducing the body weight of a mammal; Reducing food intake in mammals; Delaying the recurrence of obesity after discontinuation, Reducing body fat in a mammal; reducing the level of at least one indicator of total cholesterol level, low density lipoprotein and triglyceride level in the serum of the mammal; Increasing serum high density lipoprotein levels in a mammal; ameliorating oral glucose tolerance impairment in mammals; Reducing fasting blood glucose in a mammal; Reducing the HOMA-IR index of a mammal; Enhancement of GLP-1 sensitivity; and Avoiding GLP-1RA resistance and associated side effects due to intestinal disorders; and repairing gastrointestinal mucosal damage.

14. A composition comprising a bacterial strain of the Christensenella species described in any one of claims 1 to 4 or a Christensenella strain described in claim 5 or its descendant or subcloned strain and / or a metabolic product thereof, and used for treating or preventing at least one disease or condition selected from liver dysfunction and diseases associated with liver dysfunction, gastrointestinal mucosal disorders and diseases associated with gastrointestinal mucosal disorders, diabetes, obesity and obesity-related diseases.

15. The liver dysfunction-related disease includes at least one disease selected from the group consisting of fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and liver cirrhosis; The gastrointestinal mucosal damage refers to an increase in permeability of the gastrointestinal mucosa or an impairment of the mucosal barrier function, and the gastrointestinal mucosal damage-related disease includes at least one disease selected from the group consisting of leaky intestinal wall, peptic ulcer, gastroenteritis, and inflammatory bowel disease; The obesity-related disease includes at least one of cardiovascular disease, hyperlipidemia, insulin resistance syndrome, obesity-related gastroesophageal reflux disease, and steatohepatitis; and The composition of claim 14, wherein the diabetes includes at least one of type 1 diabetes, type 2 diabetes, insulin resistance syndrome, glucose intolerance, dyslipidemia, diabetic nephropathy complications, diabetic neuropathy, diabetic eye disease, cardiovascular disease, diabetic foot, and gestational diabetes.

16. The bacterial strain has a 16s rRNA sequence that is at least 98.65% identical to SEQ ID NO. 1; Preferably, the bacterial strain has a 16s rRNA sequence that is at least 99% identical to SEQ ID NO. 1, and 16. The composition of claim 14 or 15, wherein the bacterial strain preferably has a 16s rRNA sequence that is 99%, 99.5%, 99.9% or 100% identical to SEQ ID NO.

1.

17. A method for treating or preventing a disease or condition, comprising administering a composition described in any one of claims 14 to 16 or a composition described in claim 6 or 7 to a subject in need thereof, wherein the disease or condition is at least one selected from liver dysfunction and diseases associated with liver dysfunction, gastrointestinal mucosal disorders and diseases associated with gastrointestinal mucosal disorders, diabetes, obesity and obesity-related diseases.

18. A combination drug comprising a microorganism and a hypoglycemic or hypolipidemic drug, The microorganism is a bacterial strain of the species Christensenella sp. according to any one of claims 1 to 4 or a Christensenella strain according to claim 5 or a descendant or subcloned strain thereof and / or a metabolite thereof, The hypoglycemic or hypolipidemic drug is one or more of drugs that can improve glucagon-like peptide-1 pathway sensitivity and complement and / or enhance GLP-1 action, and is a combination drug used to treat or prevent at least one disease or condition selected from liver dysfunction and diseases associated with liver dysfunction, diabetes, obesity, and obesity-related diseases.

19. A method for treating or preventing a disease or condition, comprising administering to a subject in need thereof a composition according to any one of claims 14 to 16, or a composition according to claim 6 or 7, or a combination drug according to any one of claims 8 to 11, or a combination drug according to claim 12 or 18, wherein the disease or condition is at least one selected from liver dysfunction and diseases associated with liver dysfunction, diabetes, obesity, and obesity-related diseases.

20. A kit comprising the combination drug of claim 12 or 18.

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