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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.

SUBMITTER: Mazagova M

PROVIDER: S-EPMC4422368 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice.

Mazagova Magdalena M Wang Lirui L Anfora Andrew T AT Wissmueller Max M Lesley Scott A SA Miyamoto Yukiko Y Eckmann Lars L Dhungana Suraj S Pathmasiri Wimal W Sumner Susan S Westwater Caroline C Brenner David A DA Schnabl Bernd B

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20141202 3

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). Incr ...[more]

PMID: 25466902

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Project description:Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-κB by editing the ubiquitylation of target molecules with its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mouse develops age-dependent inflammatory constitution in multiple organs including heart, liver, skin and succumb to premature heart failure. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed that the 588 transcription alterations. SAA3 (serum amyloid A3), at 1,180-fold induction (FI), CHI3L1(361-FI), HP(187-FI), IL1B(122-FI) and SPP1/OPN(101-FI) and WIF1 (Wnt inhibitory factor 1) at 11-fold decrease implied extensive inflammation and tissue degeneration at this microenvironment. Intense Saa3 staining and significant reduction of I-κBα at the same area, massive infiltration of inflammatory lymphocytes and edema formation at the peripheral areas of sinoatrial and atrioventricular node were also observed and electrocardiogram indicated atrioventricular conduction defect (elongated PQ-interval) in TAX1BP1-KO mice. Since antibiotics-induced ‘germ free’ status for three months significantly ameliorated these chronic autoimmune and altered cardiac excitation properties, we conclude that these chronic pathological conditions, as we named ‘pseudo-infective endocarditis’ were boosted by the commensal microbiota those who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation and cardiac dysfunction. We employed laser capture microdissection (LCM) and gene expression microarray technique to obtain the specific gene expression information of pathologic organ. Total RNAs of mitral valves from three independent tissues of 8- or 16-week age (-wk) male mice of either WT or TAX1BP1-KO mice were prepared by LCM followed by total RNA extraction kit. Then the global mRNA expression profiles were analyzed by Agilent gene expression microarray.

Dataset Information

Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice.

Publications

Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice.

Similar Datasets

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