title: Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice.
abstract: Translocation of bacteria and their products across the intestinal barrier is common in patients with liver disease, and there is evidence that experimental liver fibrosis depends on bacterial translocation. The purpose of our study was to investigate liver fibrosis in conventional and germ-free (GF) C57BL/6 mice. Chronic liver injury was induced by administration of thioacetamide (TAA) in the drinking water for 21 wk or by repeated intraperitoneal injections of carbon tetrachloride (CCl4). Increased liver fibrosis was observed in GF mice compared with conventional mice. Hepatocytes showed more toxin-induced oxidative stress and cell death. This was accompanied by increased activation of hepatic stellate cells, but hepatic mediators of inflammation were not significantly different. Similarly, a genetic model using Myd88/Trif-deficient mice, which lack downstream innate immunity signaling, had more severe fibrosis than wild-type mice. Isolated Myd88/Trif-deficient hepatocytes were more susceptible to toxin-induced cell death in culture. In conclusion, the commensal microbiota prevents fibrosis upon chronic liver injury in mice. This is the first study describing a beneficial role of the commensal microbiota in maintaining liver homeostasis and preventing liver fibrosis.
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mazagova
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Lirui
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Anfora
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Wissmueller
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lesley
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Suraj
authors.initials: S
authors.lastname: Dhungana
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Wimal
authors.initials: W
authors.lastname: Pathmasiri
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Sumner
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Westwater
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.affiliation: *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA beschnabl@ucsd.edu.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000382:microbiology; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D020011:Protective Agents; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013853:Thioacetamide / Q000494:pharmacology*
chemical_list: D020011:Protective Agents; D012333:RNA, Messenger; D013853:Thioacetamide
keywords: bacterial translocation; innate immune system; microbiome