Intestinal fungi contribute to development of alcoholic liver disease

An-Ming Yang, Tatsuo Inamine, Katrin Hochrath, Peng Chen, Lirui Wang, Cristina Llorente, Sena Bluemel, Phillipp Hartmann, Jun Xu, Yukinori Koyama, Tatiana Kisseleva, Manolito G. Torralba, Kelvin Moncera, Karen Beeri, Chien-Sheng Chen, Kim Freese, Claus Hellerbrand, Serene M.L. Lee, Hal M. Hoffman, Wajahat Z. MehalGuadalupe Garcia-Tsao, Ece A. Mutlu, Ali Keshavarzian, Gordon D. Brown, Samuel B Ho, Ramon Bataller, Peter Stärkel, Derrick E. Fouts, Bernd Schnabl

Research output: Contribution to journalArticlepeer-review

326 Citations (Scopus)
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Abstract

Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin–like receptor CLEC7A on Kupffer cells and possibly other bone marrow–derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.
Original languageEnglish
Pages (from-to)2829-2841
Number of pages13
JournalThe Journal of Clinical Investigation
Volume127
Issue number7
Early online date22 May 2017
DOIs
Publication statusPublished - 1 Jul 2017

Bibliographical note

This study was supported in part by NIH grants R01 AA020703, U01 AA021856 and by Award Number I01BX002213 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.). K.H. was supported by a DFG (Deutsche Forschungsgemeinschaft) fellowship (HO/ 5690/1-1). S.B. was supported by a grant from the Swiss National Science Foundation (P2SKP3_158649). G.G. received funding from the Yale Liver Center NIH P30 DK34989 and R.B. from NIAAA grant U01 AA021908. A.K. received support from NIH grants RC2 AA019405, R01 AA020216 and R01 AA023417. G.D.B. is supported by funds from the Wellcome Trust. We acknowledge the Human Tissue and Cell Research (HTCR) Foundation for making human tissue available for research and Hepacult GmbH (Munich, Germany) for providing primary human hepatocytes for in vitro analyses. We thank Dr. Chien-Yu Lin Department of Medicine, Fu-Jen Catholic University, Taiwan for statistical analysis.

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