دورية أكاديمية
أعرض في EDS

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC.

التفاصيل البيبلوغرافية
العنوان: Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC.
المؤلفون: Awoniyi M; Division of Gastroenterology and Hepatology, University of North Carolina System, Chapel Hill, North Carolina, USA.; Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA., Wang J; Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA.; Department of Genetics, University of North Carolina System, Chapel Hill, North Carolina, USA., Ngo B; Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA., Meadows V; Department of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana, USA., Tam J; Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina, USA., Viswanathan A; Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA., Lai Y; Department of Environmental Sciences and Engineering, Gillings School of Global School of Public Health, University of North Carolina System, Chapel Hill, North Carolina, USA., Montgomery S; Department of Pathology, Division of Comparative Medicine, and Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA., Farmer M; Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA., Kummen M; Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Thingholm L; Institute of Clinical Molecular Biology, Zentrums für Molekulare Biowissenschaften, Kiel, Schleswig-Holstein, Germany., Schramm C; University Medical Centre Hamburg-Eppendorf, Hamburg, Germany., Bang C; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Lu K; Department of Environmental Sciences and Engineering, Gillings School of Global School of Public Health, University of North Carolina System, Chapel Hill, North Carolina, USA.; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Zhou H; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.; Department of Research, McGuire Veterans Affairs Medical Cente, Richmond, Virginia, USA.; Virginia Commonwealth University Medical Center, Richmond, Virginia, USA., Bajaj JS; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.; Department of Research, McGuire Veterans Affairs Medical Cente, Richmond, Virginia, USA.; Virginia Commonwealth University Medical Center, Richmond, Virginia, USA., Hylemon PB; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.; Department of Research, McGuire Veterans Affairs Medical Cente, Richmond, Virginia, USA.; Virginia Commonwealth University Medical Center, Richmond, Virginia, USA., Ting J; Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina, USA.; UNC Lineberger Comprehensive Cancer Center, Center for Translational Immunology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA., Popov YV; Department of Gastroenterology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA., Hov JR; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway., Francis HL; Indiana University School of Medicine, Indianapolis, Indiana, USA.; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA., Sartor RB; Division of Gastroenterology and Hepatology, University of North Carolina System, Chapel Hill, North Carolina, USA ryan_balfour_sartor@med.unc.edu.; Center for Gastrointestinal Biology and Disease, University of North Carolina System, Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina, USA.
المصدر: Gut [Gut] 2023 Apr; Vol. 72 (4), pp. 671-685. Date of Electronic Publication: 2022 Jun 15.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: British Medical Assn Country of Publication: England NLM ID: 2985108R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-3288 (Electronic) Linking ISSN: 00175749 NLM ISO Abbreviation: Gut Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London, British Medical Assn.
مواضيع طبية MeSH: Vancomycin* , Escherichia coli*, Animals ; Mice ; Disease Models, Animal ; RNA, Ribosomal, 16S/genetics ; Inflammation ; Liver Cirrhosis ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Clostridiales
مستخلص: Objective: Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models.
Goal: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient ( mdr2 -/- ) mice and microbial profiles in PSC patient cohorts.
Design: We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2 -/- mice and targeted metagenomic analysis in PSC patients.
Results: GF mdr2 -/- mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2 -/- mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2 -/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients' clinical severity by Mayo risk scores.
Conclusions: We identified novel functionally protective and detrimental resident bacterial species in mdr2 -/- mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.
Competing Interests: Competing interests: RBS has consulted for and received grant support from Takeda, Janssen, Second Genome, Vedanta, BiomX, Biomica, SERES and Artizan; JRH has served on advisory boards and/or given lectures for Orkla Health, Novartis, Amgen and Roche, and received research support from Biogen, all unrelated to the present study.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
التعليقات: Comment in: Gut. 2023 Apr;72(4):607-608. (PMID: 35764378)
معلومات مُعتمدة: R01 DK108959 United States DK NIDDK NIH HHS; P30 DK034987 United States DK NIDDK NIH HHS; I01 CX001076 United States CX CSRD VA; K01 DK119582 United States DK NIDDK NIH HHS; I01 BX005730 United States BX BLRD VA; IS1 BX004777 United States BX BLRD VA; U19 AI067798 United States AI NIAID NIH HHS; I01 BX003031 United States BX BLRD VA; T32 DK007737 United States DK NIDDK NIH HHS; R01 DK115377 United States DK NIDDK NIH HHS; I01 BX004033 United States BX BLRD VA; R35 CA232109 United States CA NCI NIH HHS; R21 TR003095 United States TR NCATS NIH HHS; I01 BX001328 United States BX BLRD VA; P01 DK094779 United States DK NIDDK NIH HHS; R21 AA026629 United States AA NIAAA NIH HHS; IK6 BX004477 United States BX BLRD VA; P40 OD010995 United States OD NIH HHS; R01 DK119421 United States DK NIDDK NIH HHS; IK6 BX005226 United States BX BLRD VA; R01 DK104893 United States DK NIDDK NIH HHS; R01 DK057543 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: antibiotics; cholestatic liver diseases; intestinal microbiology; primary sclerosing cholangitis; short chain fatty acids
المشرفين على المادة: 6Q205EH1VU (Vancomycin)
0 (RNA, Ribosomal, 16S)
0 (Anti-Bacterial Agents)
تواريخ الأحداث: Date Created: 20220615 Date Completed: 20230309 Latest Revision: 20240207
رمز التحديث: 20240207
مُعرف محوري في PubMed: PMC9751228
DOI: 10.1136/gutjnl-2021-326500
PMID: 35705368
قاعدة البيانات: MEDLINE
الوصف
تدمد:1468-3288
DOI:10.1136/gutjnl-2021-326500