A pharmaceutical composition for the prevention or treatment of cholestatic liver disease, containing Leuconostoc citreum strain as an active ingredient.

Abstract

The present invention relates to a composition for preventing, improving or treating cholestatic liver disease, specifically primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), containing a Leuconostoc citreum strain or a culture thereof as an active ingredient. The composition according to the present invention shows excellent preventive and therapeutic effects against several cholestatic liver diseases, and therefore can be usefully used as a composition for treating, preventing or improving cholestatic liver disease in humans or animals.

Description

Technical Field

[0001] The present invention relates to a composition for preventing, improving, or treating cholestatic liver diseases, specifically primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), which contains a Leuconostoc citreum strain or its culture as an active ingredient.

Background Art

[0002] Cholestatic liver injury is a disease caused by the accumulation of bile acids and lipids. The liver regulates central lipid metabolic processes including fatty acid synthesis, mitochondrial β-oxidation, and phospholipid transport. Bile secretion disorders caused by biliary obstruction or liver injury interfere with cholesterol and phospholipid metabolism. In a bile duct ligation (BDL) rat model, while the liver lipid concentration did not change, the serum levels of very low-density lipoprotein (VLDL) cholesterol and low-density lipoprotein (LDL) cholesterol increased significantly (T. Kamisako, et al., Hepatology Research, vol. 25, no. 2, pp. 99-104, 2003).

[0003] PBC, a type of cholestatic liver disease, is a relatively rare disease that presents with the characteristics of chronic cholestatic disease, yet it has attracted the attention of many gastroenterologists due to its distinctive clinical presentation and pathophysiology. PBC occurs in all races, with a prevalence of approximately 100-200 people per million population. The age of onset is usually between 30 and 70 years, but it is particularly common in middle-aged women. It is known that if there is a family history of PBC, the likelihood of a female family member developing PBC is about 1000 times higher than in the control group. It can be associated with various autoimmune diseases, and characteristically, anti-mitochondrial antibodies are found in almost all patients. Histologically, it is characterized by progressive nonsuppurative cholangitis.

[0004] PSC, along with PBC, is a chronic cholestatic disease whose cause is not clearly understood. It is characterized by inflammatory fibrosis and destruction of the intrahepatic and extrahepatic bile ducts and is often associated with inflammatory bowel disease. Like PBC, it progresses and causes cirrhosis and complications, but there is no effective medical treatment.

[0005] The exact cause of PSC is still unknown, but it is thought to involve autoimmune reactions, portal vein bacteremia, and genetic predisposition. The presence of various autoantibodies (ANA, SMA, ANCA), increased complement and immune complex levels in the blood, and frequent association with inflammatory bowel disease suggest that an autoimmune mechanism may be the cause. PSC has a high prevalence within patient families, and an HLA link has been partially established, suggesting that genetic predisposition is involved in its development. In individuals with a genetic predisposition, portal vein bacteremia due to inflammatory bowel disease, etc., is followed by increased TNF-α secretion by activated Kupffer cells, leading to intrahepatic lesions. However, the exact etiology has not yet been clearly elucidated (Clinical and Molecular Hepatology, Journal of the Korean Society for Hepatology, Vol. 10, No. 3s, pp. 36-53, 2004).

[0006] In recent years, the preventive or therapeutic effects of compositions containing stem cells (Korean Registered Patent No. 10-2159630) or dosage forms containing multiple bacteria (US Published Patent No. 2021-0008128) on cholestatic liver disease have been disclosed. However, there are no descriptions of the preventive or therapeutic effects of Leuconostoc citreum strains or cultures derived from lactic acid bacteria on cholestatic liver disease as active ingredients.

[0007] Against this background, the inventors conducted research to find substances for the prevention and treatment of cholestatic liver disease using lactic acid bacteria with little toxicity and side effects. As a result, they confirmed that the Leuconostoc citreum strain or its culture has preventive or therapeutic efficacy against primary biliary cirrhosis or primary sclerosing cholangitis, and thus completed the present invention. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Korean Registered Patent No. 10-2159630 [Patent Document 2] U.S. Published Patent No. 2021-0008128 [Non-patent literature]

[0009] [Non-Patent Document 1] T. Kamisako, et al., Hepatology Research, vol.25, no.2, pp.99-104, 2003 [Non-Patent Document 2] Clinical and Molecular Hepatology, Journal of the Korean Hepatology Society, Volume 10, Issue 3s, pp.36-53, 2004 [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] The object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cholestatic liver disease, comprising the Leuconostoc citreum strain as an active ingredient.

[0011] Another object of the present invention is to provide a food composition or food additive composition for the prevention or improvement of cholestatic liver disease, comprising Leuconostoc citreum strain as an active ingredient.

[0012] Another object of the present invention is to provide a feed composition or feed additive composition for the prevention and improvement of cholestatic liver disease in livestock, comprising Leuconostoc citreum strain as an active ingredient. [Means for solving the problem]

[0013] To achieve the above objective, the present invention provides a pharmaceutical composition for the prevention or treatment of cholestatic liver disease, comprising a Leuconostoc citreum strain or its culture as an active ingredient.

[0014] Furthermore, the present invention provides a food composition or food additive composition for the prevention or improvement of cholestatic liver disease, comprising a Leuconostoc citreum strain or its culture as an active ingredient.

[0015] Furthermore, the present invention provides a feed composition or feed additive composition for preventing or improving cholestatic liver disease in livestock, comprising a Leuconostoc citreum strain or its culture as an active ingredient. [Effects of the Invention]

[0016] The Leuconostoc citreum strain or culture according to the present invention exhibits excellent preventive and therapeutic effects against various cholestatic liver diseases, and can therefore be usefully used as a composition for applications such as the treatment, prevention, or improvement of cholestatic liver diseases in humans or animals. [Brief explanation of the drawing]

[0017] [Figure 1]Figure showing a photograph of the liver tissue of sacrificed mice observed after treating the Leuconostoc citreum WiKim0104 strain in an animal model induced by bile duct ligation. [Figure 2] Figure showing a photograph of the liver tissue of sacrificed mice after treating the Leuconostoc citreum WiKim0104 strain in an animal model induced by bile duct ligation, stained with H&E to observe hepatocyte necrosis. [Figure 3] Figure showing a graph evaluating the degree of cell necrosis in the liver tissue of sacrificed mice after treating the Leuconostoc citreum WiKim0104 strain in an animal model induced by bile duct ligation. [Figure 4] Figure showing a photograph of the liver tissue of sacrificed mice after treating the Leuconostoc citreum WiKim0104 strain in an animal model induced by bile duct ligation, stained with Sirius red to observe hepatocyte fibrosis. [Figure 5] Figure showing a graph evaluating the Sirius red% positive area and the degree of fibrosis index in the liver tissue of sacrificed mice after treating the Leuconostoc citreum WiKim0104 strain in an animal model induced by bile duct ligation. [Figure 6] Figure showing a graph measuring the expression levels of α-SMA and Col1a1 using cDNA synthesized from RNA isolated from the liver tissue of sacrificed mice after treating the Leuconostoc citreum WiKim0104 strain in an animal model induced by bile duct ligation. [Figure 7]Figure showing the graph of the measured expression levels of IL-6 and IL-1β using cDNA synthesized from RNA isolated from the liver tissue of sacrificed mice after treating the Leuconostoc citreum WiKim0104 strain in a bile duct ligation-induced animal model

Best Mode for Carrying Out the Invention

[0018] The composition containing the Leuconostoc citreum strain or its culture of the present invention as an active ingredient has a preventive or therapeutic effect on cholestatic liver diseases and can be used as a pharmaceutical composition.

[0019] The Leuconostoc citreum strain of the present invention is a lactic acid bacterium strain. The Leuconostoc citreum strain is a probiotic and has the general intestinal regulating effect and immune enhancing effect of lactic acid bacteria. It is a well-known fact that lactic acid bacteria of the genus Leuconostoc have intestinal regulating effect and immune enhancing effect.

[0020] The Leuconostoc citreum strain may be the Leuconostoc citreum WiKim0104 strain and has the nucleic acid sequence of SEQ ID NO:1.

[0021] The Leuconostoc citreum strain can be inoculated at 0.1 - 10% in MRS liquid medium and cultured at 25 - 37°C for 4 hours to 48 hours for use.

[0022] The culture method is preferably a static culture method, but is not limited thereto.

[0023] In this invention, "probiotics" is understood to mean "living microorganisms that improve the environment of the host's intestinal microbiota in the digestive tract of animals, including humans, and have a beneficial effect on the host's health." Probiotics are living microorganisms with probiotic activity that, when supplied to humans or animals in the form of single or complex strains, can have a beneficial effect on the host's intestinal flora in the form of dried cells or fermentation products.

[0024] The aforementioned cholestatic liver disease may be, but is not limited to, pulmonary cholestatic liver disease, renal cholestatic liver disease, or hepatic cholestatic liver disease.

[0025] The Leuconostoc citreum strain contained in the composition according to the present invention may exist as live cells or dead cells, or in a dried or freeze-dried form. Furthermore, a culture of the Leuconostoc citreum strain may be the active ingredient, and the culture may contain a live cell culture solution or a dead cell supernatant. Various forms of lactic acid bacteria suitable for inclusion in compositions and methods of formulation are widely known to those skilled in the art.

[0026] The composition may be administered orally or parenterally. Parenteral administration may be administered by intravenous infusion, subcutaneous infusion, intramuscular infusion, intraperitoneal infusion, endothelial infusion, local infusion, intranasal infusion, intrapulmonary infusion, or rectal infusion, and is preferably administered by intravenous infusion, but is not limited to these methods.

[0027] The appropriate dosage of the composition can be formulated in various ways depending on factors such as the formulation method, administration method, the patient's age, weight, sex, medical condition, diet, administration time, route of administration, excretion rate, and response sensitivity.

[0028] When the composition of the present invention is used as a pharmaceutical composition, the pharmaceutical composition of the present invention can be manufactured using pharmaceutically appropriate and physiologically acceptable adjuvants in addition to the above-mentioned active ingredient, and such adjuvants may include excipients, disintegrants, sweeteners, binders, coatings, leavening agents, lubricants, smoothing agents, or flavoring agents.

[0029] The aforementioned pharmaceutical composition can preferably be formulated as a pharmaceutical composition by further including one or more pharmaceutically acceptable carriers in addition to the active ingredients described above for administration.

[0030] For example, to formulate the active ingredient into tablet or capsule form, it can be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. Also, if desired or required, suitable binders, lubricants, disintegrants, and colorants may be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum. Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include, but are suitable for sterilization and biological use, saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures of one or more of these components. Other common additives such as antioxidants, buffers, and bacteriostatic agents may be added as needed. Diluents, dispersants, surfactants, binders, and lubricants may be added as additional agents, and the compositions can be formulated into injectable dosage forms such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, or tablets.

[0031] Furthermore, as a preferred method in this field, formulations can be preferably formulated according to each disease or component using the methods disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, and Easton PA.

[0032] The present invention provides a composition containing the Leuconostoc citreum strain or its culture as an active ingredient, which can be used as a food composition for the prevention or improvement of cholestatic liver disease, or as a food additive composition.

[0033] The aforementioned food composition may be in the form of a health functional food.

[0034] The aforementioned "health functional foods" refer to foods manufactured and processed using raw materials and ingredients that have beneficial functional properties for the human body in accordance with the Act on Health Functional Foods (Article 3, Item 1), and "functionality" refers to effects that are useful for health purposes, such as regulating nutrients in relation to the structure and function of the human body or physiological effects (Article 3, Item 2).

[0035] The aforementioned food composition may further contain food additives. Unless otherwise specified, the suitability of a food additive shall be determined according to the standards and criteria for that item, in accordance with the general provisions and general test methods of the Food Additives Compendium approved by the Ministry of Food and Drug Safety.

[0036] Examples of items listed in the aforementioned "Official Compendium of Food Additives" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as oyster pigment, licorice extract, crystalline cellulose, and guar gum; and mixed preparations such as L-sodium glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar dye preparations.

[0037] Foods containing the active ingredient of the present invention include confectionery such as bread, mochi, nuts, candies, chocolates, chewing gum, and jams; ice cream products such as ice cream, frozen fruit, and ice cream powder; milk products such as milk, low-fat milk, lactose-free milk, processed milk products, goat's milk, fermented milk products, buttermilk, concentrated milk products, milk creams, butter, natural cheese, processed cheese, milk powder, and whey products; processed meat products, processed egg products, meat products such as hamburgers; processed fish products, ham, and sausages. Examples of prohibited items include, but are not limited to, fish products such as fish paste and bacon, noodles such as ramen, dried noodles, fresh noodles, fried noodles, gelatinized dried noodles, improved semi-fresh noodles, frozen noodles, and pasta, beverages such as fruit drinks, vegetable drinks, carbonated drinks, soy milk, yogurt and other lactic acid bacteria drinks, and mixed drinks, condiments such as soy sauce, miso, gochujang, chunjang, cheonggukjang, mixed soy sauce, vinegar, sauces, tomato ketchup, curry, dressings, margarine, shortening, and pizza.

[0038] In addition to those mentioned above, the compositions of the present invention may include various nutrients, vitamins, electrolytes, flavorings, colorings, pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. Furthermore, the compositions of the present invention may include fruit pulp for producing natural fruit juices, fruit juice beverages, and vegetable beverages. These components may be used independently or in combination.

[0039] The beverage composition containing the active ingredient of the present invention is not limited in terms of other components and can contain various flavorings or natural carbohydrates as additional components, as is the case with ordinary beverages. Examples of the aforementioned natural carbohydrates include ordinary sugars such as monosaccharides (e.g., glucose, fructose); disaccharides (e.g., maltose, sucrose); and polysaccharides (e.g., dextrin, cyclodextrin); and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavorings other than those mentioned above, natural flavorings (thaumatin, stevia extract (e.g., rebaudioside A), glycyrrhizin, etc.) and synthetic flavorings (saccharin, aspartame, etc.) can be advantageously used.

[0040] Furthermore, the composition containing the Leuconostoc citreum strain or its culture as an active ingredient of the present invention can be used as a feed composition or feed additive composition for the prevention and improvement of cholestatic liver disease in livestock.

[0041] When the composition is manufactured as a feed additive, it can be produced in the form of a highly concentrated liquid, powder, or granules with a concentration of 20-90%. The feed additive may further contain one or more of the following: organic acids such as citric acid, fumaric acid, adipic acid, lactic acid, and malic acid; phosphates such as sodium phosphate, potassium phosphate, acid pyrophosphate, and polyphosphates (polyphosphates); and natural antioxidants such as polyphenols, catechins, alpha-tocopherol, rosemary extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, and phytic acid. When manufactured as feed, the composition can be formulated in the form of a normal feed and may also contain normal feed components.

[0042] The feed and feed additives may further include grains, such as ground or milled wheat, oats, barley, corn, and rice; plant-based protein feeds, such as feeds mainly composed of rapeseed, soybeans, and sunflowers; animal-based protein feeds, such as blood meal, meat and bone meal, bone meal, and fish meal; sugar powders and dairy products, such as dried components consisting of various milk powders and whey powders, and may also further include nutritional supplements, digestive and absorption enhancers, growth promoters, and the like.

[0043] The feed additive may be administered to animals alone or in combination with other feed additives in an edible carrier. Furthermore, the feed additive can be easily administered to animals as a top dressing, by mixing it directly into animal feed, or as an oral formulation separate from the feed. When the feed additive is administered separately from the animal feed, as is well known in the art, it can be manufactured in combination with a pharmaceutically acceptable edible carrier in the form of an immediate-release or sustained-release formulation. These edible carriers may be solid or liquid, such as corn starch, lactose, sucrose, soybean flakes, peanut oil, olive oil, sesame oil, and propylene glycol. When a solid carrier is used, the feed additive may be in the form of tablets, capsules, powders, lozenges, sugar-containing tablets, or a top dressing in a finely dispersed form. When a liquid carrier is used, the feed additive may be in the form of gelatin capsules, syrups, suspensions, emulsions, or solutions.

[0044] Furthermore, the feed and feed additives may contain auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifiers, and solution accelerators. The feed additives can be used by immersion, spraying, or mixing and adding them to animal feed.

[0045] The feed or feed additive of the present invention can be applied to the diets of numerous animals, including mammals, poultry, and fish.

[0046] The aforementioned mammals can include not only pigs, cows, horses, sheep, rabbits, goats, rodents, and laboratory rodents such as mice, hamsters, and guinea pigs, but also pet animals (e.g., dogs, cats), and the aforementioned poultry can include chickens, turkeys, ducks, geese, pheasants, and quail, and the aforementioned fish can include carp, crucian carp, trout, etc., but are not limited to these. [Modes for carrying out the invention]

[0047] The present invention will be described in more detail below through the examples. These examples are solely for the purpose of illustrating the present invention in more detail, and it will be obvious to those with ordinary skill in the art that, based on the gist of the invention, the scope of the present invention is not limited by these examples.

[0048] Example 1. Culture of bacterial strain The Leuconostoc citreum WiKim0104 (deposit number KCCM12420P) strain was obtained with permission from the depositor, the Korea Food Research Institute, and used for experiments.

[0049] The Leuconostoc citreum WiKim0104 strain, obtained from the above distribution, was inoculated at 1% in 30 ml of MRS liquid medium and incubated at 30°C for 18 hours. After incubation, the cultures were centrifuged at 3000 rpm for 10 minutes, the culture solutions were stored separately, and the bacterial cells were washed three times in PBS (phosphate-buffered saline) solution to remove any remaining medium components.

[0050] Example 2. Confirmation of the effect of inhibiting bile accumulation in an animal model.

[0051] 2-1. Conditions for experimental mice The experimental animals used were 8-week-old male C57BL6 mice. They were housed in an SPF (Specific Pathogen Free) environment in an animal housing room maintained at a room temperature of 20±2°C and a humidity of 55±15%, followed by a one-week stabilization period for the duration of the experiment. They were fed a standard pellet diet without added antibiotics, and water was provided as needed. After a one-week period of adaptation to the diet, the experiment was conducted.

[0052] 2-2. Creation of animal models induced by bile duct ligation. Cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are largely caused by the accumulation of cytotoxic bile in hepatocytes. Bile duct ligation was performed to confirm the efficacy of Leuconostoc citreum strains against cholestatic diseases.

[0053] The bile ducts of the mice prepared in Example 2-1 above were sutured twice with non-absorbable surgical sutures. In the control group, the same surgery was performed without suturing the bile ducts. Postoperatively, the mice were divided into groups according to the Z-sequencing method based on body weight, jaundice, and changes in urine color on the day drug administration began. After grouping, the experimental groups were given 2 × 10⁶ doses of the Leuconostoc citreum WiKim0104 strain composition. 9 The mice were orally administered at a dose of 0.2 mL / head volume once daily for two weeks at a rate of CFU / day. The control group was fed the same amount of PBS. All animals were observed for general symptoms once daily, and checked twice daily for the presence of dying or deceased animals. Observation continued from postoperatively until the end of administration. After two weeks of administration, the mice were sacrificed.

[0054] 2-2. Pathological analysis of liver tissue The sacrificial mice prepared in section 2-2 above were dissected and their tissues were analyzed. The abdominal organs were visually inspected to check for any abnormalities in the internal organs, and liver and intestinal tissue were extracted. The extracted liver tissue was washed with saline solution, and after removing the water with filter paper, the shape of the liver was photographed and compared, as shown in Figure 1.

[0055] As shown in Figure 1, in the bile duct ligation-induced control group, the liver color changed to yellow compared to the surgical control group, and it was confirmed that administration of leuconostoc citreum changed the liver shape and color to be similar to that of normal mice in the surgical control group.

[0056] Furthermore, liver tissue was fixed in 10% neutral formalin for histopathological examination. The fixed tissue underwent general tissue processing steps such as dissection, dehydration, and paraffin embedding, and was prepared as paraffin blocks and then sectioned. The sectioned tissue was stained with hematoxylin and eosin (H&E) and histologically analyzed for hepatocyte necrosis, bile duct cell proliferation, and portal vein edema. The results are shown in Figures 2 and 3.

[0057] As shown in Figures 2 and 3, H&E staining revealed hepatocyte necrosis (arrows) in the BDL model control group, and bile duct cell proliferation was observed around the bile ducts. In the Leuconostoc citreum treatment group, a significant reduction in hepatocyte necrosis was visually confirmed, and histopathological scores showed a significant decrease in the hepatocyte necrosis score.

[0058] 2-4. Evaluation of hepatic fibrosis due to cholestasis Using hepatocytes obtained from the sacrificial mice prepared in section 2-2 above, we analyzed liver fibrosis. Liver fibrosis, along with hepatocyte necrosis, is known as one of the main pathological symptoms in cholestatic liver disease. To evaluate liver fibrosis due to cholestasis, we confirmed the results using sirus red staining and the fibrosis index, as shown in graphs in Figures 4 and 5, based on histopathological evaluation.

[0059] As shown in Figure 4, the sirus red% positive area, which was increased by BDL, was significantly reduced in the group treated with the Leuconostoc citreum strain. As shown in Figure 5, the fibrosis score, which was increased by BDL, was significantly reduced in the group treated with the Leuconostoc citreum strain compared to the control group.

[0060] 2-5. Analysis of cytokine expression levels related to liver fibrosis and inflammation RNA was isolated from liver tissue obtained from the sacrificial mice prepared in section 2-2 above, and changes in α-SMA (alpha-smooth muscle actin) and Col1a1 (collagen type 1a), gene markers related to fibrosis and inflammation, were confirmed by q-RT-PCR. 1 ml of Trizole was added to the liver tissue of each group of mice, and the tissue was pulverized with a homogenizer. RNA was then separated using chloroform and isopropanol, and cDNA was synthesized. The results of observing changes in fibrosis and inflammatory cytokines using the synthesized cDNA are shown in Figures 6 and 7.

[0061] As shown in Figure 6, a significant decrease in α-SMA and Col1a1 expression was observed in the group treated with the Leuconostoc citreum strain compared to the BDL control group.

[0062] As shown in Figure 7, a significant decrease in IL-6 and IL-1β expression was observed in the group treated with the Leuconostoc citreum strain compared to the BDL control group.

[0063] Based on these results, it has been confirmed that the composition according to the present invention, when applied to liver cells, exhibits excellent effects on damage, fibrosis, and inflammation caused by bile accumulation, and can therefore be used as a composition for the prevention and treatment of cholestatic liver disease.

[0064] [Accession Number] Depository name: Korea Microbial Conservation Center (overseas) Accession number: KCCM12420P Date of acceptance: 20181214 TIFF0007852936000001.tif248169TIFF0007852936000002.tif220168

Claims

1. A pharmaceutical composition for the prevention or treatment of cholestatic liver disease, comprising as an active ingredient the Leuconostoc citreum WIKim0104 (accession number KCCM12420P) strain or culture thereof having the nucleic acid sequence of Sequence ID No.

1.

2. The pharmaceutical composition for the prevention or treatment of cholestatic liver disease according to claim 1, wherein the cholestatic liver disease is primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).

3. The pharmaceutical composition for the prevention or treatment of cholestatic liver disease according to claim 1, characterized in that the composition can be administered by oral or parenteral administration.

4. The pharmaceutical composition for the prevention or treatment of cholestatic liver disease according to claim 3, wherein the method of parenteral administration is intravenous injection, subcutaneous injection, intramuscular injection, peritoneal injection, endothelial administration, local administration, intranasal administration, intrapulmonary administration, or intrarectal administration.

5. A food composition for the prevention or improvement of cholestatic liver disease, comprising as an active ingredient the Leuconostoc citreum WIKim0104 (accession number KCCM12420P) strain or culture thereof having the nucleic acid sequence of Sequence ID No.

1.

6. The food composition for preventing or improving cholestatic liver disease according to claim 5, wherein the food is a functional food for health.

7. The food composition for preventing or improving cholestatic liver disease according to claim 5, characterized in that the food is any food selected from the group consisting of bread, rice cakes, candy, chocolate, gum, ice cream, milk, cheese, processed meat products, processed fish products, kimchi, soy sauce, miso, gochujang, chunjang, cheonggukjang, vinegar, tomato ketchup, curry, dressing, beverages, and fermented milk.

8. A food additive composition for the prevention or improvement of cholestatic liver disease, comprising as an active ingredient the Leuconostoc citreum WIKim0104 (accession number KCCM12420P) strain or culture thereof having the nucleic acid sequence of Sequence ID No.

1.

9. A feed composition for the prevention or improvement of cholestatic liver disease in livestock, comprising as an active ingredient the Leuconostoc citreum WIKim0104 (accession number KCCM12420P) strain or culture thereof having the nucleic acid sequence of Sequence ID No.

1.

10. The livestock is selected from the group consisting of pigs, cattle, horses, sheep, rabbits, goats, mice, hamsters, guinea pigs, dogs, cats, chickens, turkeys, ducks, geese, pheasants, quail, carp, crucian carp, and trout, as described in claim 9, a feed composition for preventing or improving cholestatic liver disease in livestock.

11. A feed additive composition for the prevention or improvement of cholestatic liver disease in livestock, comprising as an active ingredient the Leuconostoc citreum WIKim0104 (accession number KCCM12420P) strain or culture thereof having the nucleic acid sequence of Sequence ID No. 1.

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