WO2023058801A1 - Composition pour soulager, prévenir ou traiter un trouble intestinal, comprenant une souche de lactobacillus acidophilus kbl402 ou kbl409 - Google Patents

Composition pour soulager, prévenir ou traiter un trouble intestinal, comprenant une souche de lactobacillus acidophilus kbl402 ou kbl409 Download PDF

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WO2023058801A1
WO2023058801A1 PCT/KR2021/013946 KR2021013946W WO2023058801A1 WO 2023058801 A1 WO2023058801 A1 WO 2023058801A1 KR 2021013946 W KR2021013946 W KR 2021013946W WO 2023058801 A1 WO2023058801 A1 WO 2023058801A1
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strain
lactobacillus acidophilus
composition
accession number
kbl409
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PCT/KR2021/013946
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English (en)
Korean (ko)
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강윤경
남태욱
박성준
장성재
김운기
장유진
고광표
Original Assignee
서울대학교산학협력단
주식회사 고바이오랩
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Priority to PCT/KR2021/013946 priority Critical patent/WO2023058801A1/fr
Publication of WO2023058801A1 publication Critical patent/WO2023058801A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C12R2001/23—Lactobacillus acidophilus

Definitions

  • the present invention relates to a composition for improving, preventing or treating intestinal diseases comprising Lactobacillus acidophilus strain KBL402 or KBL409 strain, and more particularly, a novel probiotic Lactobacillus acidophilus strain KBL402 strain or KBL409 strain. It relates to a pharmaceutical composition for preventing or treating intestinal disorders, a composition for food, or a composition for animal feed, including at least one selected from the group consisting of strains, cultures thereof, lysates and extracts.
  • IBD Inflammatory bowel disease
  • inflammatory bowel disease is an incurable disease that recurs repeatedly and is difficult to treat, and a clear cause has not been identified, and a drug capable of fundamentally treating inflammatory bowel disease (IBD) has not yet been developed.
  • IBD inflammatory bowel disease
  • Immunosuppressants such as sulfasalazine, corticosteroids, and azatriopin or biological agents represented by anti-TNF- ⁇ antibodies can be used as a treatment for suppressing abnormal immune and inflammatory responses to inflammatory bowel disease.
  • many side effects related to these drugs may occur during long-term treatment, and the recurrence rate is also very high.
  • sulfasalazine can aggravate colitis, causing diarrhea, abdominal cramps, and abdominal discomfort.
  • Antibiotics are also one of the commonly used treatments for inflammatory bowel disease, but they have the side effect of killing not only pathogens but also intestinal beneficial bacteria that are very important to human health.
  • damage to intestinal microorganisms caused by antibiotics is not easily recovered even after several years, and side effects leading to chronic diseases such as hypertension, diabetes, and atopy may occur.
  • these drugs are difficult to take for a long time because they act as a mechanism to suppress the immune system, and when administered for a long time, nausea, vomiting, indigestion, anorexia, headache, as well as leukopenia due to hypersensitivity reactions, skin rash, fever, pancreatitis, Side effects such as hepatitis, hemolytic anemia, and bone marrow suppression may result.
  • Probiotics refer to microorganisms and products produced by gastric microorganisms that have antibacterial and enzymatic activities that help the balance of intestinal microorganisms.
  • probiotics are defined as live bacteria in the form of single or complex strains that are supplied to humans or animals in the form of dry cells or fermentation products to improve the intestinal flora.
  • the characteristics that probiotics should have are that the human intestine is their habitat, they are non-pathogenic and non-toxic, and they must survive while going to the intestine. Furthermore, they must retain viability and activity prior to consumption in delivered food, be sensitive to antibiotics used for prophylaxis, and not possess antibiotic-resistant plasmids. In addition, it must be resistant to acids, enzymes, and bile in the intestinal environment. Recently, as various health function improvement effects have been reported, probiotics have been spotlighted as major therapeutic substances that can replace existing compound-based treatments.
  • the present inventors have devoted themselves to research on probiotics for the treatment of intestinal diseases, including inflammatory bowel diseases, for which there is no conventional satisfactory treatment, and as a result, Lactobacillus Acidophilus strains are beneficial in reducing intestinal inflammation and in the intestine.
  • the present invention was completed by confirming that it exhibits an excellent effect in increasing the diversity of microorganisms and is useful for improving, preventing or treating intestinal diseases.
  • An object of the present invention is to provide a composition containing a Lactobacillus acidophilus strain showing excellent effects in improving, preventing or treating intestinal diseases.
  • One object of the present invention is the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, a culture of the strain, a lysate of the strain, and an extract of the strain.
  • a pharmaceutical composition for preventing or treating intestinal diseases comprising at least one member selected from the group consisting of.
  • Another object of the present invention is the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, the culture of the strain, the lysate of the strain, and the strain A food composition for improving or preventing intestinal diseases comprising at least one selected from the group consisting of extracts; Or to provide a food composition for improving intestinal health.
  • Another object of the present invention is the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, the culture of the strain, the lysate of the strain, and the strain To provide a composition for animal feed containing at least one selected from the group consisting of extracts.
  • Lactobacillus acidophilus KBL402 (Accession No. KCTC 14640BP) and KBL409 (Accession No. KCTC 13518BP) strains according to the present invention can reduce intestinal inflammation and improve the diversity of the beneficial microbial layer in the intestine. Therefore, it can be usefully used for improvement, prevention or treatment of intestinal diseases.
  • 1 is a graph showing Rarefaction plots of an experimental group and a control group.
  • PCA principal component analysis
  • Figure 3 is a graph showing the taxonomic composition of caecal microorganisms in the experimental group and the control group.
  • 5 is a heat map of the Spearman correlation between the relative abundance of genus-level taxa and specific metabolites in experimental and control groups.
  • the present invention relates to the Lactobacillus Acidophilus KBL402 strain with Accession No. KCTC 14640BP or the Lactobacillus Acidophilus KBL409 strain with Accession No. KCTC 13518BP, the culture of the strain, the lysate of the strain, and the extract of the strain. It provides a composition for improving, preventing or treating intestinal diseases comprising at least one selected from the group consisting of.
  • the composition according to the present invention may include a pharmaceutical composition for preventing or treating intestinal disease, a food composition for improving or preventing intestinal disease, or a composition for animal feed.
  • composition of the present invention may further include strains other than the Lactobacillus acidophilus KBL402 strain or the Lactobacillus acidophilus KBL409 strain, and the Lactobacillus acidophilus KBL402 strain and the Lactobacillus acidophilus KBL409 strain Of course, all of them can be included.
  • strains may be included in the form of live cell cells, dead cell cells and dried strains, cultures thereof, lysates thereof, or extracts thereof.
  • the term "culture” refers to a product obtained by culturing a strain in a known medium, and the product may include the strain itself.
  • the medium may be selected from known liquid medium or solid medium, and may be, for example, MRS liquid medium, GAM liquid medium, MRS agar medium, GAM agar medium, and BL agar medium, but is not limited thereto.
  • the term “lysate” refers to any product obtained by disrupting a strain by enzyme treatment, homogenization, or ultrasonic treatment.
  • extract refers to a product obtained by extracting a strain with a known extraction solvent.
  • extract includes a water extract and/or an organic solvent extract of Lactobacillus acidophilus KBL402 strain and/or KBL409 strain.
  • the organic solvent extract of the KBL402 strain and/or the KBL409 strain may be an organic solvent extract having 1 or more and 10 or less carbon atoms.
  • a substituted or unsubstituted alcohol extract having 1 to 10 carbon atoms, 1 to 5 carbon atoms, or 1 to 3 carbon atoms may be used as the extraction solvent.
  • alcohol extracts such as, for example, methanol extracts, ethanol extracts, iso-propanol extracts, n-propanol extracts, n-butanol extracts, iso-butanol extracts, tert-butanol extracts and/or phenol extracts; ether extracts such as dialkyl ethers such as dimethyl ether, diethyl ether, and methyl ethyl ether; n-hexane, ethyl acetate, dichloromethane, chloroform and/or acetone extracts.
  • ether extracts such as dialkyl ethers such as dimethyl ether, diethyl ether, and methyl ethyl ether
  • n-hexane ethyl acetate, dichloromethane, chloroform and/or acetone extracts.
  • live cell refers to the strain itself of the present invention
  • dead cell refers to a strain sterilized by heating, pressurization, or drug treatment.
  • composition of the present invention may be provided as a composition capable of being further combined with pharmaceutically acceptable additives such as carriers or media.
  • the additives used in the present invention are solvents, dispersants, coatings, absorption accelerators, controlled release agents (i.e. sustained release agents), and one or more inactive excipients (starch, polyols, granules, microfine cellulose, microcrystalline cellulose). (including, for example, cellphere, cellphere beads, diluents, lubricants, binders, disintegrants, etc.), etc.
  • tablet formulations of the disclosed compositions may be standard aqueous or Non-limiting examples of excipients for use as pharmaceutically acceptable carriers and pharmaceutically acceptable inert carriers and the additional ingredients include binders, fillers, disintegrants, lubricants. , antimicrobial agents and coating agents.
  • the content of the additives included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the range of content used in conventional formulations.
  • the term “improvement” is used to mean that the disease is not cured, but the severity of symptoms is reduced and certain functions are improved.
  • prevention is used to include delaying the onset of a disease, disorder or condition.
  • a treatment or treatment regimen for a disease in a subject in need thereof may include one or more of the following:
  • a subject in need of treatment may be an animal.
  • it is typically mammals that may benefit from using the compositions of the present invention.
  • Preferred examples of such subjects include primates such as humans.
  • such subjects include all subjects who have intestinal disease symptoms or are at risk of having similar symptoms.
  • composition of the present invention according to the conventional method according to each purpose of use, oral formulations such as solutions, suspensions, powders, granules, tablets, capsules, pills, extracts, emulsions, syrups, aerosols, injections of sterile injection solutions It can be formulated and used in various forms such as oral administration or parenteral administration through various routes including intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, spinal, intrathecal, or rectal topical administration or injection.
  • the dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, administration period or interval, excretion rate, constitutional specificity, nature of the preparation, severity of the disease, etc. there is.
  • liquid formulation refers to a medicine to be taken in the form of a liquid medicine dissolved in water or an organic solvent. Compared to suspensions or solid formulations, liquid formulations have the advantage of more effective drug absorption from the intestinal tract to the systemic circulation, and the liquid formulations may contain additional solutes in addition to pharmaceuticals, and additives providing color, odor, sweetness, or stability. may also be included.
  • the term “suspending agent” refers to any agent capable of providing the desired solubility and/or dispersibility of an alginate-containing composition, i.e., an aqueous formulation that is substantially clear and free of sedimentation and lumps.
  • powder refers to finely divided drugs, chemicals, or a dry mixture of both. “Powder” may include a mixture in a lyophilized state.
  • powders may contain conventional additives used in lyophilized formulations such as lyophilized strains and lyophilized preservatives.
  • the term "granule” refers to a drug or a mixture of drugs in the form of granules, which usually passes through a sieve of 4.76 to 20 mm.
  • Granules are generally produced by wetting the powder or mixture of powders and passing the mass through a sieve or granulator of appropriate mesh size depending on the size of the granules required. Since granules, like powders, are granular, the degree of contact of the drug to the tongue is high, so when a drug having a bitter taste is used in the form of granules, it may cause discomfort to patients, especially children or the elderly.
  • tablette means a powdered medicine made easy to take by compressing it into a small disc shape. Tablets may include uncoated tablets, film-coated tablets, coated tablets, multilayer tablets, press-coated tablets, inner core tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets.
  • capsule refers to a product made by filling a drug into a capsule in the form of a liquid, suspension, water, powder, granule, mini-tablet, or pellet, or encapsulated with a capsule base.
  • a pharmaceutical composition according to one embodiment may include a lyophilized strain.
  • the pharmaceutical composition of one embodiment may be formulated in the form of a capsule formulation of the lyophilized strain.
  • the storage period of the strain can be improved by minimizing the loss of the KBL693 strain that may occur due to heat.
  • the biological activity of the strain can be inactivated to improve formulation stability, and the strain can be more easily induced to rehydrate than other formulation methods, so that the original activity and growth ability can be quickly restored after supplying water to the dry strain.
  • the freeze-dried preparation is easy to formulate, such as tableting and encapsulation, and can be prepared in various dosage forms.
  • regeneration which is the most important feature of LBP (Live Biotherapeutic Products) such as strain preparations, can proceed very stably.
  • the strain when the strain is formulated by cryopreservation, skim milk, sugars (eg, trehalose, sucrose, maltose or glucose, etc.), sugar alcohols (eg, to prevent a rapid decrease in activity during freeze-drying of the strain)
  • sugars eg, trehalose, sucrose, maltose or glucose, etc.
  • sugar alcohols eg, to prevent a rapid decrease in activity during freeze-drying of the strain
  • mannitol, inositol or sorbitol, etc. may be mixed with conventional preservatives used in the art and then freeze-dried.
  • any lyophilization method commonly used in the art can be used without particular limitation.
  • pill is meant to encompass small, round solid dosage forms containing multiparticulates mixed with binders and other excipients.
  • the term "syrup" means a thick homemade sugar or sugar substitute.
  • the syrup is an easy-to-take medicine with an unpleasant taste, such as a bitter taste, in a liquid form, and is particularly suitable for use by children.
  • the syrup may include, in addition to purified water and extract, sugar or a substitute for sugar used to give sweetness and viscosity, an antibacterial preservative, a flavoring agent, or a coloring agent, but is not limited thereto.
  • sweeteners examples include, but are not limited to, white sugar, mannitol, sorbitol, xylitol, aspartame, stevioside, fructose, lactose, sucralose, saccharin, or menthol.
  • injection refers to an aseptic preparation applied to the body through the skin or mucous membrane, and in particular, any form of administration such as subcutaneous injection, intramuscular injection, intradermal injection, and intraperitoneal injection may be used as an injection route. It is possible, and the dosage form is selected according to the characteristics of each pharmacologically active substance.
  • the composition of the present invention may be a composition for oral administration.
  • oral administration means that the active substance is administered to the gastrointestinal tract through the oral route for absorption.
  • Non-limiting examples of the formulation for oral administration include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like.
  • a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate and the like; disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol may be used, and sweeteners, aromatics, syrups, and the like may also be used.
  • a liquid carrier such as fatty oil may be additionally used in addition to the above-mentioned materials.
  • the pharmaceutical composition of the present invention may be provided as an enteric-coated, enteric-coated preparation, particularly as a unit dosage form for oral use.
  • Enteric coating in the present specification includes all types of pharmaceutically acceptable known coatings that are not decomposed by gastric acid and the coating is maintained, but sufficiently decomposed in the small intestine so that the active ingredient can be released into the small intestine. do.
  • the "enteric coating” of the present invention is maintained for at least 2 hours when artificial gastric juice such as an HCl solution of pH 1 is brought into contact at 36°C to 38°C, preferably after that, a KH 2 PO 4 buffer solution of pH 6.8. Refers to coatings that disintegrate within 30 minutes in artificial intestinal juices such as
  • the enteric coating of the present invention is coated in an amount of about 16 to 30, preferably 16 to 20 or 25 mg or less per core.
  • the thickness of the enteric coating of the present invention is 5 to 100 ⁇ m, preferably 20 to 80 ⁇ m, satisfactory results are obtained as an enteric coating.
  • the material of the enteric coating is appropriately selected from known high molecular materials. Suitable polymeric materials are described in a number of well-known literature (L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd edition, 1986, pp. 365-373 H. Sucker et al., Pharmazeutician Technologie, Thieme, 1991, pp. 355-359; Hagers Handbuchder pharmazeutician fürtechnik, 4th edition, Vol. 7, pp.
  • cellulose ester derivatives cellulose ethers, methyl acrylate copolymers of acrylic resins and copolymers of maleic acid and phthalic acid derivatives may be included therein.
  • the enteric coating of the present invention can be prepared using a conventional enteric coating method in which an enteric coating solution is sprayed onto a core.
  • Suitable solvents used in the enteric coating process include alcohols such as ethanol, ketones such as acetone, and halogenated hydrocarbon solvents such as dichloromethane (CH 2 Cl 2 ), and a mixed solvent of these solvents may be used.
  • An emollient such as di(di)-n-butylphthalate or triacetin is added to the coating solution in a ratio of 1 to about 0.05 to about 0.3 (coating material to softener). It is appropriate to carry out the spraying process continuously and it is possible to adjust the amount of spraying taking into account the conditions of the coating.
  • the spray pressure can be varied, and satisfactory results are generally obtained with spray pressures of about 1 to about 1.5 bar.
  • the composition of the present invention may be a composition for parenteral administration.
  • parenteral administration means intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, spinal, intrathecal or rectal topical administration or injection.
  • Parenteral administration is by injecting a suppository preparation, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • the composition may be mixed in water with a stabilizer or a buffer to prepare a solution or suspension, which may be prepared in a unit dosage form in an ampoule or vial.
  • the preferred dosage of the composition of the present invention depends on the condition and weight of the patient, age, sex, health condition, dietary constitution specificity, the nature of the preparation, the severity of the disease, the administration time of the composition, the administration method, the administration period or interval, the excretion rate, And the range may vary depending on the type of drug, and may be appropriately selected by a person skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg/kg, but is not limited thereto, and may be divided and administered once or several times a day.
  • a food composition means a natural product or a processed product containing one or more nutrients, and preferably means a product that can be eaten directly through a certain degree of processing process, as a conventional meaning.
  • foods, food additives, health functional foods, and functional beverages are examples of the food.
  • the food may be a health functional food.
  • the food composition or composition for food additives may be included in food effective in improving or preventing intestinal diseases.
  • the food composition of the present invention can be easily utilized as a main ingredient, supplementary ingredient, food additive, health functional food or functional beverage of food.
  • Foods to which the food or food additive composition according to the present invention can be added include, for example, various foods, beverages, chewing gum, tea, vitamin complexes, and functional foods.
  • food includes special nutritional food (eg, formula milk, infant food, baby food, etc.), processed meat product, fish meat product, tofu, jelly, noodles (eg, ramen, noodles, etc.), bread, health supplement food, seasoning Foods (eg, soy sauce, soybean paste, gochujang, mixed paste, etc.), sauces, confectionery (eg, snacks), candies, chocolates, chewing gum, ice cream, dairy products (eg, fermented milk, cheese, etc.), other processed foods, kimchi, It includes, but is not limited to, pickled foods (various types of kimchi, pickled vegetables, etc.), beverages (eg, fruit drinks, vegetable drinks, soy milk, fermented beverages, etc.), and natural seasonings (eg, ramen soup, etc.).
  • the food, beverage or food includes, but
  • the term “health functional food” refers to a food group or food composition that has added value so that the function of the food acts for a specific purpose by using physical, biochemical, or bioengineering methods, etc. It refers to food designed and processed to fully express the body's regulatory functions related to disease prevention and recovery.
  • the functional food may include food additives that are acceptable in food science, and may further include appropriate carriers, excipients, and diluents commonly used in the manufacture of functional foods.
  • the food containing the food composition of the present invention is various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectins acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. and can be used.
  • the amount of the composition according to the present invention may be 0.001% to 100% by weight of the total weight of the food, preferably 1% to 99% by weight. %, and in the case of beverages, it may be included in a ratio of 0.001 g to 10 g, preferably 0.01 g to 1 g based on 100 mL, but for health and hygiene purposes or health control purposes In the case of long-term ingestion, it may be less than the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the food or food additive composition of the present invention may be prepared by adding the Lactobacillus acidophilus KBL402 strain and/or KBL409 strain to a pharmaceutically acceptable carrier, or in a composition suitable for consumption by humans or animals. That is, it can be added to and used in foods that do not contain other probiotic bacteria and foods that already contain some probiotic bacteria.
  • the additive for animal feed of the present invention may be in the form of a dry or liquid preparation, and may further contain other non-pathogenic microorganisms in addition to the Lactobacillus acidophilus strain KBL402 and/or the strain KBL409.
  • feed raw materials include various grains and soybean proteins, including peanuts, peas, sugar beets, pulp, grain by-products, and animal intestines.
  • Flour and fish meal powder may be used, and unprocessed or processed ones may be used without limitation.
  • the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, a culture of the strain, a lysate of the strain, and the strain There may be provided a method for preventing or treating intestinal diseases comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one selected from the group consisting of an extract of.
  • the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP in the preparation of a drug for preventing or treating intestinal diseases, the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, the above
  • a composition comprising at least one selected from the group consisting of a culture of a strain, a lysate of the strain, and an extract of the strain may be provided.
  • a pharmaceutical composition comprising at least one selected from the group consisting of extracts of the intestinal disease prevention or treatment may be provided.
  • the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, a culture of the strain, a lysate of the strain, and the strain There may be provided a method for improving or preventing intestinal disease comprising administering a food composition comprising at least one selected from the group consisting of extracts of.
  • Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP in the manufacture of food for improving or preventing intestinal diseases, Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, the above
  • a composition comprising at least one selected from the group consisting of a culture of a strain, a lysate of the strain, and an extract of the strain may be provided.
  • the Lactobacillus acidophilus KBL402 strain with accession number KCTC 14640BP or the Lactobacillus acidophilus KBL409 strain with accession number KCTC 13518BP, a culture of the strain, a lysate of the strain, and the strain Improvement or prevention of intestinal diseases of the food composition containing at least one selected from the group consisting of extracts of may be provided.
  • the probiotic Lactobacillus acidophilus KBL402 (accession number KCTC 14640BP) strain according to the present invention includes a 16s rDNA sequence represented by SEQ ID NO: 1 below.
  • the probiotic Lactobacillus acidophilus KBL409 (accession number KCTC 13518BP) strain according to the present invention includes a 16s rDNA sequence represented by SEQ ID NO: 2 below.
  • composition according to one embodiment of the present invention can reduce intestinal inflammation.
  • it can reduce inflammation of the large intestine, including the colon.
  • composition according to one embodiment reduces the expression of pro-inflammatory cytokines, increases the expression of anti-inflammatory cytokines, reduces myeloperoxidase (MPO) expression, induces regulatory T cells, , it may be to increase miRNA-107 expression or to decrease miRNA-146a, miRNA-155 or miRNA-223 expression.
  • MPO myeloperoxidase
  • the composition according to one embodiment can down-regulate pro-inflammatory immunomodulators, including pro-inflammatory cytokines and pro-inflammatory chemokines, and reduce their expression.
  • pro-inflammatory cytokines include IFN- ⁇ , IL-1 ⁇ , IL-4, IL-6, IL-17A and/or TNF, and the like
  • pro-inflammatory chemokines include: and chemokine (C-C motif) ligand 2 (CCL2) and chemokine C-X-C motif ligand 1 (CXCL1).
  • composition according to one embodiment reduces intestinal inflammation by reducing the expression of pro-inflammatory immunomodulators such as IFN- ⁇ , IL-1 ⁇ , IL-4, IL-6, IL-17A, TNF, CCL2, and CXCL1.
  • pro-inflammatory immunomodulators such as IFN- ⁇ , IL-1 ⁇ , IL-4, IL-6, IL-17A, TNF, CCL2, and CXCL1.
  • composition according to one embodiment can up-regulate anti-inflammatory cytokines and reduce their expression.
  • the composition according to one embodiment can reduce intestinal inflammation by increasing the expression of anti-inflammatory cytokines such as IL-10.
  • composition according to one embodiment can reduce the expression of myeloid cell type peroxidase and reduce intestinal inflammation.
  • composition according to one embodiment may induce expression of regulatory T cells (Tregs).
  • Tregs regulatory T cells
  • it can reduce intestinal inflammation by inducing the expression of CD4+ CD25+ Foxp3+ regulatory T cells (Tregs).
  • composition according to one embodiment can increase miRNA-107 expression, thereby down-regulating pro-inflammatory cytokines and reducing their expression.
  • it may reduce expression of IL-6, IFN- ⁇ , TNF- ⁇ and/or TGF- ⁇ and reduce intestinal inflammation.
  • composition according to one embodiment may improve the relative intestinal distribution of beneficial bacteria.
  • composition of one embodiment can enhance the diversity of beneficial microflora in the gut.
  • the composition can enhance the relative intestinal distribution of one or more bacteria of the genus Akkermansia and bacteria of the genus Prevotella .
  • the composition may reduce the relative intestinal distribution of one or more bacteria of the genus Bacteroides and bacteria of the genus Mucispirillum .
  • Bacteria of the genus Akkermansia can induce Foxp3+ regulatory T cells and increase the expression of anti-inflammatory cytokines such as IL-10. Bacteria of the genus Prevotella can induce T regulatory cells and regulate the secretion of cytokines.
  • the relative intestinal distribution of bacteria of the genus Akkermansia and/or of the genus Prevotella improves, the relative intestinal distribution of bacteria of the genus Bacteroides and one or more of the bacteria of the genus Musspirillum decreases, and the relative intestinal distribution of beneficial bacteria can be improved.
  • composition of one embodiment can improve intestinal inflammation by improving the relative intestinal distribution of one or more bacteria of the genus Akkermansia and bacteria of the genus Prevotella.
  • Administration of the composition of one embodiment may reduce the concentration of various amino acids such as aspartic acid, cysteine, glutamine, glycine, serine and/or threonine in the intestine of a subject.
  • concentration of short chain fatty acids such as acetate, butyrate and/or propionate may be increased. This seems to be because the administration of the Lactobacillus acidophilus KBL402 strain or the KBL409 strain improves the balance and diversity of the intestinal microflora, thereby affecting the increase in the concentration of short-chain fatty acids.
  • the short-chain fatty acids described above may exhibit excellent effects in improving, preventing, and treating intestinal diseases by contributing to epithelial cell differentiation related to intestinal homeostasis, stimulating and inducing regulatory T cells, or improving mucosal inflammation.
  • the intestinal disease may be an inflammatory disease occurring in the large intestine or small intestine.
  • intestinal diseases include inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, irritable bowel syndrome, enteritis, ischemic colitis, intestinal Behçet's disease, hemorrhagic rectal ulcer and/or ileocystitis. (pouchitis) and the like.
  • the bowel disease of one embodiment may be inflammatory bowel disease.
  • composition according to one embodiment of the present invention may also improve intestinal function.
  • the composition of one embodiment can ameliorate reduced intestinal function by ameliorating intestinal inflammation.
  • Lactobacillus acidophilus strains KBL402 and KBL409 were isolated from feces of healthy Koreans and cultured as described in a previous study, and the two strains were identified by 16S ribosomal RNA (rRNA) gene sequencing.
  • rRNA ribosomal RNA
  • Lactobacillus acidophilus KBL402 and KBL409 strains were cultured in Lactobacilli MRS Agar (BD Difco, Sparks, MD, USA) supplemented with 0.05% L-cysteine hydrochloride at 37° C. for 24 hours under anaerobic conditions. Bacterial cells were collected by centrifugation at 3000 rpm and washed twice with 1 ⁇ Phosphate-buffered saline (PBS) before use. The bacterial concentration was measured by the culture method, and the bacterial community containing 1 ⁇ PBS containing 20% glycerol was stored at -80 ° C until use.
  • PBS Phosphate-buffered saline
  • Lysates of each of the Lactobacillus acidophilus KBL402 and KBL409 strains were obtained by the following method. 1 mL of cell solution was put in a tube containing 0.2 mm zirconia beads, and disrupted by bead-beating at a beat frequency of 1/30 3 times for 5 minutes. The whole tube containing the lysate was centrifuged at 5,000 rpm for 10 minutes. Thereafter, only the supernatant was transferred, filtered through a 40 ⁇ m cell strainer, and then filtered twice through a 0.2 ⁇ m syringe filter to prepare a lysate.
  • Extracts of each of the Lactobacillus acidophilus KBL402 and KBL409 strains were obtained by the following method. 20 g (wet weight) of microbial cells were prepared, and the prepared cells were resuspended in 140 mL of 0.1 M sodium citrate buffer (pH 4.5). Cells suspended in the buffer were sonicated for 60 minutes using a water bath type sonicator. 140 mL of n-butanol was added to the sonicated sample and stirred for 1 hour. The mixed solution was centrifuged for 20 minutes at 10,000 g and 4° C. to separate the phases.
  • the organic solvent layer and aqueous solution layer obtained by phase separation were collected separately, and each was subjected to dialysis against pure water (2 kDa dialysis membrane, 4° C., 7 days). After dialysis, the solution was lyophilized to evaporate all solvents. The dried sample obtained after lyophilization was dissolved using 30 mL of ultrapure water, and filtered through a 0.2 ⁇ m syringe filter to obtain a strain extract.
  • a mouse colitis model using DSS is a useful tool to elucidate the efficacy and mechanisms of probiotics for the improvement of acute IBD.
  • mice Eight mice were used in each experimental condition. Mice were housed in air-conditioned cages with free access to drinking water and food on a 12-h light/dark cycle. In order to induce colitis, DSS (Dextran Sodium Sulfate, MW 36 000-50,000 Da; MP Biomedicals, LLC, Santa Ana, CA, USA) was dissolved in water to prepare a 2% by weight DSS solution, which was then administered to mice for 7 days. supplied.
  • DSS Extran Sodium Sulfate, MW 36 000-50,000 Da; MP Biomedicals, LLC, Santa Ana, CA, USA
  • Approximately 1 ⁇ 10 9 colony forming units of strain Lactobacillus acidophilus KBL402 or KBL409 were administered simultaneously with 200 ⁇ L of 1 ⁇ PBS by daily oral gavage.
  • the body weight and disease activity indices (DAI) of the mouse including information on weight change (%), stool concentration and bloody stool, were measured three times at each time point, and are described in Table 1 to be described later.
  • mice After 8 days of Lactobacillus acidophilus treatment, all mice were sacrificed, and caecal weight and colon length of the mice were measured. Colon, feces and cecal samples were immediately stored at -80°C for future use.
  • the collected colon was divided into two parts: proximal and distal colon.
  • Distal segments were fixed with 10% formaldehyde and stained with hematoxylin and eosin. Histological scores of distal segments were examined using Panoramic Viewer (3DHISTECH, Ltd, Budapest, Hungary).
  • Histological scores were scored from 0 to 12 for the following four categories.
  • Colon samples were weighed using a MM 400 Mixer Mill homogenizer (Retsch, GmbH, Haan, Germany) in 1 ⁇ RIPA buffer (Thermo Fisher Scientific, Inc., Waltham, MA, USA) and Halt Protease Inhibitor Cocktail (Thermo Fisher Scientific). was homogenized.
  • Cytokines including IFN- ⁇ , IL-4, IL-6, IL-10, IL-17A and tumor necrosis factor (TNF), were measured in BD cytometric bead array mouse Th1/Th2/Th17 cytokines. Measurements were made using the Cain kit (BD Biosciences, San Jose, CA, USA) according to the manufacturer's instructions.
  • Cytokine IL-1 ⁇ in colon samples was measured using the Murine IL-1 ⁇ Mini ABTS ELISA development kit (#900-M47; PeproTech, RockyHill, NJ, USA).
  • C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1) were detected using JE/MCP-1 (CCL2) and CXCL1 Mini ABTS ELISA development kits (#900-M126 and #900-M127; PeproTech), respectively.
  • T regulatory cells Flow cytometric analysis of T regulatory cells (Tregs) was performed as follows. First, mesenteric lymph node (MLN) samples were carefully ground on wet slides to reduce friction and filtered using a cell strainer (70 ⁇ m pore size, SPL Life Science Co., Ltd, Pocheon-si, Gyeonggi-do, Korea). To confirm cell viability, T cells were stained using fixable viability stain 510 (FVS510; BD Biosciences).
  • RNA ( ⁇ 200 nucleotides) fractions were extracted from distal colon samples using the miRNeasy mini kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions.
  • RNA samples were then quantified using the Nanodrop ® ND 1000 (Thermo Fisher Scientific), and 500 ng RNA samples were reverse transcribed using the miScript II RT kit (Qiagen).
  • miRNA-107 miRNA-107 (MS00023961), miRNA-146 (MS00001638), miRNA-155 (MS00001701) and miRNA-223 using QuantiTects SYBR green PCR master mix (Qiagen), miScript universal primers (Qiagen) and miScript primer assay (Qiagen) (MS00001960) complementary DNA (2 ng) was amplified.
  • PCR reactions were performed using a real-time PCR system (Applied Biosystems) under the following conditions: after initial denaturation at 95 °C for 15 min, followed by 94 °C for 15 sec, 55 °C for 30 sec and 72 °C for 30 sec. 40 cycles were performed. miRNA expression was normalized using small nuclear RNA (snRNA) and C/D box 95 (Qiagen).
  • snRNA small nuclear RNA
  • C/D box 95 Qiagen
  • Amino acids were identified using AA-S-19 assay standard mixture (Sigma-Aldrich, St Louis, MO, USA). Data collection and quantification was performed using MassLynx software 4.1 (Waters Corporation).
  • Cecal samples were homogenized in distilled water and centrifuged at 13,000 g for 5 minutes. The supernatant was collected and 1% of 2-methylpentanoic acid was added to the supernatant as an internal standard. Ethyl ether was used as an extraction solvent.
  • the organic layer of the sample was measured using an Agilent 7890A gas chromatograph (Agilent Technologies, Santa Clara, CA, USA) under the following conditions: 1.5 kV capillary voltage, 600 L/h desolvation gas flow, 50 L/h cone ) gas flow, 170°C oven temperature and 225°C (flame ionization detector and injection port temperature). Nitrogen was used as a carrier gas. Retention times and peak areas of the samples were confirmed using standard mixtures.
  • the experimental group was administered KBL402 strain and KBL409 strain together with DDS, respectively, water and PBS were administered to the negative control group, and DSS and PBS were administered to the positive control group.
  • FIG. 1 is a graph showing Rarefaction plots of an experimental group and a control group.
  • 2 is a graph showing a principal component analysis (PCA) plot using the weighted UniFrac distances of the experimental group and the control group.
  • Figure 3 is a graph showing the taxonomic composition of caecal microorganisms in the experimental group and the control group.
  • 4 is a graph that clearly shows the significantly different microbial populations between the experimental and control groups using a linear discriminant analysis (LDA) effect size (LEfSe) analysis. (threshold > 3.0)
  • FIG. 5 is a heat map of the Spearman correlation between the relative abundance of genus-level taxa and specific metabolites in the experimental and control groups. In Fig. 5, the color of the matrix represents the degree of correlation between the taxon and the metadata variable, and * marks indicate statistical significance ( * , P ⁇ 0.05; ** , P ⁇ 0.01).
  • mice After 7 days of DSS treatment, the mice showed clinical symptoms such as weight loss, diarrhea and rectal bleeding, and it was confirmed that the colon was seriously damaged. However, referring to Table 1 and FIG. 4, it was confirmed that colitis symptoms of mice treated with Lactobacillus acidophilus KBL402 or KBL409 were significantly reduced. It is confirmed that the DAI score after 8 days of treatment in DSS + KBL402-treated and DSS + KBL409-treated mice is reduced compared to the DAI score after 8 days in DSS + PBS-treated mice.
  • DSS + KBL402 treated and DSS + KBL409 treated mice also showed significantly longer colon length and lower histological scores when compared to those of DSS + PBS treated mice.
  • mice with DSS-induced colitis are treated with Lactobacillus acidophilus strain KBL402 and KBL409, anti-inflammatory effects are achieved in intestinal diseases, which can be usefully used for improvement, prevention, and treatment of intestinal diseases explain in detail.
  • Lactobacillus acidophilus treatment was found to significantly affect the overall downregulation of Th1-, 2- and 17-related cytokines in mice with DSS induced colitis.
  • pro-inflammatory cytokines are up-regulated, but when mice with DSS-induced colitis are treated with Lactobacillus acidophilus KBL402 strain and KBL409 strain, it is confirmed that pro-inflammatory cytokines are down-regulated. From this, it can be confirmed that the treatment of the Lactobacillus acidophilus KBL402 strain and the KBL409 strain shows an excellent anti-inflammatory effect in a subject with intestinal disease by regulating the secretion of inflammatory cytokines and inflammation-related molecules.
  • CCL2 is an important pro-inflammatory chemokine mainly produced by macrophages
  • CXCL1 is a major chemokine involved in the recruitment and activation of neutrophils.
  • MPO is an important indicator of neutrophil infiltration. High levels of CCL2, CXCL1 and MPO were highly correlated with increased leukocyte infiltration.
  • mice with DSS-induced colitis showed a significant decrease in MPO levels. Therefore, it is confirmed that IBD can be improved, prevented and treated when treated with Lactobacillus acidophilus.
  • mice with DSS-induced colitis using Lactobacillus acidophilus treatment 2-3. Regulatory T cell differences in mice with DSS-induced colitis using Lactobacillus acidophilus treatment
  • mice with DSS-induced colitis were treated with Lactobacillus acidophilus, the effect of inducing T regulatory cells in mesenteric lymph nodes was confirmed.
  • CD4+ CD25+ Foxp3+ T regulatory cells are found to be significantly higher in the mesenteric lymph nodes of DSS + KBL409 treated mice than in the mesenteric lymph nodes of DSS + PBS treated mice. Through this, it was confirmed that when the Lactobacillus acidophilus KBL402 strain and the KBL409 strain are treated, T regulatory cells such as CD4+CD25+Foxp3+ are induced in the lymph nodes and can be usefully used for the improvement, prevention, and treatment of intestinal diseases.
  • miRNA expression is closely related to various important biological processes such as cell differentiation, proliferation, apoptosis, tumorigenesis, and apoptosis.
  • miRNA-107 is closely related to the downregulation of IL-6, IFN- ⁇ , TNF- ⁇ and TGF- ⁇ promotion, and miRNA-146a can inhibit various intestinal barrier or inflammatory genes within immune-related signaling pathways. there is.
  • miRNA-146a knockout mice show resistance to ulcerative colitis.
  • miRNA-155 or miRNA-223 is known to be a regulator of macrophages, various immune cells including Th1 and Th17 or inflammasome complex and IL-1 ⁇ production, and both miRNAs are increased in inflammatory conditions such as IBD. can do.
  • microRNA miRNA
  • miRNA-107 was significantly higher in DSS + KBL409 treated mice compared to DSS + PBS treated mice.
  • miRNA-146a expression was lower in DSS + KBL409 treated mice than in DSS + PBS treated mice.
  • the expression levels of miRNA-155 and miRNA-223 were significantly lower in DSS + KBL402 treated mice compared to DSS + PBS treated mice.
  • the KBL402 strain and the KBL409 strain show an effect in the treatment of colitis through the regulation of miRNAs closely related to host inflammation, and it was confirmed that they can be usefully used for the improvement, prevention, and treatment of intestinal diseases.
  • Lactobacillus acidophilus KBL402 strain and the KBL409 strain can be usefully used to improve, prevent, and treat intestinal diseases.
  • metabolites including amino acids and short chain fatty acids were identified in the caecum of mice with DSS-induced colitis.
  • the genus Lactobacillus in DSS + KBL402 treated mice showed a significant correlation with acetate, and the genus Prevotella in DSS + KBL409 treated mice also showed negative correlations with glycine and aspartic acid.
  • Amino acids are important precursors of short-chain fatty acids, mainly produced by the gut microbiota.
  • Short-chain fatty acids such as acetate, butyrate, and propionate contribute to various processes related to intestinal homeostasis, such as epithelial cell differentiation, regulatory T cell stimulation, and improvement of mucosal inflammation, while showing effects in preventing and treating IBD.
  • Butyrate is also a major energy source for the epithelium and can exert beneficial effects on intestinal diseases such as ulcerative colitis because it can extensively induce regulatory T cells.

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Abstract

La présente invention concerne une composition qui comprend au moins un élément choisi dans un groupe constitué par une souche de Lactobacillus acidophilus KBL402 sous le numéro d'ordre KCTC 14640 BP ou une souche de Lactobacillus acidophilus KBL409 sous le numéro d'ordre KCTC 13518 BP, une culture de la souche, des débris de la souche et un extrait de la souche, et qui possède un excellent effet pour soulager, prévenir ou traiter un trouble intestinal.
PCT/KR2021/013946 2021-10-08 2021-10-08 Composition pour soulager, prévenir ou traiter un trouble intestinal, comprenant une souche de lactobacillus acidophilus kbl402 ou kbl409 WO2023058801A1 (fr)

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