WO2023140657A1 - Analyse de la flore intestinale chez des patients greffés du foie, surveillance ainsi de l'état de transplantation, et composition de théranostic immunomodulatrice - Google Patents

Analyse de la flore intestinale chez des patients greffés du foie, surveillance ainsi de l'état de transplantation, et composition de théranostic immunomodulatrice Download PDF

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WO2023140657A1
WO2023140657A1 PCT/KR2023/000969 KR2023000969W WO2023140657A1 WO 2023140657 A1 WO2023140657 A1 WO 2023140657A1 KR 2023000969 W KR2023000969 W KR 2023000969W WO 2023140657 A1 WO2023140657 A1 WO 2023140657A1
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composition
expression
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microbiome
transplantation
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Korean (ko)
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이순규
조미라
최종영
전주연
이승윤
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가톨릭대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • 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
    • 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
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/51—Bifidobacterium
    • A23V2400/517—Bifidum
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/51—Bifidobacterium
    • A23V2400/533—Longum

Definitions

  • the present invention relates to an analysis of the intestinal flora of a liver transplant patient, monitoring of transplantation status through the analysis, and an immunoregulatory theragnosis composition.
  • Organ, tissue or cell transplantation can be used to save the lives of patients suffering from various types of diseases. Allotransplantation of human organs such as kidney, liver, heart, kidney, lung, and pancreas, tissue such as skin, and bone marrow is already commonly performed in hospitals as a method for treating intractable diseases such as end-stage organ failure. In addition, xenotransplantation using a non-human mammal as a donor is also being actively researched as a method to replace the shortage of donors for allotransplantation. In particular, recently, transplantation of stem cells capable of regenerating themselves permanently and differentiating into various types of cells constituting the body under appropriate conditions has emerged as one of the cell replacement treatments for various intractable diseases.
  • Acute rejection is also a known risk factor for progression to chronic rejection and thus detection and treatment of acute rejection episodes as early as possible is a major goal to minimize graft damage and arrest downstream rejection episodes.
  • an adaptive immune response to the transplanted tissue is a major obstacle to successful transplantation. Rejection is caused by an immune response to alloantigens on the graft, which are proteins that vary from person to person within the species and are therefore recognized as foreign by the recipient.
  • Immunosuppression-related toxicities may be significant. For example, a number of studies in adult liver transplant recipients have demonstrated a time-dependent serial decline in renal function following exposure to immunosuppressive therapy. Other important complications of long-term immunosuppression include new onset of post transplant diabetes (NODAT), hypertension, hyperlipidemia and the need for statin therapy. To rectify this situation, research priorities in organ transplantation are shifting from the search for new potent immunosuppressive drugs to strategies to minimize immunosuppression, with the goal being to maintain the transplanted tissue for a long time without prolonged immunosuppression.
  • NODAT post transplant diabetes
  • the microbiome refers to microorganisms living in the human body, and includes the microorganisms in the intestine.
  • the number of microbiome is more than twice the number of pure human cells, and the number of genes is more than 100 times. Therefore, it is also called the Second Genome because it is impossible to discuss human genes without mentioning microorganisms.
  • the microbiome is a field that can be widely used in the development of new drugs and research on treatments for incurable diseases, as it can analyze the relationship between the principle of production of beneficial and harmful bacteria and diseases.
  • the microbiome is also used in the development of food, cosmetics, and therapeutics.
  • NGS Next Generation Sequencing
  • probiotics that can directly control the structure of the human intestinal microbiome are emerging.
  • probiotics have been known to be deeply related to the human microbiome through many studies, and their function as a regulator that changes the intestinal environment is attracting attention.
  • Ingestion of probiotics is known to promote digestion through microbiome regulation, as well as suppress inflammatory bowel disease, infectious diseases, and harmful bacteria.
  • Prebiotics are defined as "substances that are selectively used by beneficial bacteria conducive to health among host microorganisms", and dietary fiber and oligosaccharides serving as food for lactic acid bacteria are representative examples.
  • Synbiotics are a combination of probiotics and prebiotics.
  • postbiotics which has recently been attracting attention, is a material containing useful metabolites produced by probiotics and components of microorganisms, and is clearly defined as "a non-living form of microorganisms beneficial to the host's health or a formulation containing components of the microorganisms”.
  • the present inventors identified and selected a microbiome with reduced diversity and taxa in a patient group who received organ transplant treatment, and the selected strains improved the immunity of the patient group who received organ transplant treatment, and the metabolites of the strain also improved the immune response, thereby completing the present invention.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating transplant rejection, comprising sodium butyrate or microbiome as an active ingredient.
  • Another object of the present invention is to provide a food composition for preventing or improving transplant rejection, containing sodium butyrate or microbiome as an active ingredient.
  • Another object of the present invention is to administer a composition comprising sodium butyrate or a microbiome as an active ingredient to an individual; including, Faecalibacterium sp. Increases strains of liver transplant patients, and to provide a method for reducing Bacteroides sp. strains.
  • Another object of the present invention is a composition for preventing or treating transplant rejection, comprising sodium butyrate or microbiome as an active ingredient,
  • cytokine or chemokine selected from the group consisting of IL-17, GM-CSF, IL-6, IL-15, IFN- ⁇ , IL-2, IL-1 ⁇ , TNF- ⁇ and IL-8;
  • composition that increases the expression of anti-inflammatory cytokine IL-10 or T cell regulatory cytokine TGF- ⁇ .
  • Another object of the present invention is to provide a method for treating transplant rejection comprising administering to a subject a pharmaceutically effective amount of sodium butyrate or microbiome.
  • the present invention provides a pharmaceutical composition for preventing or treating transplant rejection, comprising sodium butyrate or microbiome as an active ingredient.
  • the present invention provides a food composition for preventing or improving transplant rejection, containing sodium butyrate or microbiome as an active ingredient.
  • the present invention includes the step of administering a composition containing sodium butyrate or a microbiome as an active ingredient to an individual; Faecalibacterium sp. Increases the strain of liver transplant patients, and provides a method for reducing the strain of Bacteroides sp .
  • the present invention is a composition for preventing or treating transplant rejection, comprising sodium butyrate or microbiome as an active ingredient,
  • cytokine or chemokine selected from the group consisting of IL-17, GM-CSF, IL-6, IL-15, IFN- ⁇ , IL-2, IL-1 ⁇ , TNF- ⁇ and IL-8;
  • the present invention provides a method for treating transplant rejection comprising administering to a subject a pharmaceutically effective amount of sodium butyrate or microbiome.
  • the present invention confirmed that the diversity of intestinal flora was reduced in the liver transplant patient group, and in particular, in the liver transplant patient group, it was confirmed that B. bifidum and B. longum , a microbiome of the genus Bifidobacterium known as intestinal beneficial bacteria , F. prausnitzii , a microbiome of the genus Faecalibacterium, and A. mucinipilla , a strain of the genus Acamencia, were significantly reduced.
  • FIG. 1 is a diagram illustrating the diversity of intestinal flora in liver transplant patients and healthy adults by ⁇ -diversity and ⁇ -diversity (A: Observed OTU and Shannon analysis results, B: PCoA plot and bray curstis distance analysis results).
  • LDA linear discriminant analysis
  • Figure 3 is a diagram comparing the intestinal flora of each group in a liver transplant patient group and a healthy adult group by analyzing with LEfSe (A: result of individual flora analysis, B: comparison of increased flora in each group).
  • Figure 4 is a comparison of strains increased or decreased in the liver transplant patient group and healthy adult group.
  • FIG. 5 is a diagram confirming the expression of immune cells in a liver transplant patient group and a healthy adult group by flow cytometry.
  • FIG. 6 is a diagram illustrating the diversity of intestinal flora according to the amount of immunosuppressant in the body in the liver transplant patient group by ⁇ -diversity and ⁇ -diversity (A: Observed OTU and Shannon analysis results, B: ⁇ -diversity analysis results).
  • LDA linear discriminant analysis
  • FIG. 8 is a diagram comparing strains that increase or decrease according to the amount of immunosuppressant in the body in a liver transplant patient group.
  • FIG. 9 is a diagram illustrating the diversity of intestinal flora in the liver transplant patient group and the immune tolerant patient group by ⁇ -diversity and ⁇ -diversity analysis (A: Observed OTU and Shannon analysis results, B: PCoA plot and bray curstis distance analysis results)
  • FIG. 10 is a diagram illustrating the analysis of taxa of intestinal flora in a liver transplant patient group and an immune tolerant patient group using linear discriminant analysis (LDA) effect size (LEfSe).
  • LDA linear discriminant analysis
  • 11 is a diagram comparing the intestinal microflora of individuals in each group in a liver transplant patient group and an immune tolerant patient group by LEfSe analysis.
  • FIG. 12 is a diagram comparing increased or decreased strains in a liver transplant patient group and an immune tolerant patient group.
  • FIG. 13 is a diagram confirming the expression of immune cells in a liver transplant patient group and an immune tolerant patient group by flow cytometry.
  • FIG. 14 is a diagram comparing differences in cytokine and chemokine expression between a liver transplant patient group and an immune tolerant patient group.
  • 15 is a diagram comparing differences in cytokine and chemokine expression between a liver transplant patient group and an immune tolerant patient group.
  • FIG. 16 is a flow cytometry analysis of Treg expression in PBMCs of a liver transplant patient group according to microbiome treatment (A: result of flow cytometry, B: quantification of Treg expression).
  • FIG. 17 is a flow cytometric analysis of Th17 expression in PBMC of a liver transplant patient group following microbiome treatment (A: result of flow cytometry, B: quantification of Th17 expression).
  • cytokine expression is an ELISA analysis of cytokine expression according to the treatment of the microbiome, which is reduced in PBMC of a liver transplant patient group (A: IL-17 expression quantification, B: IL-10 expression quantification, C: TGF- ⁇ expression quantification).
  • 19 is an ELISA analysis of the expression of IL-17 according to the treatment of sodium butyrate, a metabolite of the biobiome, in PBMCs of the liver transplant patient group.
  • the present invention provides a pharmaceutical composition for preventing or treating transplant rejection, comprising sodium butyrate or microbiome as an active ingredient.
  • prevention refers to any action that suppresses symptoms or delays the progression of a specific disease by administering the composition of the present invention.
  • treatment refers to all activities that improve or beneficially change the symptoms of a specific disease by administration of the composition of the present invention.
  • the pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient.
  • an adjuvant in addition to the active ingredient.
  • any one may be used without limitation, but, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the effect.
  • the pharmaceutical composition according to the present invention may be prepared in the form of incorporating the active ingredient into a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field.
  • Pharmaceutically acceptable carriers usable in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be prepared by mixing active ingredients with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like.
  • excipients for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to commonly used diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • As a base for suppositories witepsol, tween 61, cacao paper, laurin paper, glycerogelatin, and the like may be used.
  • composition according to the present invention can be administered to a subject by various routes. All modes of administration are contemplated, eg oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
  • the dosage of the pharmaceutical composition according to the present invention is selected in consideration of the age, weight, sex, and physical condition of the subject. It is obvious that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected according to the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 ⁇ g/ml. If the concentration is less than 0.01 ⁇ g/ml, pharmacological activity may not appear, and if the concentration exceeds 5,000 ⁇ g/ml, toxicity to the human body may be exhibited.
  • the microbiom is the FAECALIBACTERIUM Prausnitzii, Bifidobacterium Bipidum , Bifido Bacterium Long Sword ONGUM) and Akkermansia Muciniphilla may be a selected strain, but it is not limited thereto.
  • microbiome refers to the entire genetic information of microorganisms living in the human body or the microorganisms themselves. It is a compound word of microbiota and genome, which are microorganisms that live and coexist in the human body. It means a field that can be widely used in the study of the microbial environment in the human body, such as
  • the composition may regulate immune cells, and the immune cells may be Th17 or Treg.
  • regulating the immune cells may decrease Th17 expression or increase Treg expression.
  • the composition may reduce the expression of an inflammatory cytokine or chemokine selected from the group consisting of IL-17, GM-CSF, IL-6, IL-15, IFN- ⁇ , IL-2, IL-1 ⁇ , TNF- ⁇ , and IL-8.
  • an inflammatory cytokine or chemokine selected from the group consisting of IL-17, GM-CSF, IL-6, IL-15, IFN- ⁇ , IL-2, IL-1 ⁇ , TNF- ⁇ , and IL-8.
  • the composition may increase the expression of anti-inflammatory cytokine IL-10 or T cell regulatory cytokine TGF- ⁇ .
  • the transplant rejection may be one or more types of transplant rejection selected from the group consisting of cells, blood, tissues and organs.
  • the transplant rejection may be at least one selected from the group consisting of bone marrow transplantation, heart transplantation, corneal transplantation, intestinal transplantation, liver transplantation, lung transplantation, pancreas transplantation, kidney transplantation, and skin transplantation rejection.
  • the present invention provides a food composition for preventing or improving transplant rejection, containing sodium butyrate or microbiome as an active ingredient.
  • the term “improvement” refers to any action that at least reduces a parameter associated with the condition being treated, eg, the severity of a symptom.
  • the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional food compositions.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents thaumatin
  • stevia extracts eg rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the food composition of the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods.
  • Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements.
  • the food composition may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like.
  • the food composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages.
  • the functional food composition of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or treating transplant rejection.
  • 'health functional food composition' refers to a food manufactured and processed using raw materials or ingredients having useful functionalities for the human body in accordance with Act No. 6727 on Health Functional Foods, and nutrients for the structure and function of the human body.
  • the health functional food of the present invention may contain ordinary food additives, and its suitability as a food additive is determined by the standards and standards for the item in accordance with the General Rules and General Test Methods of Food Additives approved by the Korea Food and Drug Administration, unless otherwise specified.
  • Examples of the items listed in the 'Food Additive Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.
  • chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid
  • natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum
  • mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.
  • a health functional food in the form of a tablet is a mixture obtained by mixing the active ingredient of the present invention with excipients, binders, disintegrants, and other additives, granulated in a conventional manner, and then compression-molded by adding a lubricant or the like, or the mixture can be directly compressed.
  • the health functional food in the form of a tablet may contain a flavoring agent and the like as needed.
  • hard capsules can be prepared by filling ordinary hard capsules with a mixture of the active ingredient of the present invention mixed with additives such as excipients
  • soft capsules can be prepared by filling a mixture of the active ingredient of the present invention mixed with additives such as excipients into a capsule base such as gelatin.
  • the soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
  • the health functional food in the form of a pill can be prepared by molding a mixture of the active ingredient of the present invention mixed with an excipient, a binder, a disintegrant, etc.
  • a health functional food in the form of granules may be prepared in a granular form by a conventionally known method of mixing an excipient, a binder, a disintegrant, etc. of the active ingredient of the present invention, and may contain a flavoring agent, a flavoring agent, etc., if necessary.
  • the present invention includes the step of administering a composition containing sodium butyrate or a microbiome as an active ingredient to an individual; Faecalibacterium sp. Increases the strain of liver transplant patients, and provides a method for reducing the strain of Bacteroides sp .
  • the present invention is a composition for preventing or treating transplant rejection, comprising sodium butyrate or microbiome as an active ingredient,
  • cytokine or chemokine selected from the group consisting of IL-17, GM-CSF, IL-6, IL-15, IFN- ⁇ , IL-2, IL-1 ⁇ , TNF- ⁇ and IL-8;
  • the present invention provides a method for treating transplant rejection comprising administering to a subject a pharmaceutically effective amount of sodium butyrate or microbiome.
  • the treatment method of the present invention comprises administering to a subject a therapeutically effective amount of the sodium butyrate or microbiome.
  • the specific therapeutically effective amount for a specific individual is preferably applied differently depending on the type and degree of response to be achieved, the specific composition including whether other agents are used as the case may be, the individual's age, body weight, general health condition, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, various factors including drugs used together with or concurrently used with the specific composition, and similar factors well known in the medical field.
  • the daily dosage is 0.0001 to 100 mg/kg, preferably 0.01 to 100 mg/kg, based on the amount of the pharmaceutical composition of the present invention, and may be administered 1 to 6 times a day.
  • the dosage or dosage of each active ingredient should be such that the content of each active ingredient is too high to prevent side effects. Therefore, the effective amount of the composition suitable for the purpose of the present invention is preferably determined in consideration of the above.
  • the subject is applicable to any mammal, and the mammal includes humans and primates as well as livestock such as cattle, pigs, sheep, horses, dogs, and cats.
  • the sodium butyrate or microbiome of the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes. All modes of administration can be envisaged, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • liver transplantation Liver transplantation, LT
  • healthy adult healthy control, H
  • fecal samples from healthy adults and liver transplant patients were collected and stored at -70°C until analysis.
  • metagenome analysis bacterial genomic DNA isolation, microbial-specific 16S rRNA gene amplification, next-generation sequencing (NGS) analysis, and gut flora analysis and profiling were analyzed.
  • NGS next-generation sequencing
  • gut flora analysis and profiling were analyzed.
  • the gene was amplified with primers prepared at a site capable of containing the V3 and V4 parts of the variant region among the bacterial-specific 16S gene sequences, and an index sequence capable of distinguishing samples was attached.
  • PCR was performed twice to construct a library, and sequencing was performed using Illumina's Miseq.
  • Intestinal flora profiling was performed using Quantitative Insights into Microbiological Ecology 2 (QIIME 2) and Lefse, which are bioinformatic analysis tools, and Prism and R for statistical processing.
  • QIIME 2 Quantitative Insights into Microbiological Ecology 2
  • Lefse which are bioinformatic analysis tools, and Prism and R for statistical processing.
  • ⁇ -diversity analysis and ⁇ -diversity analysis were performed to analyze the similarity between each group.
  • Observed OTUs and Shannon analysis were performed for ⁇ -diversity analysis, and PCoA plot analysis was performed based on bray curstis distance for ⁇ -diversity analysis.
  • Th17 cells which are known to be pathological cells in autoimmunity
  • Treg cells which are known to regulate various pathological T cells
  • the purpose of this study was to examine changes in the intestinal flora according to immunosuppressant (IS) administration in liver transplant patients. Specifically, the same analysis as in Examples 1-1 to 1-2 was used. Specifically, the ratio of concentration in the body to immunosuppressant dose was calculated in the liver transplant patient group, and based on the median value of DC (Drug Concentrations), the group was classified into a group with a value of 1.6 or less and a group with a DC value exceeding 1.6, and differences according to the dosage of the immunosuppressant were confirmed. The clinical characteristics of each group are shown in Table 1 below.
  • the purpose of this study was to determine whether there was a difference in the intestinal microbiota between liver transplant patients and patients who maintained immune tolerance without taking immunosuppressive drugs after liver transplantation. Specifically, in the same manner as in Examples 1-1 and 1-2, the intestinal flora of the liver transplant patient group (LT) and the immune tolerance group (Tolerance, T) were compared. In addition, the analysis of immune cells for each group was confirmed in the same manner as in Examples 1-3. The clinical and demographic parameters of patients in each group are shown in Table 2 below.
  • cytokines and chemokines were compared between liver transplant patients and immune cells of patients who maintained immune tolerance without taking immunosuppressive drugs after liver transplantation.
  • the analyzed cytokines and chemokines include granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine ligand (CCL), C-X-C motif chemokine ligand (CXCL), IFN- ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-6, IL-8, IL-12p70, IL-15, IL-23, IP-10 (interferon ⁇ - induced protein), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 ⁇ (MIP-1 ⁇ ), and tumor necrosis factor- ⁇ (TNF- ⁇ ) were analyzed.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • CCL chemokine ligand
  • CXCL C-X-C motif chemok
  • ProcartaPlex Human 14-Plex (PPX-14-MXPRMK7) panel InvitrogenTM, Thermo Fisher Scientific, Massachusetts, USA) multiple cytokine assays were analyzed using Luminex® xMAPTM fluorescent bead-based technology (Luminex Corporation, 12,212 Technology Blvd, Austin, TX, 78727, USA).
  • PBMCs peripheral blood mononuclear cells
  • mucinipilla a strain of the genus Acamencia, respectively, and cultured for 3 days, using flow cytometry to detect Th17 and immune regulatory cells, Treg cells.
  • the expression of was confirmed and, using ELISA, the expression of IL-17, an inflammatory cytokine, IL-10, an anti-inflammatory cytokine, and transforming growth factor beta (TGF- ⁇ ), a T cell regulatory cytokine, were confirmed.
  • a control group a vehicle group cultured by treating normal PBMC (Nil) and patient-derived PBMC with PBS was used.
  • sodium butyrate a metabolite of a strain of the genus Faecalibacterium, has an anti-inflammatory effect in liver transplant patients
  • sodium butyrate was treated with 0.5 mM and 1 mM, respectively, in the same manner as in the ELISA described above, and the expression of IL-17 was confirmed.
  • the present invention confirmed that the diversity of intestinal flora was reduced in the liver transplant patient group, and in particular, in the liver transplant patient group, it was confirmed that B. bifidum and B. longum , a microbiome of the genus Bifidobacterium known as intestinal beneficial bacteria , F. prausnitzii , a microbiome of the genus Faecalibacterium, and A. mucinipilla , a strain of the genus Acamencia, were significantly reduced.

Abstract

La présente invention se rapporte à une composition de métabolite de microbiome destinée au diagnostic spécifique et au théranostic thérapeutique de patients greffés du foie. La présente invention a confirmé que la diversité de la flore intestinale était réduite dans un groupe de patients greffés du foie, et a confirmé que B. bifidum et B. longum, qui sont des microbiomes dans bifidobacterium connus comme des bactéries bénéfiques dans l'intestin, F. prausnitzii, qui est un microbiome dans faecalibacterium, et A. muciniphilla, qui est une souche du genre Akkermancia, étaient significativement réduits. De plus, il a été confirmé que lorsque la souche de microbiome ou le butyrate de sodium, qui est un métabolite de la souche, était traité avec des PBMC dérivées d'un patient greffé du foie, l'expression de Th17 et de Treg, qui sont des cellules immunitaires du groupe de patients greffés du foie, était régulée. En outre, il a été confirmé que l'expression de l'IL-17, du GM-CSF, de l'IL-6, de l'IL-15, de l'IFN-α, de l'IL-2, de l'IL-1β TNF-α et de l'IL-8, qui sont des cytokines ou chimiokines inflammatoires, était inhibée, et que l'expression de l'IL-10, qui est une cytokine anti-inflammatoire, et du TGF-β, qui est une cytokine régulatrice de lymphocytes T, était augmentée. Par conséquent, il a été confirmé que le médicament personnalisé peut être réalisé par diagnostic du rapport de composition et des anomalies de la flore intestinale d'un groupe de patients greffés du foie et par confirmation de l'augmentation de la flore intestinale utile selon le traitement d'une substance active de la présente invention.
PCT/KR2023/000969 2022-01-20 2023-01-19 Analyse de la flore intestinale chez des patients greffés du foie, surveillance ainsi de l'état de transplantation, et composition de théranostic immunomodulatrice WO2023140657A1 (fr)

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