Composition for treating, preventing, or improving psoriasis, rheumatoid arthritis, type-i diabetes, or systemic lupus erythematosus

Abstract

To provide an agent for inhibiting the production of CCL20 and / or the migration of Th17 cells. The present invention also provides a composition for treating, preventing, or improving psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus.SOLUTION: An agent for inhibiting CCL20 production and / or migration of Th17 cells, the agent comprising a fermented plant extract, wherein the fermented plant extract comprises yeasts capable of surviving in pH2 and sporulating in a complete medium, and a composition for treating, preventing, or ameliorating systemic lupus erythematosis, the composition comprising a fermented plant extract, wherein the fermented plant extract comprises yeasts capable of surviving in pH2 and sporulating in a complete medium.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for suppressing CCL20 production and / or Th17 cell migration, and also to a composition for treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus. [Background technology]

[0002] For the past several decades, cytotoxic chemotherapy has dominated the systematic management of cancer according to the maximum tolerated dose (MTD). MTD therapy requires that the highest tolerated drug dose be administered to patients to achieve the greatest therapeutic effect. Due to low tumor selectivity, MTD therapy cannot be extended to reduce healthy tissue recovery and bone marrow suppression. Rapid tumor growth and metastasis during treatment hiatus can lead to rapid cancer cell proliferation accompanied by chemotherapy resistance and accelerated angiogenesis. Therefore, the management of advanced cancers is evolving from maximum tolerated to minimum effective doses by combining supplements and treatments. A prime example is the lack of a clear dose-response curve for anti-PD-1 antibodies, despite a very rough dose-response relationship between efficacy and safety. There are cases in which even very low doses have been shown to be safe and effective (Non-Patent Document 1).

[0003] Furthermore, Patent Document 1 reports that when a plant fermentation extract obtained by fermenting a plant extract using yeast that can survive in an environment of pH 1 and exhibits the ability to form spores in a complete medium was administered to an in vivo mouse model using breast cancer cells, the transplanted tumor tended to shrink, lung metastasis was highly inhibited, and splenomegaly was suppressed.

[0004] IL-17, a type of interleukin (IL), is known to induce the production of inflammatory cytokines. IL-17-producing Th17 (helper T cell type 17) cells have been identified, and while IL-17 and Th17 cells function as a defense mechanism against extracellular bacteria and fungi, they are also deeply associated with autoimmune diseases and non-infectious inflammatory diseases. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2020 / 004299 [Non-patent literature]

[0006] [Non-Patent Document 1] Topalian SL, et al. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012;366:2443-2454. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide an agent for suppressing CCL20 production and / or Th17 cell migration, and a composition for treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus. [Means for solving the problem]

[0008] As a result of extensive research to achieve the above-mentioned object, the present inventors have found that a plant fermentation extract obtained by fermenting a plant extract using a yeast that can survive in an environment of pH 2 and exhibits the ability to form spores in complete medium exhibits excellent inhibitory effects on CCL20 (CC motif chemokine ligand 20) production and Th17 cell migration.

[0009] The present invention was completed based on these findings and after further investigation, and provides the following inhibitors of CCL20 production and / or Th17 cell migration, and compositions for treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus.

[0010] Item 1. An inhibitor of CCL20 production and / or Th17 cell migration, comprising a fermented plant extract, The plant fermentation extract contains yeast that can survive in an environment of pH 2 and exhibits the ability to form spores in a complete medium. Item 2. The agent according to Item 1, wherein the fermented plant extract is obtained by fermenting a plant extract using the yeast. Item 3. The agent according to Item 1 or 2, wherein the raw materials for the fermented plant extract include vegetables, fruits, beans, seaweed, and mushrooms. Item 4. The agent according to any one of Items 1 to 3, wherein the yeast belongs to the genus Saccharomyces kudryabzevii. Item 5. The agent according to any one of Items 1 to 4, which is a food, drink, or pharmaceutical product. Item 6. A composition for treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus, comprising a fermented plant extract, The plant fermentation extract is a composition comprising a yeast that is viable in an environment of pH 2 and exhibits the ability to form spores in a complete medium. Item 7. The composition according to Item 6, wherein the fermented plant extract is obtained by fermenting a plant extract using the yeast. Item 8. The composition according to Item 6 or 7, wherein the raw materials for the fermented plant extract include vegetables, fruits, beans, seaweed, and mushrooms. Item 9. The composition according to any one of Items 6 to 8, wherein the yeast is a yeast belonging to Saccharomyces kudriabzevii. Item 10. The composition according to any one of Items 6 to 9, which is a food, drink, or pharmaceutical product. [Effects of the Invention]

[0011] The fermented plant extract of the present invention has excellent inhibitory effects on CCL20 production and Th17 cell migration, and is therefore useful as an active ingredient of an inhibitor of CCL20 production and / or Th17 cell migration.The fermented plant extract of the present invention is also useful as an active ingredient of a composition for treating, preventing, or ameliorating diseases associated with CCL20 and Th17 cells, such as psoriasis, rheumatoid arthritis, type I diabetes, and systemic lupus erythematosus.

[0012] Furthermore, the fermented plant extract of the present invention is produced by fermenting a plant extract, and is therefore a natural product, highly safe, and can be used as a supplement (food). [Brief explanation of the drawings]

[0013] [Figure 1] 1 is a graph showing the effect of suppressing IL-1b-induced CCL20 expression in human gastrointestinal epithelial cells. n=4 [Figure 2] Photographs showing the results of fluorescent immunohistochemistry on the effect of suppressing IL-17 expression in a cross-section of the inside of a primary cancer tumor. Left: Water administration group, Right: ITO Probio administration group [Figure 3] This figure shows the results of flow cytometry on the suppressive effect of CD45+CCR4+CCR6+CCR10+Th17 on colonic cells. Left: Water administration group, Right: ITO Probio administration group. DETAILED DESCRIPTION OF THE INVENTION

[0014] Hereinafter, an embodiment of the present invention will be described.

[0015] The inhibitor of CCL20 production and / or Th17 cell migration, and the composition for treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus of the present invention (sometimes referred to herein as the "inhibitor, etc. of the present invention") are characterized by comprising a plant fermented extract (sometimes referred to herein as the "plant fermented extract of the present invention"), which is characterized by comprising a yeast that is viable in an environment of pH 2 and exhibits the ability to form spores in a complete medium. The plant fermented extract is preferably produced by fermenting a plant extract using a yeast that is viable in an environment of pH 2 and exhibits the ability to form spores in a complete medium.

[0016] In the present invention, "being able to survive in an environment of pH 2" means that the yeast can survive for preferably 3 hours or more, more preferably 4 hours or more, and even more preferably 5 hours or more in an environment of pH 2. Such high acid resistance allows the yeast, when ingested orally, to reach the intestines alive without dying in the stomach.

[0017] In the present invention, "exhibiting sporulation ability in a complete medium" means that when the yeast is cultured in a complete medium such as YPD medium, the sporulation rate is preferably 10% or more, more preferably 50% or more, and even more preferably 70% or more. Thus, sporulation in a complete medium also means that spores are formed in the product, resulting in high product stability.

[0018] Plants that can be used as raw materials for the fermented plant extract of the present invention are not particularly limited, and include, for example, vegetables, fruits, beans, seaweed, and mushrooms. Specific examples include green shiso, red shiso, melon, perilla, young barley leaves, turnip, pumpkin, cauliflower, cabbage, cucumber, kale, bitter melon, burdock, celery, komatsuna, zucchini, chrysanthemum, ginger, radish, onion, bok choy, tomato, eggplant, chive, carrot, garlic, leek, parsley, bell pepper, butterbur, Examples of vegetables include broccoli, spinach, mizuna, Brussels sprouts, mulukhiyah, and mugwort; fruits such as akebia, strawberries, figs, persimmons, kumquats, mulberries, sudachi, summer mandarins, hassaku, blueberries, mandarins, yuzu, lemons, and blackberries; beans such as soybeans; grains such as brown rice; (organic) sugars; seaweeds such as kelp and fucus; and mushrooms such as agaric, chaga, shiitake, and maitake. It is preferable to use all of the above (59 types) as raw vegetables. These 59 types of vegetables include a variety of cruciferous vegetables. It is particularly desirable to use raw vegetables that are grown without chemical fertilizers or pesticides, harvested in season, and grown outdoors. Examples of products grown without chemical fertilizers or pesticides include agricultural products that meet the organic JAS standards.

[0019] The method for extracting vegetable extract from raw vegetables is not particularly limited, and various known methods can be used. Among these, it is preferable to extract vegetable extract by osmotic extraction, particularly osmotic extraction using (organic) brown sugar. In this extraction process, lactic acid fermentation occurs due to lactic acid bacteria attached to the vegetables, causing a decrease in pH. As a result, the growth of unwanted bacteria can be suppressed.

[0020] After obtaining a vegetable extract from raw vegetables, the vegetable extract is subjected to fermentation with yeast. The yeast used for fermentation is preferably one that can survive at pH 2 and exhibits the ability to form spores in complete medium. Among such yeasts, yeasts belonging to the genus Saccharomyces are preferred, with Saccharomyces kudriavzevii being particularly preferred. By using such yeast for fermentation, the final product contains the yeast. When the product is ingested, the yeast reaches the intestine alive without dying in the stomach. Furthermore, the yeast forms spores in the product, resulting in high product stability. Because the yeast has strong acid tolerance, it can survive and undergo fermentation even in the low pH of the vegetable extract, as described above. Furthermore, it is desirable for the yeast used for fermentation to be one that is commonly consumed.

[0021] Fermentation can be carried out by conventional methods, and examples of fermentation procedures include controlling conditions such as temperature, pH, and humidity so that fermentation is carried out within suitable ranges, stirring appropriately, etc. The fermentation period is not particularly limited, and is preferably 3 months or longer, more preferably 6 months or longer, even more preferably 9 months or longer, still more preferably 1 year or longer, particularly preferably 2 years or longer, and most preferably 3 years or longer.

[0022] The fermented plant extract of the present invention may be, for example, a commercially available product sold by Respect Co., Ltd. Commercially available products using the fermented plant extract of the present invention include, for example, "Hieizan Enzyme" and "Bitternal Paste."

[0023] The proportion of the fermented plant extract of the present invention contained in the inhibitor of the present invention is not particularly limited, and may be, for example, 0.01 to 99% by mass. The upper or lower limit of this range may be, for example, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% by mass.

[0024] The inhibitor etc. of the present invention can be appropriately blended with known components other than the fermented plant extract of the present invention, as long as the effects of the present invention are not impaired.

[0025] The inhibitors etc. of the present invention can be used as foods and beverages (particularly foods and beverages intended for health, maintenance, or promotion of health (e.g., health foods, functional foods, nutritional supplements, dietary supplements, foods for specified health uses, foods with nutrient functions, or foods with functional claims)), pharmaceuticals (including quasi-drugs), etc. Furthermore, the inhibitors etc. of the present invention also encompass the meaning of additives that impart an inhibitory effect on CCL20 production and / or Th17 cell migration, and an effect of treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus.

[0026] The fermented plant extract of the present invention can be used as is in the above-mentioned foods and beverages, but if necessary, vitamins, flavonoids, minerals, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, colorants, flavorings, stabilizers, preservatives, disintegrants, lubricants, sustained-release regulators, surfactants, solubilizers, humectants, etc. can also be added.

[0027] Food and beverage products include any food and beverage product that can be consumed by animals (including humans). The types of food and beverage products are not particularly limited, and examples include dairy products; fermented foods (yogurt, cheese, etc.); beverages (soft drinks such as coffee, juice, and tea drinks, dairy drinks, lactic acid bacteria drinks, lactic acid bacteria-containing drinks, yogurt drinks, carbonated drinks, sake, Western liquor, and alcoholic beverages such as fruit wine); spreads (custard cream, etc.); pastes (fruit paste, etc.); Western confectionery products (chocolate, donuts, pies, cream puffs, gum, candy, jelly, cookies, cakes, puddings, etc.); Japanese confectionery products (daifuku, mochi, manju, castella, anmitsu, yokan, etc.); frozen desserts (ice cream, popsicles, sorbet, etc.); foods (curry, beef bowls, rice porridge, miso soup, soup, meat sauce, pasta, pickles, jam, etc.); and seasonings (dressings, furikake, umami seasonings, soup bases, etc.).

[0028] The method for producing the food or drink is not particularly limited, and any known method can be used as appropriate.

[0029] When using foods and drinks as supplements, the dosage unit form is not particularly limited and can be selected appropriately, and examples include tablets, capsules, granules, liquids, powders, etc.

[0030] The intake amount of food and drink can be appropriately determined depending on various conditions such as the weight, age, sex, and symptoms of the person consuming the food and drink.

[0031] When prepared as a pharmaceutical, the fermented plant extract of the present invention can be used as is, or can be prepared together with non-toxic carriers, diluents or excipients acceptable for pharmaceuticals into the form of tablets (including plain tablets, sugar-coated tablets, film-coated tablets, effervescent tablets, chewable tablets, troches, etc.), capsules, pills, powders (dispersed medicines), fine granules, granules, liquids, suspensions, emulsions, syrups, pastes, etc. to form pharmaceutical preparations.

[0032] The dosage of the pharmaceutical can be determined appropriately depending on various conditions such as the patient's weight, age, sex, and symptoms.

[0033] The inhibitors and the like of the present invention described above are applicable to mammals including humans.

[0034] As will be shown in the Examples below, the present inventors have found that the fermented plant extract of the present invention exhibits excellent inhibitory effects on CCL20 production and Th17 cell migration.

[0035] Therefore, the fermented plant extract of the present invention has excellent inhibitory effects on CCL20 production and Th17 cell migration, and can therefore be suitably used as an active ingredient in an inhibitor of CCL20 production and / or Th17 cell migration. CCL20 is a chemokine that recruits Th17, an inflammatory helper T cell, and therefore, inhibiting CCL20 production can inhibit Th17 cell migration. As a result, the fermented plant extract of the present invention can inhibit Th17 cell migration by inhibiting CCL20 production, and is therefore useful as an active ingredient in compositions for treating, preventing, or ameliorating various autoimmune diseases associated with CCL20 and Th17 cells, such as psoriasis, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus.

[0036] As used herein, "diseases associated with CCL20 and Th17 cells" refer to diseases in which the amounts of CCL20, Th17, and cytokines induced by Th17 differ from those in healthy states. As used herein, diseases associated with CCL20 and Th17 cells include autoimmune diseases. Examples of autoimmune diseases include psoriasis, rheumatoid arthritis, type I diabetes, and systemic lupus erythematosus.

[0037] Furthermore, the fermented plant extract of the present invention is produced by fermenting a plant extract, and is therefore a natural product and highly safe.

[0038] It should be noted that in this specification, the term "comprising" includes "consisting essentially of" and "consisting of."

[0039] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present invention may be combined in any way to specify the subject matter encompassed by the present invention. In other words, the present invention encompasses all subject matter consisting of any combination of the combinable characteristics described herein. [Example]

[0040] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0041] The EXT (ITO Probio Extract, Respect Corporation) used in the following experiments corresponds to the fermented plant extract of the present invention. ITO Probio Extract was produced by using 59 types of pesticide-free and organic vegetables (listed above). Each raw material was macerated in organic brown sugar in separate barrels to extract the extract, and then each extract was squeezed without adding water. The resulting extracts were combined in barrels, periodically stirred, and aged for approximately four years. The resulting paste was then manually strained. The ITO Probio Extract was fermented using ITO Probio Yeast (registered trademark). It has been confirmed that ITO Probio Yeast exhibits spore-forming ability in complete medium and high acid tolerance at pH 2.

[0042] <Experimental Method> Cell culture and establishment of reporter cells Plat-E cells and CT26 cells were cultured in 10% FCS-RPMI1640 containing antibiotics. Then, firefly luciferase (Luc) / pMXs-Puro and green fluorescent protein (GFP) / pMXs-neo were transfected into Plat-E cells independently. The two supernatants from the packaging cells were exposed to CT26 cells with polybrene and selected for 2 weeks with 200 μg / mL neomycin and 8 μg / mL puromycin. The resulting clones were suspended in Matrigel (Corning) and transferred to the cecal membrane for 10 min under anesthesia. 6Cells / 50 μL were transplanted using a Hamilton syringe equipped with a disposable minimally invasive microinjection needle (UNIVER; Unisys Corporation) (31G x 4.00 mm). Mice were sutured with dissolvable sutures (ELmett; Akiyama Seisakusho Co., Ltd.). Approximately 3 weeks later, the laparotomy was performed, and clones that frequently metastasized to the liver were isolated and cultured again. This procedure was repeated three times, and clones with a confirmed phenotype were used for subsequent studies.

[0043] Mice and experimental methods Seven-week-old female Balb / c mice were obtained from a commercial supplier (Japan SLC Co., Ltd.) and housed in a semi-barrier animal care room (12:12 light / dark cycle, free access to food) for one week. The mice were divided into three groups: control, transplanted (INT), and INT + 2% EXT (INT + EXT). Briefly, tumor cell transplantation was performed on anesthetized mice by disinfecting them with povidone-iodine and ethanol. 1 × 10 6 Tumor cells were injected into the cecal membrane and transplanted into the exposed cecum through a 5 mm skin incision. After cell transplantation, penicillin was administered intraperitoneally for 3 days to prevent infection. Mice were euthanized on days 19–21, and samples were collected. Primary tumors were observed using a Leica MZ10F / DFC7000T stereo microscope (Leica Microsystems), and images were acquired using the LAS ver. 4.12 application (Leica Microsystems). All animal experiments were approved by the Ritsumeikan University Animal Care and Use Committee (BKC2021-025).

[0044] Histology and Fluorescence Immunohistochemistry (F-IHC) Analysis After tissue isolation, samples were fixed in 10% neutral-buffered formalin and embedded in paraffin blocks. Fluorescence-immunohistochemistry (F-IHC) analysis was performed as previously described [Cells 2021, 10, 3513]. Briefly, samples were incubated with anti-IL-17 (66241) (Biolegend). Slides were mounted in Fluor-KEEPER anti-fade reagent containing 4',6-diamidino-2-phenylindole (DAPI; Nacalai Tesque). Observations were performed using a BX51 / DP74 fluorescence microscope (Olympus Corporation) and CellSens software (Olympus Corporation).

[0045] In vitro cell experimentation methods WiDr cells (JCRB0224) purchased from the National Institute of Biomedical Innovation (NIBIO) were cultured in 10% FCS-DMEM containing antibiotics. The cells were plated at 1 × 10 5 Cells were seeded at a concentration of 1%. The cells were divided into a control group (CRL), an IL-1β group, an ITO Probio Extract (EXT), and an IL-1β + EXT group. The cells were first pretreated with EXT at a concentration of 1%, and then 50 ng / mL of IL-1β (Peprotech) was added. 24 hours later, the cells were harvested and total RNA was prepared. Reverse transcription was then performed using specific primers and measured using QuantStadio 3 (Thermo Fisher Scientific).

[0046] RNA isolation and quantitative real-time polymerase chain reaction (QPCR) Total RNA was isolated using Sepasol® (Nacalai Tesque, Inc.), and complementary DNA was synthesized using ReverTra Ace (Toyobo Co., Ltd.). Quantitative real-time PCR analysis based on intercalation of SYBR Green (Thermo Fisher Scientific) was performed as previously described [Int J Mol Sci 2020, 21, 2180]. The following primer sequences were used: CCL20-F 5'-CTGGCTGCTTTGATGTCAGT-3', CCL20-R 5'-CGTGTGAAGCCCACAATAAA-3' (NM_001130046, 125 bp), GAPDH-F 5'-TGGCAAATTCCATGGCA-3', GAPDH-R 5'-CCTTCTCCATGGTGGT-3' (NM_001256799, 178 bp). The housekeeping gene GAPDH served as an internal control and was used to normalize for differences in input RNA.

[0047] Flow cytometry The isolated tissues were digested with serum-free RPIM1640 containing 0.025% collagenase and 1 μg / mL DNase I (Roche) using a gentleMACS quarto separator (Miltenyi Biotech). Cells from each tissue were analyzed using a MACS Quant analyzer 10 (Miltenyi Biotech). Cells were washed using AUTOMACS Running buffer. Approximately 1 × 10 6 1 x 10 cells stained 5 Each cell was analyzed. All analyzed events were cut off at 10,000 events.

[0048] <Result> Conventional subcutaneous tumor models involve inoculation of cancer cells ectopically or into immunocompromised mice, making them unsuitable for colorectal cancer research. Orthotopic models of colorectal cancer, on the other hand, allow cancer cells to grow in situ, allowing for highly accurate reproduction of human disease. Therefore, these models are valuable for estimating events that occur in humans.

[0049] On the 21st day after cell transplantation, the ITO Probio Extract group showed a significant suppression of cancer ascites compared to the water-administered group. This suggests that the ITO Probio Extract inhibits the progression of cancer at an early stage.

[0050] The results regarding cancer metastasis are shown in Table 1 below. The degree of metastasis increases in the order of -<+<++. The results show that in the water-administered group, metastasis was observed in the liver, peritoneum, diaphragm, mesentery, and lymph nodes, while in the ITO Probio extract-administered group, metastasis was observed only in the mesentery. Furthermore, GFP signals were observed in the primary cancer lesions, indicating that GFP-positive cells had been successfully transplanted and established.

[0051] [Table 1]

[0052] Figure 1 shows the effect of suppressing IL-1b-induced CCL20 expression in human gastrointestinal epithelial cells in vitro. IL-1b induces CCL20 expression, but administration of ITO Probio suppresses CCL20 expression by almost 100%.

[0053] Figure 2 shows the results of fluorescent immunohistochemistry, which shows the effect of suppressing IL-17 expression in a cross-section of the primary cancer tumor. In the water-administered group, IL-17 was localized and Th17 cells accumulated, but in the ITO Probio extract-administered group, IL-17 was barely localized.

[0054] Figure 3 shows the CD45 expression in colon cells. + CCR4 + CCR6 + CCR10 + The results of flow cytometry show the effect of suppressing Th17. It can be seen that Th17 was reduced in the ITO Probio extract group compared to the water group.

[0055] The above experimental results suggest that CCL20 is a chemokine that recruits Th17, an inflammatory helper T cell, and that ITO Probio Extract suppresses the expression of CCL20, thereby suppressing the recruitment of Th17.

Claims

1. An inhibitor of CCL20 production and / or Th17 cell migration, comprising a fermented plant extract, The plant fermentation extract contains yeast that can survive in an environment of pH 2 and exhibits the ability to form spores in a complete medium.

2. The agent according to claim 1 , wherein the fermented plant extract is obtained by fermenting a plant extract using the yeast.

3. The agent according to claim 1 or 2, wherein the raw materials for the plant fermented extract include vegetables, fruits, beans, seaweed, and mushrooms.

4. The agent according to claim 1 or 2, wherein the yeast is a yeast belonging to Saccharomyces kudriabzevii.

5. The agent according to claim 1 or 2, which is a food, drink or pharmaceutical product.

6. A composition for treating, preventing, or ameliorating psoriasis, rheumatoid arthritis, type I diabetes, or systemic lupus erythematosus, comprising a fermented plant extract, The plant fermentation extract comprises a yeast that is viable in an environment of pH 2 and exhibits the ability to form spores in a complete medium.

7. The composition according to claim 6 , wherein the fermented plant extract is obtained by fermenting a plant extract using the yeast.

8. The composition according to claim 6 or 7, wherein the raw materials for the plant fermented extract include vegetables, fruits, beans, seaweed, and mushrooms.

9. The composition according to claim 6 or 7, wherein the yeast is a yeast belonging to Saccharomyces kudriabzevii.

10. The composition according to claim 6 or 7, which is a food, drink or pharmaceutical product.

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