WO2020055193A1 - Micro-organisme à activité antibactérienne pour des bactéries pathogènes entériques et composition pharmaceutique pour la prévention et le traitement d'une maladie induite par des bactéries pathogènes entériques utilisant celui-ci - Google Patents

Micro-organisme à activité antibactérienne pour des bactéries pathogènes entériques et composition pharmaceutique pour la prévention et le traitement d'une maladie induite par des bactéries pathogènes entériques utilisant celui-ci Download PDF

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WO2020055193A1
WO2020055193A1 PCT/KR2019/011879 KR2019011879W WO2020055193A1 WO 2020055193 A1 WO2020055193 A1 WO 2020055193A1 KR 2019011879 W KR2019011879 W KR 2019011879W WO 2020055193 A1 WO2020055193 A1 WO 2020055193A1
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microorganism
pathogenic bacteria
acid
pharmaceutical composition
enteric
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PCT/KR2019/011879
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English (en)
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WO2020055193A9 (fr
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Sang Sun Yoon
Mi Young Yoon
Jin Sun You
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Industry-Academic Cooperation Foundation, Yonsei University
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • C12N1/205—Bacterial isolates
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure relates to a microorganism with antibacterial activity for enteric pathogenic bacteria and a pharmaceutical composition for preventing or treating enteric pathogenic bacteria-inducing diseases including the same, and more particularly, to a microorganism that symbiosis with enteric pathogenic bacteria to inhibit growth or activity thereof, a pharmaceutical composition effective against diseases induced by infection of pathogenic bacteria by including the microorganism as an active ingredient, and a food composition for improving enteric infection by enteric pathogenic bacteria.
  • Enteric pathogenic bacteria include Salmonella, Cholera, Escherichia coli , and Typhoid , and the like, and these pathogenic bacteria may cause enteric diseases such as food poisoning and enteritis when infected in the intestines.
  • antibiotics that kill or reduce causative pathogens may be proposed.
  • Treatment based on antibiotic administration may provide an immediate therapeutic effect for infectious diseases in a short time.
  • antibiotic abuse thereby increasing the frequency of the appearance of various antibiotic-resistant pathogens.
  • Salmonella typhimurium DT104 has been reported as a pathogen with a multiple antibacterial resistance pattern against antibiotics such as ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline.
  • antibiotic treatment causes changes in the enteric microbial community in humans and other mammals and may increase susceptibility of a host to infection by enteric pathogenic bacteria such as Shigella flexneri, Salmonella enterica, Clostridium difficile , and vancomycin-resistant Enterococcus .
  • the antibiotic resistance of a host may be implemented through a number of factors, including inhibition of specific microbial species, changes in the metabolic environment and/or host responses as a result of a changed microbial community.
  • the inventors of the present disclosure further paid attention to the association between the onset of infectious enteric diseases by enteric pathogens and the enteric microbial community.
  • the inventors of the present disclosure observed a change in enteric microbial community after infecting Vibrio cholerae , one of the enteric pathogens in mice inoculated with a plurality of types of antibiotics.
  • the inventors of the present disclosure have observed species that increase in the enteric microbial community according to infection of Vibrio cholerae .
  • the inventors of the present disclosure confirmed that the microorganism of the species was co-cultured with Vibrio cholerae , as a result, the growth of Vibrio cholerae was inhibited.
  • the inventors of the present disclosure have found a new microorganism with enteric pathogen suppression ability and recognized that the microorganism may be used for the treatment and prevention of infection of the pathogen and thus enteric disease.
  • the inventors of the present disclosure have developed a pharmaceutical composition for the prevention or treatment of enteric pathogenic bacteria-inducing diseases including a microorganism with antibacterial activity for enteric pathogenic bacteria.
  • the inventors of the present disclosure identified newly discovered microorganism with antibacterial activity for enteric pathogenic bacteria and thus confirmed that the new microorganism belonged to the Bacteroides vulgatus species.
  • an object to be solved by the present disclosure is to provide a microorganism of Bacteroides vulgatus VIC01 (Accession number: KCTC18713P) with antibacterial activity for enteric pathogenic bacteria and a pharmaceutical composition for preventing or treating enteric pathogenic bacteria-inducing diseases and a food composition for improving enteric infection by enteric pathogenic bacteria including the same.
  • the present disclosure provides a Bacteroides vulgatus VIC01 (Accession number: KCTC18713P) microorganism with antibacterial activity for enteric pathogenic bacteria.
  • Bacteroides vulgatus microorganism the Bacteroides vulgatus microorganism, the microorganism with antibacterial activity for enteric pathogenic bacteria, the novel microorganism, and the microorganism of the present disclosure may be referred to as a Bacteroides vulgatus VIC01 (Accession number: KCTC18713P) microorganism.
  • antibacterial activity used in this specification may mean the activity or growth inhibition of enteric pathogenic bacteria, furthermore, the killing of pathogenic bacteria. However, it is not limited thereto, and in the present specification, “antibacterial activity” may mean inhibitory activity of all phenomena caused by enteric pathogenic bacteria.
  • the enteric pathogenic bacteria may be at least one selected from the group consisting of Vibrio cholerae, Salmonella gallinarum, Salmonella enteritidis, Salmonella typhimurium, Salmonella choleraesuis, Salmonella derby, Staphylococcus aureus, enterotoxigenic E. coli, Listeria monocytogenes, Campylobacter jejuni, Shigella flexneri, Salmonella enterica, Clostridium difficile, vancomycin-resistant Enterococcus and Clostridium perfringens .
  • enteric pathogenic bacteria are not limited to those described above and may be various microorganisms causing enteric infection.
  • the Bacteroides vulgatus VIC01 (Accession number: KCTC18713P) microorganism may have a base sequence having at least 80% homology with a base sequence represented by SEQ ID NO: 1.
  • homology used in this specification may refer to the same degree as the base sequence disclosed in the present specification. Specifically, the comparison of homology may represent homology between two or more sequences in percentage (%). For example, through the comparison of homology, a microorganism having at least 80% homology with the base sequence represented by SEQ ID NO: 1, preferably a microorganism having at least 90% homology, and more preferably a microorganism having at least 95% homology may substantially have enteric pathogen inhibitory ability.
  • the microorganism may be microorganisms producing short-chain fatty acids (SCFAs).
  • SCFAs short-chain fatty acids
  • short-chain fatty acid used in the present specification refers to a fatty acid with one double bond.
  • the level of short-chain fatty acids may decrease in patients with enteric infection symptoms of pathogens such as diarrhea and may increase in patients who have returned to normal. That is, the level of short-chain fatty acids may be associated with enteric infectious pathogens, furthermore, diseases caused by these pathogens. For example, the short-chain fatty acids may provide an effective barrier against the invasion of pathogens. Furthermore, the short-chain fatty acids may suppress the activity for pathogens.
  • the short-chain fatty acid may include at least one selected from the group consisting of butyric acid, isobutyric acid, propionic acid, valeric acid, and isovaleric acid.
  • the present disclosure is not limited thereto.
  • the present disclosure provides a pharmaceutical composition for preventing or treating enteric pathogenic bacteria-inducing diseases, including a Bacteroides vulgatus (Accession number: KCTC18713P) microorganism thereof with antibacterial activity for enteric pathogenic bacteria or a culture medium, as an active ingredient.
  • enteric pathogenic bacteria-inducing diseases including a Bacteroides vulgatus (Accession number: KCTC18713P) microorganism thereof with antibacterial activity for enteric pathogenic bacteria or a culture medium, as an active ingredient.
  • the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism and the culture medium thereof may be excellent in bile resistance and acid resistance.
  • the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism and the culture medium thereof are effective in preventing or treating diseases caused by enteric pathogenic bacteria by reaching the intestine to balance the enteric microbial community or substantially inhibit the activity of enteric pathogenic bacteria.
  • the term "culture medium” used in the present specification may refer to a liquid culture medium including the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism of the present disclosure and a medium component necessary for its growth, or a culture filtrate which the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism has been removed.
  • the culture filtrate may include an active ingredient with antibacterial activity for enteric pathogenic bacteria secreted from the microorganism during the culture process.
  • prevention used in the present specification may mean all actions that inhibit diseases or delay the onset of the diseases by administration of the pharmaceutical composition, and “treatment” may refer to all actions in which symptoms of the diseases are improved or beneficially changed by the administration of the pharmaceutical composition.
  • the enteric pathogenic bacteria-inducing disease may be at least one selected from the group consisting of food poisoning, typhoid, peritonitis, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious diarrhea, gastroenteritis, inflammatory bowel disease, nervous enteritis syndrome, small intestinal bacterial overgrowth, intestinal acute diarrhea and ischemic enteritis.
  • the present disclosure is not limited thereto, and the enteric pathogenic bacteria-inducing diseases may include all symptoms caused by infection of enteric pathogenic bacteria.
  • the pharmaceutical composition may include the microorganism in an amount of 10 5 to 10 12 CFU/mL, or the culture medium of the microorganism in an amount of 10 5 to 10 12 ml/g, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition may include the microorganism in an amount of 10 7 to 10 10 CFU/mL, or the culture medium of the microorganism in an amount of 10 7 to 10 10 ml/g, based on the total weight of the pharmaceutical composition.
  • the content of the microorganism or culture medium of the microorganism is not limited thereto.
  • the enteric pathogenic bacteria secrete the toxicity, and the microorganism may be effective in improving enteric disease by removing the secreted toxicity in the intestine.
  • a pharmaceutical composition including a Bacteroides vulgatus (Accession number: KCTC18713P) microorganism or a culture medium thereof is administered, the level of enteric toxin by pathogenic bacteria may be reduced by about five times than before administration.
  • the pharmaceutical composition according to an embodiment of the present disclosure can be formulated in various forms.
  • the pharmaceutical composition when the pharmaceutical composition is prepared in a solid formulation, the pharmaceutical composition may be prepared in the form of tablets, pills, powders, granules, and capsules.
  • a solid formulation may further include one or more excipients, for example, starch, calcium carbonate, sucrose, lactose or gelatin.
  • the composition of the solid formulation may further include lubricants such as magnesium stearate, talc and the like in addition to simple excipients.
  • the pharmaceutical composition when the pharmaceutical composition according to one embodiment of the present disclosure is prepared as a liquid formulation, the pharmaceutical composition may be prepared in forms of aqueous solutions, suspensions and pharmaceutically acceptable fats and oils, alcohols or organic solvents, esters, emulsions, syrups or elixirs, suspensions reconstituted from non-foam granules, and foam formulations reconstituted from foam granules.
  • the composition of the liquid formulation may be administered orally in a liquid dosage formulation in combination with an inert carrier.
  • Suitable inert carriers may be pharmaceutically acceptable inert carriers such as ethanol, glycerol, and water.
  • composition of the liquid formulation may further include solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners and melt aids.
  • composition of the liquid formulation may further include colorants and flavoring agents to increase patient acceptance.
  • the pharmaceutical composition according to one embodiment of the present disclosure may be administered to a subject by oral or parenteral administration. More specifically, the parenteral administration may include intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration or topical administration.
  • a suitable formulation, dosage, and mode of administration of the pharmaceutical composition may include factors such as the age, weight, gender, the extent of disease symptoms, food ingested, time of administration, route of administration, rate of excretion and response sensitivity of the subject.
  • the skilled physician or veterinarian may readily determine and prescribe the dosage and mode of administration of the pharmaceutical composition effective for the desired treatment.
  • the pharmaceutical composition may further include at least one metabolite selected from the group consisting of cholic acid, butyric acid, isobutyric acid, propionic acid, valeric acid, isovaleric acid, and trimethylamine.
  • the metabolite may enhance the antibacterial activity of the microorganism according to various embodiments of the present disclosure.
  • the metabolite may include a metabolite of the microorganism according to various embodiments of the present disclosure but is not limited thereto.
  • the pharmaceutical composition of the present disclosure may include at least one metabolite selected from the group consisting of butyric acid, isobutyric acid, propionic acid, valeric acid, and isovaleric acid.
  • the metabolite may be present at a concentration of 0.1 to 30 mM with respect to the composition.
  • the metabolite may be present at a concentration of 15 to 25 mM with respect to the pharmaceutical composition. More preferably, the metabolite may be present at a concentration of 18 to 22 mM with respect to the pharmaceutical composition.
  • the concentration of the metabolite is not limited thereto, and may be set in various ranges according to a type of subject to be administered with the pharmaceutical composition, a desired therapeutic effect, and the like.
  • the pharmaceutical composition may further include short-chain fatty acids.
  • the present disclosure provides a food composition for improving enteric infection by enteric pathogenic bacteria, including a Bacteroides vulgatus (Accession number: KCTC18713P) microorganism thereof with antibacterial activity for enteric pathogenic bacteria or a culture medium, as an active ingredient.
  • a Bacteroides vulgatus accesion number: KCTC18713P
  • KCTC18713P Bacteroides vulgatus
  • a kind of food to which the food composition of the present disclosure may be added is not particularly limited.
  • the foods which may be added with the food composition of the present disclosure may include drinks, meat, sausages, bread, biscuit, rice cake, chocolate, candies, snacks, cookies, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, alcohol drinks, vitamin complex, and the like, and include all general health functional foods.
  • the food composition may include the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism in an amount of 10 5 to 10 12 CFU/mL, or the culture medium of the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism in an amount of 10 5 to 10 12 ml/g, based on the total weight of the food composition.
  • Bacteroides vulgatus accesion number: KCTC18713P
  • KCTC18713P culture medium of the Bacteroides vulgatus
  • the enteric pathogenic bacteria may secrete the toxicity
  • the Bacteroides vulgatus (Accession number: KCTC18713P) microorganism may remove the secreted toxicity in the intestine.
  • the food composition of the present disclosure may further include at least one metabolite selected from the group consisting of cholic acid, butyric acid, isobutyric acid, propionic acid, valeric acid, isovaleric acid, and trimethylamine.
  • the metabolite may be present at a concentration of 0.1 to 30 mM with respect to the food composition.
  • the food composition of the present disclosure may further include short-chain fatty acids (SCFAs).
  • SCFAs short-chain fatty acids
  • the present disclosure has an effect of providing a novel microorganism that inhibits enteric pathogenic bacteria.
  • the microorganism may induce balance of enteric microbial community or substantially induce the removal of the toxin generated by pathogens causing enteric infection and the inhibition of growth of pathogens causing enteric infection, thereby being used as the pharmaceutical compositions for preventing or treating diseases caused by enteric pathogenic bacteria, and furthermore, the food composition for improving enteric infection by enteric pathogenic bacteria.
  • the present disclosure may contribute to reducing the use of antibiotics and to solving problems caused by the use of antibiotics.
  • the present disclosure has an effect of providing an effective content of the microorganism in the pharmaceutical composition.
  • the present disclosure provides a pharmaceutical composition and a food composition including a metabolite that contributes to the enhancement of antibacterial activity for enteric pathogenic bacteria, thereby providing a better therapeutic prognosis than a composition composed of a microorganism alone.
  • FIG. 1 illustrates a process of isolating microorganisms with antibacterial activity for enteric pathogenic bacteria, according to an embodiment of the present disclosure
  • FIGS. 2A and 2B illustrate experimental results of analyzing colony formation of Vibrio cholerae after co-culture of microorganisms with antibacterial activity for enteric pathogenic bacteria, according to an embodiment of the present disclosure
  • FIG. 2C illustrates experimental results of analyzing a concentration of toxin by Vibrio cholerae after co-culture of microorganisms with antibacterial activity for enteric pathogenic bacteria, according to an embodiment of the present disclosure
  • FIG. 2D illustrates results of analyzing proliferation of Vibrio cholerae in the small intestine, large intestine, and feces of a mouse model according to whether microorganisms with antibacterial activity for enteric pathogenic bacteria are taken and whether Vibrio cholerae is infected, according to an embodiment of the present disclosure
  • FIG. 3A illustrates a change in enteric microbial community, depending on antibiotic treatment
  • FIG. 3B illustrates results of analyzing proliferation of Vibrio cholerae in the small intestine, colon, and feces of a germ-free mouse model according to a state of microorganisms with antibacterial activity for enteric pathogenic bacteria, according to an embodiment of the present disclosure
  • FIG. 3C illustrates results of analyzing proliferation of Vibrio cholerae in the small intestine of an infant mouse model according to inoculation of microorganisms with antibacterial activity for enteric pathogenic bacteria, according to an embodiment of the present disclosure
  • FIG. 4A illustrates a change in enteric microbial community, depending on antibiotic treatment
  • FIG. 4B illustrates a change in metabolites isolated from the cecum depending on antibiotic treatment
  • FIG. 4C illustrates a change in growth inhibition of Vibrio cholerae according to the treatment of metabolites, used in various compositions according to an embodiment of the invention
  • FIG. 4D illustrates a change in growth stimulation of Vibrio cholerae according to the treatment of metabolites, used in various compositions according to an embodiment of the invention.
  • FIG. 4E illustrates a change in infection of Vibrio cholerae according to the presence of microorganisms with antibacterial activity for enteric pathogenic bacteria and metabolites, used in various compositions according to an embodiment of the invention.
  • the microorganism according to an embodiment of the present disclosure may have inhibitory ability for at least one enteric pathogenic bacterium selected from the group consisting of Salmonella gallinarum, Salmonella enteritidis, Salmonella typhimurium, Salmonella choleraesuis, Salmonella derby, Staphylococcus aureus, enterotoxigenic E. coli, Listeria monocytogenes, Campylobacter jejuni , and Clostridium perfringens .
  • the microorganism may be used as a pharmaceutical composition for the treatment or prevention of various diseases induced by enteric pathogenic bacteria infection.
  • Example 1 Method for isolating microorganisms used in various embodiments of the present disclosure
  • FIG. 1 illustrates a process of isolating microorganisms with antibacterial activity for enteric pathogenic bacteria according to an embodiment of the present disclosure.
  • feces were collected from three 12 to 15-week-old mice of females of C57BL6/J for isolation of microorganisms with antibacterial activity for enteric pathogenic bacteria.
  • a bacterial suspension was prepared using a pre-substituted BBE (Bacteroides Bile Esculin) broth medium under an anaerobic condition, and then diluted step by step by 10-step dilution.
  • the diluted suspension was spread on the BBE solid medium and incubated in an anaerobic incubator at 37°C for 48 to 72 hours.
  • formed colonies were again spread on a fresh BBE solid medium to confirm single bacteria.
  • Bacteroides vulgatus microorganism was Bacteroides vulgatus VIC01 (Accession Number: KCTC18713P), which may be used in various embodiments.
  • Example 2 First evaluation of antibacterial activity of microorganisms used in various embodiments of the present disclosure
  • FIGS. 2A and 2B illustrate experimental results of analyzing colony formation of Vibrio cholerae after co-culture of microorganisms with antibacterial activity for enteric pathogenic bacteria according to an embodiment of the present disclosure.
  • FIG. 2C illustrates experimental results of analyzing a concentration of toxin by Vibrio cholerae after co-culture of microorganisms with antibacterial activity for enteric pathogenic bacteria according to an embodiment of the present disclosure.
  • 2D illustrates results of analyzing proliferation of Vibrio cholerae in the small intestine, large intestine, and feces of a mouse model according to whether microorganisms with antibacterial activity for enteric pathogenic bacteria are taken and whether Vibrio cholerae is infected, according to an embodiment of the present disclosure.
  • colonies of Vibrio cholerae were formed after co-culture of microorganisms isolated from mouse feces and Vibrio cholerae under anaerobic conditions for one day by the method described above in Example 1. More specifically, in contrast to a medium cultured only Vibrio cholerae (Only Vc), in a medium co-cultured with the microorganisms isolated from mouse feces and Vibrio cholera (Bv and Vc), colony formation of Vibrio cholerae did not occur.
  • Such isolated Bacteroides vulgatus microorganisms may have inhibitory activity for enteric pathogenic bacteria, particularly Vibrio cholera .
  • the Bacteroides vulgatus microorganisms may have activity to inhibit the activity or growth of Vibrio cholerae , and furthermore to kill Vibrio cholerae .
  • the viable cell count of Vibrio cholerae in a medium cultured only with Vibrio cholerae was about 8 times higher than the viable cell count of live Vibrio cholerae in a medium co-cultured with the isolated Bacteroides vulgatus microorganism and Vibrio cholera (Bv and Vc). That is, such a result may mean that the isolated Bacteroides vulgatus microorganism inhibits formation of colonies of enteric pathogenic bacteria, particularly Vibrio cholerae .
  • the control of Vibrio cholerae of the Bacteroides vulgatus microorganism may be less associated with a decrease in pH.
  • FIG. 2C through an ELISA experiment using an antibody for detecting CTX A and B subunit, it is illustrated a result of measuring CTX, a Vibrio cholerae toxin in a supernatant of the medium cultured only with Vibrio cholerae (Only Vc) and the medium co-cultured with the isolated Bacteroides vulgatus microorganism and Vibrio cholera (Bv and Vc). More specifically, a level of toxins of CTX in the medium co-cultured with the isolated Bacteroides vulgatus microorganism and Vibrio cholerae (Bv and Vc) was reduced about 5 times or more unlike the medium (Only Vc) cultured only with Vibrio cholerae .
  • the level of CTX observed in the co-culture may be a measure of the residual amount of cholerae toxin already produced in a single culture before the initial co-culture.
  • FIG. 2D with respect to a mouse model in which live Bacterioides vulgatus that may be a microorganism having bacterial inhibitory ability used in various embodiments of the present disclosure was ingested at 10 9 CFU, after 10 9 CFU of Vibrio cholerae was inoculated, the small intestine, large intestine and feces were isolated and then the number of Vibrio cholerae in each isolated sample was measured.
  • the Bacteroides vulgatus microorganism isolated from the mouse may be used as the microorganism with antibacterial activity for enteric pathogenic bacteria used in various embodiments of the present disclosure.
  • the microorganism may be used as a composition for inhibiting infection of enteric pathogenic bacteria, a pharmaceutical composition for treating or preventing diseases caused by the enteric pathogenic bacteria, and a food composition for improving enteric infection by enteric pathogenic bacteria.
  • the pharmaceutical composition and the food composition according to an embodiment of the present disclosure may have an improved effect for at least one selected from the group consisting of food poisoning, typhoid, peritonitis, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious diarrhea, gastroenteritis, inflammatory bowel disease, nervous enteritis syndrome, small intestinal bacterial overgrowth, intestinal acute diarrhea and ischemic enteritis.
  • the pharmaceutical composition may include the microorganism in an amount of 10 5 to 10 12 CFU/mL, or the culture medium of the microorganism in an amount of 10 5 to 10 12 ml/g, based on the total weight of the pharmaceutical composition.
  • the content of the microorganism or culture medium of the microorganism is not limited thereto.
  • Example 3 Second evaluation of antibacterial activity of microorganisms used in various embodiments of the present disclosure
  • FIG. 3A illustrates a change in enteric microbial community, depending on antibiotic treatment.
  • FIG. 3B illustrates results of analyzing proliferation of Vibrio cholerae in the small intestine, colon, and feces of a germ-free mouse model according to a state of microorganisms with antibacterial activity for enteric pathogenic bacteria according to an embodiment of the present disclosure.
  • FIG. 3C illustrates results of analyzing proliferation of Vibrio cholerae in the small intestine of an infant mouse model according to inoculation of microorganisms with antibacterial activity for enteric pathogenic bacteria according to an embodiment of the present disclosure.
  • FIG. 3A changes in species-level of the enteric microbial community were shown for a mouse model group inoculated with Vibrio cholerae to an untreated control group (Con-Vc), a mouse model group inoculated with Vibrio cholerae after administration of streptomycin (SM-Vc), a mouse model group inoculated with Vibrio cholerae after administration of bencomycin (VAN-Vc), and a mouse model group inoculated with Vibrio cholerae after administration of clindamycin (CL-Vc), in addition to a mouse model group as an untreated control group (Con), a mouse model group administered with streptomycin (SM), a mouse model group administered with vancomycin (VAN), and a mouse model group administered with clindamycin (CL).
  • the species-level analysis was performed via 16S rRNA sequencing analysis using PCR.
  • this result may mean a change in the microbial colony due to enteric pathogen infection and may mean that the Bacteriodes vulgaris microorganism is associated with an immune response according to enteric Vibrio cholerae infection of a host.
  • Vibrio cholerae was performed after 24 hours of ingestion of Bacteroides vulgatus microorganism (or PBS), and the analysis was performed after 24 hours of the infection of Vibrio cholerae .
  • this result may mean that the Bacteroides vulgatus microorganism used in various embodiments of the present disclosure inhibits colony formation of Vibrio cholerae .
  • the infection with Vibrio cholerae was performed after 12 hours of ingestion of Bacteroides vulgatus microorganism (or PBS), and the analysis was performed after 12 hours of the infection of Vibrio cholerae .
  • FIG. 3C (b) As a result of proliferation analysis of Vibrio cholerae in the intestine, in the mouse model group ingesting the live Bacteroides vulgatus (Live B. vulgatus ) microorganism, the level of Vibrio cholerae was significantly reduced compared to the control group. Furthermore, referring to the results of analyzing fluid accumulation induced by infection, in the mouse model group ingesting the live Bacteroides vulgatus (Live B. vulgatus ) microorganism, a fluid accumulation rate was significantly lower than that of the mouse model group of the control group.
  • this result may mean that the Bacteroides vulgatus microorganism used in various embodiments of the present disclosure inhibits colony formation of Vibrio cholerae , particularly, enteric colony formation by infection of Vibrio cholerae in an infant mouse model.
  • the Bacteroides vulgatus microorganism may be used as a microorganism with antibacterial activity for enteric pathogenic bacteria, particularly, Vibrio cholerae .
  • the microorganism may be used as a composition for inhibiting infection of enteric pathogenic bacteria, a pharmaceutical composition for treating or preventing diseases caused by the enteric pathogenic bacteria, and a food composition for improving enteric infection by enteric pathogenic bacteria.
  • the pharmaceutical composition and the food composition according to an embodiment of the present disclosure may have an improved effect for at least one selected from the group consisting of food poisoning, typhoid, peritonitis, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious diarrhea, gastroenteritis, inflammatory bowel disease, nervous enteritis syndrome, small intestinal bacterial overgrowth, intestinal acute diarrhea and ischemic enteritis.
  • the content of Bacteroides vulgatus microorganisms in the pharmaceutical composition or the food composition may be 10 5 to 10 12 CFU/mL, preferably 10 7 to 10 10 CFU/mL, and more preferably 10 8 to 10 9 CFU/mL, but is not limited thereto.
  • Example 4 Evaluation for metabolites used in various embodiments of the present disclosure
  • FIG. 4A illustrates a change in enteric microbial community, depending on antibiotic treatment.
  • FIG. 4B illustrates a change in metabolites isolated from the cecum depending on antibiotic treatment.
  • FIG. 4C illustrates a change in growth inhibition of Vibrio cholerae according to the treatment of metabolites, used in various compositions according to an embodiment of the invention.
  • FIG. 4D illustrates a change in growth stimulation of Vibrio cholerae according to the treatment of metabolites, used in various compositions according to an embodiment of the invention.
  • FIG. 4E illustrates a change in infection of Vibrio cholerae according to microorganisms with antibacterial activity for enteric pathogenic bacteria and metabolites, used in various compositions according to an embodiment of the invention.
  • the mouse group administered with clindamycin may exhibit antibiotic resistance according to the decrease of the Bacteroidetes phylum including Bacteroides vulgatus microorganism having antibacterial activity for Vibrio cholerae .
  • metabolites having a high abundance ratio were observed in 50 mg of cecal contents obtained from each of a specific pathogen free mouse model group (SPF control mice) as a control group and a clindamycin-administered mouse model group (CL-treated mice).
  • the metabolites present in the cecal contents may be detected by Capillary Electrophoresis-Time of Flight Mass Spectrometry (CE-TOFMS) analysis.
  • CE-TOFMS Capillary Electrophoresis-Time of Flight Mass Spectrometry
  • the specific pathogen free mouse model group of the control having a relatively high abundance ratio of enteric Bacteroidetes phylum had a high abundance ratio for a metabolite such as butyric acid, isobutyric acid, cholic acid, propionic acid, valeric acid, isovaleric acid, trimethylamine, glucose 6-phosphate, fructose 6-phosphate, 2-hydroxyglutaric acid, 2-oxoglutaric acid, N -acetylglutamic acid, 3-(4-hydroxyphenyl) propionic acid, trans -glutaconic acid, and N -acetylaspartic acid.
  • a metabolite such as butyric acid, isobutyric acid, cholic acid, propionic acid, valeric acid, isovaleric acid, trimethylamine, glucose 6-phosphate, fructose 6-phosphate, 2-hydroxyglutaric acid, 2-oxoglutaric acid, N -acetylglutamic acid, 3-(4-hydroxyphenyl
  • cholic acid, butyric acid, isobutyric acid, propionic acid, valeric acid, and isovaleric acid may be short-chain fatty acids (SCFAs) providing an effective barrier against invasion of pathogens and inhibiting activity for pathogen.
  • SCFAs short-chain fatty acids
  • the short-chain fatty acid may be a metabolite produced by Bacteroides vulgatus microorganism used in various embodiments of the present disclosure and may be associated with antibacterial activity for enteric pathogenic bacteria.
  • the clindamycin-administered mouse group having a relatively high abundance ratio of enteric Proteobacteria phylum had a high abundance ratio for the metabolite such as urea, N -acetylgalactosamine/ N -acetylmannosamine/ N -acetylglucosamine, N-acetylneuraminic acid, creatine, gluconic acid, gluonic acid, glucuronic acid-1/galacturonic acid-1, glucaric acid, gluconolactone, galactosamine, glucosamine, mannosamine, putrescine, N -acetylalanine, and fumaric acid.
  • the metabolite such as urea, N -acetylgalactosamine/ N -acetylmannosamine/ N -acetylglucosamine, N-acetylneuraminic acid, creatine, gluconic acid, gluonic acid,
  • FIG. 4C among the metabolites found in the mouse group having a relatively high abundance ratio of Proteobacteria phylum, it is illustrated an evaluation result of inhibition of growth of Vibrio cholerae for A. fumaric acid, B. urea, and C. N -acetylgalactosamine (NAG), D. mannosamine, E. putrescine, F. gluconic acid, G. galacturonic acid, H. glucaric acid, and I. gluconolactone. Furthermore, among the metabolites found in the mouse group having a relatively high abundance ratio of Bacteroidetes phylum, it is further illustrated an evaluation result of inhibition of growth of Vibrio cholerae for J. cholic acid, K. isobutyric acid, L. propionic acid, M. valeric acid, and N. isovaleric acid.
  • Vibrio cholerae for J. cholic acid, K. isobutyric acid, L. propionic acid, M.
  • an M9 medium cultured with Vibrio cholerae was treated with 20 nM of the remaining metabolites except for N -acetylgalactosamine, gluconic acid, gluconolactone, mannoseamine, and cholic acid, and the growth of Vibrio cholerae was analyzed by measuring an OD 600 value.
  • N -acetylgalactosamine, gluconic acid, gluconolactone, mannoseamine and cholic acid were treated at concentrations of 4 nM, 4 nM, 10 nM, 1 nM, and 0.2 nM, respectively, in the M9 medium cultured with Vibrio cholerae , and then the OD 600 value was measured.
  • a culture group of Vibrio cholerae without addition of the metabolite was set as a control.
  • Vibrio cholerae was similar to the control or more active than the control.
  • A. fumaric acid, B. urea, C. N -acetylgalactosamine, E. putrescine, and H. glucaric acid stimulated the growth of Vibrio cholerae .
  • the above results may indicate that in a mouse group with antibiotic resistance, metabolites A to I, which are present at relatively high concentrations, may contribute to the antibiotic resistance of a host by rather stimulating the growth of Vibrio cholerae .
  • the microorganism of the present disclosure the metabolites J to N present at high concentrations inhibit the growth of Vibrio cholera.
  • they can provide antibacterial activity for enteric pathogenic bacteria such as Vibrio cholerae .
  • the metabolites of K. isobutyric acid, L. propionic acid, M. valeric acid, and N. isovaleric acid may be short-chain fatty acids produced by the Bacteroides vulgatus microorganism and may provide antibacterial activity to Vibrio cholerae .
  • the metabolites of J. cholic acid, K. isobutyric acid, L. propionic acid, M. valeric acid, and N. isovaleric acid may be used to enhance antibacterial activity together with the microorganism with antibacterial activity, in the compositions of various embodiments of the present disclosure.
  • FIG. 4D among the metabolites found in the mouse group having a relatively high abundance ratio of Proteobacteria phylum, it is illustrated an evaluation result for stimulation of the growth of Vibrio cholerae for A. fumaric acid, B. urea, and C. N -acetylgalactosamine, D. mannosamine, E. putrescine, F. gluconic acid, G. galacturonic acid, H. glucaric acid, and I. gluconolactone. Furthermore, among the metabolites found in the mouse group having a relatively high abundance ratio of Bacteroidetes phylum, it is further illustrated an evaluation result for stimulation of the growth of Vibrio cholerae for J. cholic acid, K. isobutyric acid, L. propionic acid, M. valeric acid, and N. isovaleric acid.
  • A. fumaric acid, C. N -acetylgalactosamine, F. gluconic acid, and I. gluconolactone stimulated the growth of Vibrio cholerae .
  • the above results may indicate that in a mouse group with antibiotic resistance, the metabolites A to I, which are present at relatively high concentrations, may contribute to the antibiotic resistance of a host by rather stimulating the growth of Vibrio cholerae .
  • the microorganism of the present disclosure the metabolites J to N present at high concentrations inhibit the growth of Vibrio cholera .
  • they can provide antibacterial activity for enteric pathogenic bacteria such as Vibrio cholerae .
  • the metabolites of K. isobutyric acid, L. propionic acid, M. valeric acid, and N. isovaleric acid may be short-chain fatty acids produced by the Bacteroides vulgatus microorganism and may provide antibacterial activity to Vibrio cholerae .
  • the metabolites of J. cholic acid, K. isobutyric acid, L. propionic acid, M. valeric acid, and N. isovaleric acid may be used to enhance antibacterial activity together with the microorganism with antibacterial activity, in the compositions of various embodiments of the present disclosure.
  • short-chain fatty acids including propionic acid, valeric acid and butyric acid produced by Bacteroides vulgatus ( B. vulgatus ) microorganism may form barriers to the intestinal wall.
  • the short-chain fatty acids may inhibit colony formation for enteric pathogenic bacteria such as V. cholerae , and as a result, provide antibacterial activity for Vibrio cholerae .
  • N -acetyl amino sugars such as N -acetylgalactosamine, N -acetylglucosamine and N -acetylneuramine may be produced in the intestine.
  • the N -acetyl amino sugar as described above may be used as a nutrient source of Vibrio cholerae .
  • the N -acetyl amino sugars may stimulate colony formation for enteric pathogenic bacteria, such as V. cholerae , and as a result, may cause antibiotic resistance.
  • the Bacteroides vulgatus microorganism may be used as a microorganism with antibacterial activity for enteric pathogenic bacteria, particularly, Vibrio cholerae .
  • the metabolites of cholic acid, butyric acid, isobutyric acid, propionic acid, valeric acid and isovaleric acid which inhibit the colony formation of Vibrio cholerae and have antibacterial activity for the bacteria may be provided as the pharmaceutical composition and the food composition according to various embodiments of the present disclosure together with the Bacteroides vulgatus microorganism.
  • the pharmaceutical composition and the food composition according to an embodiment of the present disclosure may have an improved effect for at least one selected from the group consisting of food poisoning, typhoid, peritonitis, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious diarrhea, gastroenteritis, inflammatory bowel disease, nervous enteritis syndrome, small intestinal bacterial overgrowth, intestinal acute diarrhea and ischemic enteritis.
  • the metabolites in the pharmaceutical composition and the food composition may be present at a concentration of 0.1 to 30 mM with respect to the composition but is not limited thereto.

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Abstract

L'invention concerne une composition pharmaceutique pour la prévention ou le traitement de maladies induites par des bactéries pathogènes entériques et une composition d'aliment pour l'amélioration d'une infection entérique par des bactéries pathogènes entériques, comprenant un micro-organisme Bacteroides vulgatus à activité antibactérienne pour des bactéries pathogènes entériques ou un milieu de culture de celui-ci, en tant que principe actif.
PCT/KR2019/011879 2018-09-14 2019-09-11 Micro-organisme à activité antibactérienne pour des bactéries pathogènes entériques et composition pharmaceutique pour la prévention et le traitement d'une maladie induite par des bactéries pathogènes entériques utilisant celui-ci WO2020055193A1 (fr)

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