KR102593538B1 - Pharmaceutical composition for preventing or treating liver fibrosis comprising Bacteroides dorei train - Google Patents

Abstract

It relates to a pharmaceutical composition for preventing or treating liver fibrosis, a health functional food composition for preventing or improving liver fibrosis, and a health food composition for preventing or improving liver fibrosis containing the Bacteroides dorey strain.

Description

Pharmaceutical composition for preventing or treating liver fibrosis comprising Bacteroides dorei train}

The present invention relates to a pharmaceutical composition for preventing or treating liver fibrosis containing the Bacteroides dorey strain, a health functional food composition for preventing or improving liver fibrosis, and a health food composition for preventing or improving liver fibrosis.

Since about 60% of the body's immune cells are impaired, the body must be healthy only if the intestines are healthy. Modern people's irregular lifestyle habits and stress cause an imbalance in intestinal bacteria, which affects intestinal health. At this time, lactic acid bacteria regulate the intestinal microflora by helping to increase beneficial bacteria and reduce harmful bacteria in the intestines. In this way, intestinal microorganisms play an important role in health and disease. By increasing the ratio of beneficial bacteria by controlling the intestinal microflora, it can be used to improve various diseases such as immunomodulating effect, reducing fasting blood sugar, and preventing attachment and invasion of pathogenic bacteria [Hallajzadeh J, Eslami RD, Tanomand A. Effect of Lactobacillus delbrueckii Subsp. lactis PTCC1057 on Serum Glucose, Fetuin-A, and Sestrin 3 Levels in Streptozotocin-Induced Diabetic Mice. Probiotics Antimicrob Proteins 2020, Yu Q, Zhu L, Wang Z, Li P, Yang Q. Lactobacillus delbrueckii ssp. lactis R4 prevents Salmonella typhimurium SL1344-induced damage to tight junctions and adherens junctions. J Microbiol 2012; 50:613-7].

Imbalances in the composition and function of the gut microbiota are associated with chronic diseases ranging from gastrointestinal inflammation and metabolic conditions to neurological, cardiovascular, and respiratory diseases. Considerable effort is currently being focused on understanding the microbiome genome in parallel with improving our knowledge of microbiome-host interactions. These efforts ultimately aim to develop effective approaches to rebuild disturbed human microbial ecosystems as a means to restore health or prevent disease. Liver fibrosis is a condition in which there is increased fiber in the liver and is caused by excessive accumulation of extracellular matrix proteins, including collagen, which occurs mostly in chronic liver disease. Advanced liver fibrosis causes cirrhosis, liver failure, and portal hypertension and may require liver transplantation [Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115:209-18].

Hepatic cholestatic disease represents a relevant cause of chronic liver disease associated with significant mortality. Understanding and addressing treatment strategies for this is essential to develop in vivo models that recapitulate pathological features. The supply of 3,5-diethoxycarbonyl-1,4-dihydrocolidine, named DDC, is a biomodel of cholestatic disease in which the main pathological features of human cholestatic disease, such as fibrosis and inflammatory infiltrate, are reproduced [ Pose E, Sancho-Bru P, Coll M. 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine Diet: A Rodent Model in Cholestasis Research. Methods Mol Biol 2019; 1981:249-57].

Thioacetamide, named TAA, is a thiono-sulfur containing compound that induces liver fibrosis in animal experiments and is widely used to investigate the basic mechanisms and therapeutic effects of potential anti-fibrotic drugs. TAA itself is not hepatotoxic, but reactive metabolites covalently bind to proteins and lipids, causing oxidative stress and centromere necrosis [Delire B, Starkel P, Leclercq I. Animal Models for Fibrotic Liver Diseases: What We Have, What We Need , and What Is Under Development. J Clin Transl Hepatol 2015; 3:53-66].

Antibiotics work to eliminate harmful bacteria from our body. However, overuse and abuse of antibiotics can cause side effects such as allergic reactions, rashes, and diarrhea, and continuous exposure to low concentrations of antibiotics can lead to resistance, which reduces the effectiveness of the drug. When antibiotics are used to prevent harmful bacterial infections in animal farming, antibiotic residues may remain on milk, eggs, and meat. These residues can cause various immunopathological side effects in antibiotic-resistant bacteria [Bacanli M, Basaran N. Importance of antibiotic residues in animal food. Food Chem Toxicol 2019; 125:462-6].

Probiotics can be used as a substitute for live lactic acid bacteria antibiotics to be fed to livestock to improve livestock productivity by increasing resistance to harmful bacteria, and can play a role in controlling harmful bacteria in the human body. To take advantage of the beneficial properties of these probiotics, it is important to determine their effectiveness against microorganisms in the digestive tract of humans and animals. Probiotics that restore or improve the intestinal microflora can be expected to develop treatments for modern diseases.

The purpose of the present invention is to propose a candidate strain as a treatment for liver fibrosis because the Bacteroides dorei strain improves liver fibrosis and has an immune-enhancing effect by regulating intestinal microflora.

In addition, the problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

In order to achieve the above object, according to one embodiment of the present invention, a pharmaceutical composition for preventing or treating liver fibrosis containing Bacteroides dorey strain as an active ingredient is provided.

According to one embodiment of the present invention, the Bacteroides dorey strain may be isolated from fermented raw milk.

According to one embodiment of the present invention, the Bacteroides dorey strain may be contained in the form of a powdered probiotic.

According to another embodiment of the present invention, a health functional food composition for preventing or improving liver fibrosis containing the Bacteroides dorey strain is provided.

According to one embodiment of the present invention, the health functional food may be in the form of tablets, capsules, pills, or liquid.

Meanwhile, according to another embodiment of the present invention, a health food composition for preventing or improving liver fibrosis containing the Bacteroides dorey strain is provided.

According to one embodiment of the present invention, the health food consists of drinks, meat, sausages, bread, candies, snacks, noodles, ice cream, dairy products, soups, isotonic drinks, beverages, alcoholic beverages, gum, tea and vitamin complexes. It may be at least one selected from the group.

The isolated Bacteroides dorei strain according to the present invention has the effect of improving the degree of fibrosis by regulating the intestinal microflora due to ingestion of the B. dorei strain in a liver fibrosis-induced mouse model.

In addition, when the Bacteroides dorei strain according to the present invention is administered to mice inducing liver fibrosis, it modifies the intestinal microflora, which lowers the expression of fibrosis genes in liver tissue through the intestinal-liver axis and causes pathological liver damage. Since it has the effect of protecting and inhibiting fibrosis, it can be used to prevent and treat liver fibrosis.

Figure 1 is a schematic diagram of a mouse model of liver fibrosis induced by DDC dietary intake.
Figure 2 is a comparative diagram of the protective effects of B. dorei strains on body weight and liver weight in the DDC model.
Figure 3 is a measurement of total bilirubin reduction in the blood of B. dorei strains in the DDC model.
Figure 4 is a comparative diagram of the inhibition of fibrosis gene expression of B. dorei strains in the DDC model liver.
Figure 5 is a comparative diagram of inhibition of fibrosis gene expression of B. dorei strains in DDC model hepatic stellate cells.
Figure 6 is a pathological comparison diagram of inhibition of fibrosis progression of B. dorei strains in the DDC model.
Figure 7 is a comparative diagram of changes in intestinal microbiota at the phylum level due to ingestion of B. dorei strains in the DDC model.
Figure 8 is a comparative diagram of changes in intestinal microbiota at the species level due to ingestion of B. dorei strains in the DDC model.
Figure 9 shows the main coordinate analysis and diversity of intestinal microorganisms due to ingestion of B. dorei strains in the DDC model.
Figure 10 is a schematic diagram of a liver fibrosis mouse model induced by intraperitoneal injection of TAA.
Figure 11 is a comparative diagram of the protective effects of B. dorei strains on body weight and liver weight in the TAA model.
Figure 12 is a measurement diagram of inhibition of fibrosis gene expression of B. dorei strain in the TAA model.
Figure 13 is a pathological comparison diagram of inhibition of fibrosis progression of B. dorei strains in the TAA model.
Figure 14 is a comparative diagram of changes in intestinal microbiota at the phylum level due to ingestion of B. dorei strains in the TAA model.
Figure 15 is a comparative diagram of changes in intestinal microbiota at the species level due to ingestion of B. dorei strains in the TAA model.
Figure 16 is a comparative diagram of the main coordinate analysis and diversity of intestinal microorganisms due to ingestion of B. dorei strains in the TAA model.

Hereinafter, the present invention will be described in detail. Prior to this, the terms or words used in this specification and patent claims should not be construed as limited to their usual or dictionary meanings, and the inventor must appropriately use the concept of the term to explain his or her invention in the best way. It must be interpreted as meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined clearly. Accordingly, the configuration described in the embodiments described in this specification is only one of the most preferred embodiments of the present invention and does not represent the entire technical idea of the present invention, so at the time of filing this application, various equivalents and It should be understood that variations may exist.

According to one embodiment of the present invention, a pharmaceutical composition for preventing or treating liver fibrosis containing Bacteroides dorey strain as an active ingredient is provided.

Throughout the present invention , Bacteroides dorei may be used interchangeably with B. dorei strain.

Meanwhile, according to one embodiment of the present invention, the Bacteroides dorey strain may be isolated from fermented raw milk.

Additionally, the Bacteroides dorei strain can be cultured and used at a concentration of 10 ⁹ CFU/mL.

According to one embodiment of the present invention, a health functional food composition for preventing or improving liver fibrosis containing a Bacteroides dorey strain is provided.

At this time, the health functional food may be in the form of tablets, capsules, pills, or liquid.

According to one embodiment of the present invention, a health food composition for preventing or improving liver fibrosis containing a Bacteroides dorey strain is provided.

When using the Bacteroides dorey strain of the present invention as a health functional food or health food composition, there is no particular limitation on the type of food. Examples of foods to which the Bacteroides dorey strain of the present invention can be added include drinks, meat, sausages, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, and ice cream. It includes dairy products, various soups, beverages, alcoholic beverages and vitamin complexes, dairy products and milk products, and includes both health functional foods and health food compositions in the conventional sense.

The health functional food and health food composition containing the Bacteroides dorey strain according to the present invention can be added as is to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the Bacteroides dorei strain can be appropriately determined depending on the purpose of use (prevention or improvement). In general, the amount of the composition in health functional foods and health food compositions can be 0.1 to 90 parts by weight of the total weight of the food. However, in the case of long-term intake for the purpose of maintaining health or controlling health, the amount may be below the above range.

Other than containing the Bacteroides dorey strain of the present invention, there are no particular restrictions on other ingredients, and various flavoring agents or natural carbohydrates can be contained as additional ingredients like ordinary drinks. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 of the health functional food and health food composition of the present invention.

Other than the above, health functional foods and health food compositions containing the Bacteroides dorey strain of the present invention contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, and thickening agents (cheese). , chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated drinks, etc. In addition, the health functional food and health food composition of the present invention may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1. Isolation and preparation of BACTEROIDES DOREI

1. Characterization and identification of probiotic microorganism candidates

In the present invention, the isolated Bacteroides dorei strain was identified through whole-genome analysis and was provided by Cheonlab Co., Ltd.

2. Preparation of Bacteroides dorei composition

Bacteroides dorei strains were supplied by Cheonlab Co., Ltd. Bacteroides torei was spread on solid RCM medium, an anaerobic pack and indicator were placed in a jar (Mitsubishi Gas Chemical, Japan), and cultured at 37°C for 48 hours. Cultured Bacteroides dorei is prepared at a concentration of 10 ⁹ CFU/mL.

Example 3. Induction and analysis method of liver fibrosis-induced mouse model

For animal model evaluation, 5-week-old C57BL/6J male mice without specific pathogens were purchased from Duyeol Biotech (Seoul, Korea). All mice were individually housed in dedicated cages at a temperature of 22°C ± 2°C with a 12/12 hour light/dark cycle. During the experiment, all mice had free access to water and food and were observed daily. The experiment included an adaptation period for all groups, during which normal food was provided for one week. The experimental animals received humane treatment, all procedures followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, and were approved by the Institutional Animal Care and Use Committee of Hallym University College of Medicine (2019-4).

1. 3,5-diethoxycarbonyl-1,4-dihydrocolidine model

To induce a liver fibrosis model through dietary intake, 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) mixed feed was manufactured by Duyeol Biotech and allowed to be freely consumed for 3 weeks. Liver fibrosis model mice were divided into four groups (Figure 1): normal (n = 10), disease-induced (n = 10), B. dorei administered with disease induction (n = 10), and with disease induction. Ursodeoxycholic acid administration (n=10).

2. Thioacetamide model

To induce a liver fibrosis model by intraperitoneal injection, thioacetamide (hereinafter abbreviated as TAA) (Sigma, USA) and physiological saline (Jeil Pharmaceutical, Korea) were diluted and injected intraperitoneally at increasing concentrations three times a week for 6 weeks (1st treatment). A liver fibrosis model was established (dose 50mg/kg, 2nd dose: 100mg/kg, 3rd to 6th dose: 200mg/kg, all subsequent doses: 300mg/kg). Liver fibrosis model mice were divided into four groups (Figure 10): normal (n = 10), disease induced (n = 10), B. dorei administered with disease induction (n = 10), and with disease induction. Ursodeoxycholic acid (Daewoong Pharmaceutical, Korea) administered (n=10).

3. Processing method

에 보관했다.Depending on each animal model, animals were sacrificed through inhalation anesthetic administration (Airlane solution, USA) after 4 and 11 weeks. Body weight and liver weight were measured, and blood and liver tissue were separated. Whole blood (800 μL) samples were centrifuged (19,000 g, 5 min) to separate serum. Liver tissue is quickly separated and 80

stored in

4. Pathological analysis

The isolated liver tissue was fixed with 10% formalin and embedded in paraffin, and the tissue sections were stained with hematoxylin eosin (H&E), Masson's trichrome (MT), and Sirius red (SR). Grading, a pathological analysis used for the analysis of cirrhosis (degree of inflammation, fragmentary or bridging necrosis [grade 0: none, 1: portal inflammation or lobular inflammation without necrosis, 2: mild periportal inflammation and fragmentary necrosis or focal hepatocellular necrosis; 3: moderate portal inflammation and fragmentary necrosis or severe focal cellular damage; 4: severe periportal inflammation and fragmentary necrosis or bridging necrosis]) and staging (degree of fibrosis [grade 0: no fibrosis; 1: dilated fibrous portal tract; 2” periportal fibrosis or portal to portal septum, no structural distortion, 3: fibrotic connection with structural distortion, no apparent cirrhosis, 4: probable or definite cirrhosis]) were evaluated.

5. Liver tissue analysis for fibrosis factors

Isolation of mRNA from tissues was performed using the Trizol reagent kit (Invitrogen, USA) according to the manufacturer's instructions. mRNA (2 μg) was synthesized into cDNA using a cDNA synthesis kit (Applied Biosystems, USA). cDNA was subjected to quantitative PCR (qPCR) using Luna Universal Master Mix (New England Biolab, USA) and each target-specific probe-primer.

6. Fecal microbiome analysis

Metagenomic DNA was extracted using the QIAamp stool kit (Qiagen, Germany), and amplification of the V3 - V4 region of the bacterial 16S rRNA gene was performed using barcode universal primers. Microbiome profiling was performed using the 16S-based microbial taxonomic profiling platform of EzBioCloud (Chunlab, Korea). All 16S rRNA sequences have been deposited in the Cheonlab database, and the base sequence reads of the 16S rRNA gene obtained in this study are archived under the bioproject number PRJNA532302.

7. Data analysis

Continuous variables were analyzed by mean and standard deviation. One-way ANOVA, the Kruskal-Wallis test, and independent sample T-test were performed to analyze body weight, fibrosis factors, and histology. For further statistical analysis, data were based on MSTUS55 from NOREVA (http://idrb.zju.edu.cn/noreva). Hierarchical cluster analysis (HCA) was performed and analysis of variance (ANOVA) with post hoc test was performed using Multiple Experiment Viewer (MeV). Significance probability P value <0.05 is considered to indicate statistical significance. All statistical analyzes were performed using SPSS software (ver. 19, SPSS Inc., Chicago, IL, USA).

Example 4. Comparison of protective effects on body weight and liver weight in a liver fibrosis-induced mouse model of B. dorei strains.

1. Weight protection effect due to consumption of B. dorei strains

What weight/liver weight means in liver disease

A) DDC model

When DDC mixed feed was consumed, body weight decreased in the normal group (21.8±1.1) and the disease-induced group (18.9±1.1). However, the B. dorei strain group (19.4 ± 1) and the UDCA group (20.2 ± 0.8) were protected from weight loss (see Figure 2).

B) TAA model

Upon intraperitoneal injection of TAA, body weight decreased in the normal group (25.9±1.5) and the disease-induced group (24.1±1.3), and in both the B. dorei monarch group (22.4±1.9) and the UDCA group (22.6±1.3). There was no protection from weight loss in the TAA model (see Figure 11).

2. Protective effect on liver weight due to ingestion of B. dorei strains

A) DDC model

When consuming DDC mixed feed, the liver weight of the disease-induced group (1.3±0.1) increased from the normal group (0.9±0.1). However, the B. dorei strain group (1.1 ± 0.1) and the UDCA group (1.1 ± 0.1) showed a protective effect against liver weight increase (see Figure 2).

B) TAA model

When liver fibrosis was induced by intraperitoneal injection of TAA, the liver weight of the disease-induced group (1.5±0.1) increased from the normal group (1.4±0.1). However, the B. dorei strain group (1.3 ± 0.1) and the UDCA group (1.3 ± 0.1) showed a protective effect against liver weight increase (see Figure 11).

Example 5. Measurement of decrease in total bilirubin level in blood of mouse model inducing liver fibrosis of B. dorei strain

Total biliruville levels are reduced in the blood upon ingestion of B. dorei strains in the DDC model.

When consuming DDC feed, the total bilirubin level in the blood increases from the normal group (0.5±0.1) to the liver fibrosis induced group (0.7±.0.1). When administered with the B. dorei strain, the effect is reduced to (0.5±0.1) as much as the normal group. The UCDA group (0.6±0.1) also decreased (see Figure 3).

Example 6. Measurement of liver fibrosis inhibition ability in mouse model of liver fibrosis induction of B. dorei strain

1. Inhibitory effect of liver fibrosis factors in liver fibrosis-induced mouse model

The most notable characteristic of liver fibrosis disease is the progression of fibrosis. There are various causes of fibrosis, including overexpression of TGF-β and abnormal activity of hepatic stellate cells. Although the exact cause is not yet known, representative fibrosis factors (Timp1, Col1a, and TGF-β) in liver fibrosis can be useful in evaluating the disease. Therefore, we compared and analyzed the expression of each fibrosis factor in the liver fibrosis induction model through qPCR. It was confirmed that the expression of Timp1, Col1a, and TGF-β, which were greatly increased due to the induction of liver fibrosis, were significantly decreased upon ingestion of the B. dorei strain.

A) DDC model

While feeding a liver fibrosis inducing diet with DDC compound feed for 3 weeks, each B. dorei strain and UDCA were administered to the normal diet group, liver fibrosis induction group, and liver fibrosis induction group. When B. dorei strain was administered while inducing liver fibrosis, the expression of Col1a, Timp1, and TGF-β, which are representative fibrosis factors in liver cirrhosis, were significantly decreased. For Col1a, from 15.2±7.2 in the control group that induced liver fibrosis to 8.6±1.4 ( p <0.05) when administered with the B. dorei strain, for Timp1, from 4.2±1.5 to 2.2±0.5 ( p <0.05), and for TGF-β1. In this case, it decreased from 2.9 ± 1.0 to 2.1 ± 0.5 ( p < 0.05) (see Figure 4). Hepatic stellate cells were isolated from hepatocytes and the expression of the same fibrotic factors was compared and analyzed. When DDC feed was consumed for 3 weeks, the expression of Col1a (17 ± 0.2) in hepatic stellate cells also decreased (2.3 ± 0.4) ( p < 0.01) when B. dorei strain was administered. Timp1 also decreased from 21.8 ± 16.3 to 4.5 ± 3.4 ( p < 0.01) in the disease-induced group, and TGF-β1 also decreased from 2.4 ± 0.3 to 1.2 ( p < 0.01) (see Figure 5).

B) TAA model

Each B. dorei strain, UDCA, was administered to the normal diet group, liver fibrosis induction group, and liver fibrosis induction group by intraperitoneal injection for 10 weeks. For Col1a, from 7.5 ± 1.4 in the control group that induced liver fibrosis to 4.5 ± 2.7 ( p < 0.05) when administered with B. dorei strain, for Timp1, from 8.8 ± 1.9 to 5.5 ± 1.6 ( p < 0.05), and for TGF-β. In this case, it was reduced from 1.7 ± 0.4 to 1.4 ± 0.3 (see Figure 12).

2. Protective effect against liver cirrhosis in a mouse model of liver fibrosis induced by B. dorei strains

Pathological analysis was performed to more clearly confirm liver fibrosis in cirrhosis. Liver tissue was subjected to hematoxylin eosin, Masson's trichrome, and Sirius red staining. In the liver fibrosis-induced model, fibrosis increased, and grading, staging, and Sirius red measurement areas increased significantly compared to the normal control group. The protective effect was confirmed by reducing all increased grading, staging, and Sirius Red measured areas through consumption of B. dorei strains.

A) DDC model

When inducing a liver fibrosis model, it decreased from grading 2 to 1.9±0.5 when B. dorei was administered, and from staging 2.7±0.5 to 1.9±0.5 ( p <0.01). The measured area of Sirius Red staining decreased from 16.4 ± 2.2 to 8.9 ± 1.3 ( p < 0.05) when administered with B. dorei (see Figure 6).

B) TAA model

When inducing the liver fibrosis model, it decreased from grading 2.4±0.5 to 1.4±0.5 when B. dorei was administered, and from staging 2.8±0.4 to 1.4±0.5 when B. dorei was administered ( p <0.01). The area measured by Sirius Red staining decreased from 26.5 ± 4.3 to 19.2 ± 1.7 ( p < 0.01) when B. dorei was administered (see Figure 13).

Example 7. Changes in intestinal microflora due to ingestion of B. dorei strains

1. Comparison of intestinal microflora

A) DDC model

When comparing intestinal microbiota at the phylum level, DDC compound feed intake increases Proteobacteria from the normal group. When B. dorei strain was administered, Verrucomicrobi increased and Firmicutes decreased compared to the disease-inducing group (see Figure 7). Changes at the species level were expressed as a heatmap for easy viewing (see Figure 8).

B) TAA model

When comparing the intestinal microbiota at the phylum level, TAA intraperitoneal injection increased Firmicutes , the proportion of Proteobacteria disappeared, and Verrucomicrobia appeared in the normal group. When B. dorei strain is administered, compared to the disease-inducing group, Bacteroidetes increases, Firmicutes decreases, and the proportion of Verrucomicrobia disappears, showing results similar to the normal group (see Figure 14). Changes at the species level were expressed as a heatmap for easy viewing (see Figure 15).

2. Comparison of diversity

A) DDC model

Intestinal microbial main coordinate analysis and diversity comparison (see Figure 9),

B) TAA model

Intestinal microbial main coordinate analysis and diversity comparison (see Figure 16),

Claims (9)

A pharmaceutical composition for preventing or treating liver fibrosis comprising Bacteroides dorey strain as an active ingredient. delete According to paragraph 1,
A pharmaceutical composition for preventing or treating liver fibrosis, wherein the Bacteroides dorey strain is contained in the form of a powdered probiotic. A health functional food composition for preventing or improving liver fibrosis containing the Bacteroides doray strain. According to clause 4,
The health functional food is a health functional food composition for preventing or improving liver fibrosis, which is a food in the form of tablets, capsules, pills, or liquid. delete According to clause 4,
A health functional food composition for preventing or improving liver fibrosis, wherein the Bacteroides doray strain is contained in the form of a powdered probiotic. delete delete