Use of Fusarium in the preparation of a medicament for preventing or treating metabolic dysfunction or its related complications

Abstract

The present invention belongs to the technical field of biomedicine, and particularly relates to the application of Fusarium in the preparation of drugs for preventing or treating metabolic dysfunction or its related complications. The Fusarium is selected from one or more of the following Fusarium: Fusarium foetens ( Fusarium foetens ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium catenatum ), or Fusarium liriodendri ( Fusarium liriodendri ). The Fusarium provided by the present invention can significantly control body weight, improve blood glucose, blood lipids and symptoms of metabolic dysfunction related to steatohepatitis, and can be used to prepare drugs for treating diabetes, hyperlipidemia, obesity and metabolic dysfunction related to steatohepatitis.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine. Specifically, the present invention relates to the application of Fusarium ( Fusarium spp. ) in the treatment and prevention of metabolic diseases, specifically in the treatment of metabolic dysfunction and its complications associated with steatohepatitis. Background Art

[0002] Metabolic diseases refer to diseases caused by disorders in one or more links of the human metabolism process, characterized by obesity, hypertension, hyperglycemia, and lipid metabolism disorders, and are gradually becoming a severe challenge to global public health. With the change of lifestyle and the westernization of diet structure, the incidence of these diseases is increasing continuously, posing a major threat to human health. Steatohepatitis, especially steatohepatitis associated with metabolic dysfunction, is closely related to metabolic diseases such as type 2 diabetes, obesity, and insulin resistance, and is a concomitant disease of multiple metabolic diseases. Finding targets and drugs for metabolic dysfunction associated with steatohepatitis has become one of the important directions in the research field of metabolic diseases.

[0003] In recent years, many studies have reported that gut microbiota regulates the occurrence and development process of host metabolic diseases through multiple mechanisms. Regulating the composition of gut microbiota through diet intervention, probiotic supplementation, and fecal microbiota transplantation has become a potential treatment approach for metabolic diseases. At present, it has been found that the phyla Bacteroidetes, Firmicutes, and Proteobacteria in gut bacteria regulate liver lipid metabolism disorder-related phenotypes such as hepatocyte injury, inflammation, and fibrosis. Gut fungi are an important part of the gut microecology, and their rich active metabolites have important regulatory functions on the metabolic process and immune system of the host. However, at present, there is little research on the role of gut fungi in metabolic diseases such as obesity, cardiovascular and cerebrovascular diseases, and metabolic dysfunction associated with steatohepatitis, and its mechanism of action is not clear.

[0004] Fusarium is a common environmental fungus. Recent studies have found that Fusarium is also a common symbiotic fungus in the human and mouse intestines, and some studies have shown that its content is reduced in the intestines of patients with metabolic dysfunction associated with steatohepatitis. However, at present, no study has found the role of Fusarium ( Fusarium spp. ) in metabolic diseases, and there is no report on whether its mycelium can relieve or treat metabolic dysfunction and its complications associated with steatohepatitis. After extensive and in-depth research and experiments, the inventor of the present invention found that Fusarium foetens ( Fusarium wilt ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium catenatum ) or Fusarium liriodendri ( Fusarium liriodendrum) It has the function of preventing and treating metabolic diseases (including diabetes, hyperlipidemia, obesity, and metabolic dysfunctions related to steatohepatitis, etc.). By feeding experimental subjects with the active substance containing Fusarium wilt ) Fusarium foetens Fusarium pseudocircinatum ) Fusarium pseudocircinatum Fusarium catenatum ) Fusarium catenatum Fusarium liriodendrum ) or Fusarium liriodendri Summary of the Invention

[0005] In order to overcome the defects of the prior art, the present invention provides the application of Fusarium in the preparation of drugs for preventing or treating metabolic dysfunctions or their related complications.

[0006] Specifically, the present invention is achieved through the following technical solutions:

[0007] In the first aspect, the present invention provides a Fusarium with the function of preventing or treating metabolic dysfunctions or their related complications, and the Fusarium is selected from the following:

[0008] Fusarium foetens Fusarium wilt ) LM0001, with the preservation number of CGMCC No. 41901, the preservation time is April 2, 2025, the preservation place is the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing;

[0009] Fusarium pseudocircinatum Fusarium pseudocircinatum ) LM1063, with the preservation number of CGMCC No. 41902, the preservation time is April 2, 2025, the preservation place is the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing;

[0010] Fusarium catenatum Fusarium catenatum ) LM0193, with the preservation number of CGMCC No. 41903, the preservation time is April 2, 2025, the preservation place is the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; or

[0011] Fusarium liriodendri Fusarium liriodendrum)LM0200, with the deposit number of CGMCC No. 41904, deposited on April 2, 2025 at the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing.

[0012] In a second aspect, the present invention provides the use of Fusarium in the preparation of a drug for preventing or treating metabolic dysfunction or its related complications, and the Fusarium is selected from one or more of the following Fusarium: Fusarium foetens ( Fusarium stinking ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium chained ), or Fusarium liriodendri ( Fusarium liriodendrum ).

[0013] In one embodiment, the present invention provides the use of Fusarium foetens ( Fusarium wilt ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium catenatum ), and / or Fusarium liriodendri ( Fusarium liriodendrum ) in the treatment of metabolic dysfunction and its complications associated with steatohepatitis. More specifically, when the test animals are fed a high-fat model diet without choline, the Fusarium foetens ( Fusarium stinking ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium chained ), and Fusarium liriodendri ( Fusarium liriodendrum ) have the ability to inhibit the increase in the liver weight / body weight ratio, the exacerbation of inflammation, and the exacerbation of fibrosis in the test animals.

[0014] In one embodiment, the related complications are selected from one or more of the following: overweight, obesity, diabetes, hypercholesterolemia, hypertriglyceridemia, or cirrhosis.

[0015] In one embodiment, the Fusarium is selected from one or more of the following Fusarium:

[0016] Fusarium foetens ( Fusarium wilt ) LM0001, with the deposit number of CGMCC No. 41901, deposited on April 2, 2025 at the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing;

[0017] Fusarium pseudocircinatum ( Fusarium pseudocircinatum)LM1063, with the deposit number of CGMCC No. 41902, the deposit date of April 2, 2025, the deposit location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository unit being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing;

[0018] Fusarium catenulatum ( Fusarium catenatum )LM0193, with the deposit number of CGMCC No. 41903, the deposit date of April 2, 2025, the deposit location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository unit being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; or

[0019] Fusarium liriodendri ( Fusarium liriodendrum )LM0200, with the deposit number of CGMCC No. 41904, the deposit date of April 2, 2025, the deposit location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository unit being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing.

[0020] According to a preferred example of the present invention, in the choline-deficient, aminoacid-defined and high-fat diet (CDAA-HFD)-induced obese mouse model treated with the above-mentioned Fusarium foetens ( Fusarium wilt ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium catenatum ), and / or Fusarium liriodendri ( Fusarium liriodendrum ), compared with the untreated control group, the liver weight / body weight ratio can be maintained without increase, and it helps to reduce AST, ALT, and alleviate inflammation and fibrosis. Therefore, the said strains can be used to treat metabolic dysfunctions related to steatohepatitis and diseases caused thereby, such as hypercholesterolemia, liver cirrhosis, etc.

[0021] In one embodiment, the said drug is used to treat diabetes, hyperlipidemia, obesity, steatohepatitis or liver cirrhosis.

[0022] In one embodiment, the said drug further contains pharmaceutically acceptable excipients, drug-permitted media and carriers, which can be selected according to the administration route. The said drug can further contain auxiliary active components, carriers, excipients, diluents, sweeteners or flavors, etc.

[0023] The pharmaceutically acceptable excipients refer to conventional pharmaceutical carriers in the field of pharmaceutical preparations, and are selected from one or more of fillers, binders, disintegrants, lubricants, suspending agents, wetting agents, pigments, flavoring agents, solvents, and surfactants.

[0024] The fillers described in the present invention include but are not limited to starch, microcrystalline cellulose, sucrose, dextrin, lactose, powdered sugar, glucose, etc.; the lubricants include but are not limited to magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, poloxamer, etc.; the binders include but are not limited to water, ethanol, starch paste, syrup, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium alginate, polyvinylpyrrolidone, etc.; the disintegrants include but are not limited to starch effervescent mixtures such as sodium bicarbonate and citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, etc.; the suspending agents include but are not limited to polysaccharides such as acacia gum, agar, alginic acid, cellulose ethers, and carboxymethyl chitin ester, etc.; the solvents include but are not limited to water, balanced salt solutions, etc.

[0025] The drug can be made into various solid oral preparations, liquid oral preparations, etc. Pharmaceutically acceptable oral solid preparations include: ordinary tablets, dispersible tablets, enteric-coated tablets, granules, capsules, dripping pills, powders, etc., and oral liquid preparations include oral liquids, emulsions, etc. The above various dosage forms can be prepared according to the conventional processes in the field of pharmaceutical preparations.

[0026] In the pharmaceutical uses described herein, for the administration time, administration frequency, and dosing frequency of Fusarium, etc., it needs to be determined according to the specific diagnosis results of the condition, which is within the technical scope mastered by those skilled in the art.

[0027] Applying the treatment plan for the test animals to humans, the effective dose of all drugs for humans can be converted from the effective dose of the drug for the test animals, which is also easily achievable for those of ordinary skill in the art.

[0028] To better understand the essence of the present invention, the following specific implementation part uses pharmacodynamic experiments and their results to further illustrate the new use of Fusarium in the pharmaceutical field of the present invention.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The advantages of the present invention are that the Fusarium provided by the present invention can significantly control the liver weight / body weight ratio, improve liver inflammation and fibrosis, and can be used to prepare drugs for treating metabolic dysfunctions and their complications related to steatohepatitis. Specific Embodiments

[0031] The preferred embodiments of the present invention will be described below. It should be understood that the preferred embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not intended to limit the present invention. For those without specific technical or conditions noted in the embodiments, the techniques or conditions described in the literature in this field or according to the product specifications shall be followed. Unless otherwise specified, the experimental methods used in the following embodiments are all conventional methods. For reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through regular channels.

[0032] The strains used in the following examples were isolated from the feces of healthy individuals, and the specific names are Fusarium foetens ( Fusarium stinking ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenatum ( Fusarium chained ), and Fusarium liriodendri ( Fusarium liriodendrum ).

[0033] Fusarium foetens ( Fusarium wilt ), LM0001, with the deposit number CGMCC No. 41901, the deposit date being April 2, 2025, and the deposit location being the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Building 1, Yard 1, Beichen West Road, Chaoyang District, Beijing;

[0034] Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), LM1063, with the deposit number CGMCC No. 41902, the deposit date being April 2, 2025, and the deposit location being the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Building 1, Yard 1, Beichen West Road, Chaoyang District, Beijing;

[0035] Fusarium catenatum ( Fusarium catenatum ), LM0193, with the deposit number CGMCC No. 41903, the deposit date being April 2, 2025, and the deposit location being the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Building 1, Yard 1, Beichen West Road, Chaoyang District, Beijing; or

[0036] Fusarium liriodendri ( Fusarium liriodendrum ), LM0200, with the deposit number CGMCC No. 41904, the deposit date being April 2, 2025, and the deposit location being the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Building 1, Yard 1, Beichen West Road, Chaoyang District, Beijing.

[0037] Example: Fusarium Fusarium spp. Effects on liver weight / body weight ratio, liver function, inflammation, liver fibrosis, total cholesterol, and triglycerides in mice with metabolic dysfunction associated with steatohepatitis induced by a choline-deficient, amino acid-defined, and high-fat diet (CDAA-HFD).

[0038] 1. Materials and methods:

[0039] Fusarium Fusarium spp. was adjusted to a concentration of 10 6 spores / mL, and the intragastric administration dose was 0.1 mL / 10 g body weight, once a week. The bacterial solution needed to be cultured in advance, activated weekly to ensure freshness, and the concentration was measured separately.

[0040] C57BL / 6J mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The temperature was 20 - 24°C, the humidity was kept at 50 - 60%, the light was on for 12 hours (8:00 - 20:00), the environment was soundproof, and the mice had free access to food and water. After adapting to the environment for one week, the experiment was carried out. The alanine aminotransferase (ALT) and aspartate aminotransferase (AST) detection kits (Zhong Sheng Bei Kong) were purchased from Beijing Boyu Zhongkang Trading Co., Ltd. The total cholesterol (TC) and triglyceride (TG) detection kits (Biosino) were purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.

[0041] C57BL / 6J Six 16-week-old C57BL / 6J mice with a body weight of 28 - 30 g were used as the normal control group (Group 1). Male hepatitis model mice induced by CDAA-HFD, 8-week-old C57BL / Ff mice were fed a CDAA-HFD diet for 5 weeks. After successful modeling, they were continued to be fed a CDAA-HFD diet for 3 weeks and were divided into 6 groups: PBS administration group (model group) (Group 2), Fp administration group (administered Fusarium foetens, Group 3), Fc administration group (administered Fusarium pseudocircinatum, Group 4), Fl administration group (administered Fusarium catenatum, Group 5),

[0042] Fl administration group (administered Fusarium liriodendri, Group 6), and negative control strain administration group (Candida albicans, Group 7), with 6 mice in each group. The model control group was given an equal amount of PBS, and the mice in the administration groups were intragastrically administered 0.1 mL / 10 g body weight of the bacterial solution for 3 consecutive weeks. One week after the last administration, blood was collected, centrifuged at 3000 rpm at 4°C, and the liver weight, body weight, alanine aminotransferase, and aspartate aminotransferase of the mice in each group were measured.

[0042] Data analysis was performed using SPSS 27.0, and measurement data were expressed as mean ± standard deviation (mean ± SD). The sample distribution was determined by the Shapiro-Wilk normality test. Student’s t test (between two groups) or One-way ANOVA (between multiple groups) was used to compare normally distributed variables. Tukey’s test was used for the same standard deviation, and Dunnett’s T3 test was used for different standard deviations; the Mann-Whitney U test (between two groups) or Kruskal-Wallis test (between multiple groups) was used to compare non-normally distributed data; P <0.05 was considered statistically significant.

[0043] 2. Experimental results:

[0044] The experimental results are shown in Tables 1 - 9 below. The experimental results showed that compared with the control group and the model group, Fusarium could significantly improve the increased liver weight and liver weight / body weight ratio caused by CDAA-HFD, improve the levels of alanine aminotransferase and aspartate aminotransferase in mice, and improve the levels of total cholesterol and triglycerides in mice.

[0045] Table 1 Effects of Fusarium on the body weight of mice in the CDAA-HFD-induced hepatitis model

[0046]

[0047] Table 2 Effects of Fusarium on the liver weight of mice in the CDAA-HFD-induced hepatitis model

[0048]

[0049] Table 3 Effects of Fusarium on the liver weight / body weight ratio of mice in the CDAA-HFD-induced hepatitis model

[0050]

[0051] Table 4 Effects of Fusarium on ALT in mice in the CDAA-HFD-induced hepatitis model

[0052]

[0053] Table 5 Effects of Fusarium on AST in mice in the CDAA-HFD-induced hepatitis model

[0054]

[0055] Table 6 Effects of Fusarium on plasma TC in mice in the CDAA-HFD-induced hepatitis model

[0056]

[0057] Table 7 Effects of Fusarium on Plasma TG in CDAA-HFD-induced Hepatitis Mouse Model

[0058]

[0059] Table 8 Effects of Fusarium on Liver TC in CDAA-HFD-induced Hepatitis Mouse Model

[0060]

[0061] Table 9 Effects of Fusarium on Liver TG in CDAA-HFD-induced Hepatitis Mouse Model

[0062]

[0063] Note: In Tables 1-9, compared with Group 1, P <0.05, P <0.01; compared with Group 2, # P <0.05, ## P <0.01.

[0064] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described hereinafter (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here.

Claims

1. A Fusarium having a preventive or therapeutic effect on metabolic dysfunction associated with steatohepatitis, characterized in that: The Fusarium is selected from the following: Fusarium foetens Fusarium foetens LM0001, with the preservation number of CGMCC No. 41901, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC). The address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), LM1063, with the preservation number of CGMCC No. 41902, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; Fusarium catenulatum ( Fusarium catenatum ), LM0193, with the preservation number of CGMCC No. 41903, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; or Fusarium liriodendri ( Fusarium liriodendri ), LM0200, with the preservation number of CGMCC No. 41904, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit being the Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing.

2. Use of Fusarium in the preparation of a drug for preventing or treating metabolic dysfunction associated with steatohepatitis, characterized in that: The Fusarium is selected from one or more of the following Fusarium: Fusarium foetens ( Fusarium foetens ), Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), Fusarium catenulatum ( Fusarium catenatum ), or Fusarium liriodendri ( Fusarium liriodendri ): Fusarium foetens ( Fusarium foetens ), LM0001, with the preservation number of CGMCC No. 41901, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; Fusarium pseudocircinatum ( Fusarium pseudocircinatum ), LM1063, with the preservation number of CGMCC No. 41902, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; Fusarium catenulatum ( Fusarium catenatum ), LM0193, with the deposit number of CGMCC No. 41903, the deposit date of April 2, 2025, the deposit location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the depository unit being Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing; or Fusarium liriodendri Fusarium liriodendri LM0200, with the preservation number of CGMCC No. 41904, the preservation date of April 2, 2025, and the preservation location at the China General Microbiological Culture Collection Center (CGMCC), and the address of the preservation unit is Institute of Microbiology, Chinese Academy of Sciences, No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing.

3. The application according to claim 2, wherein: The metabolic dysfunction associated with steatohepatitis is selected from one or more of the following: overweight, obesity, high cholesterol or high triglycerides.

4. The application according to claim 2, wherein: The drug further comprises a pharmaceutically acceptable excipient.

5. The application according to claim 4, characterized in that: The dosage form of the drug is an oral dosage form.

6. The application according to claim 5, characterized in that: The oral dosage form is selected from freeze-dried powder, capsules, tablets or granules.

Images