Intestinal fungi contribute to development of alcoholic liver disease
An-Ming Yang, … , Derrick E. Fouts, Bernd Schnabl
An-Ming Yang, … , Derrick E. Fouts, Bernd Schnabl
Published June 30, 2017; First published May 22, 2017
Citation Information: J Clin Invest. 2017;127(7):2829-2841. https://doi.org/10.1172/JCI90562.
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Categories: Research Article Hepatology

Intestinal fungi contribute to development of alcoholic liver disease

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.

Authors

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. Mehal, Guadalupe Garcia-Tsao, Ece A. Mutlu, Ali Keshavarzian, Gordon D. Brown, Samuel B. Ho, Ramon Bataller, Peter Stärkel, Derrick E. Fouts, Bernd Schnabl

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Figure 4

Fungal products induce IL-1β in Kupffer cells.

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Fungal products induce IL-1β in Kupffer cells. (A–C) C57BL/6 mice were f...
(A–C) C57BL/6 mice were fed an oral control diet (n = 5–11) or ethanol diet (n = 13–15) and given vehicle or amphotericin B (Ampho B). (A) Hepatic expression of Il1b mRNA. (B) Hepatic levels of IL-1β protein. (C) Immunofluorescence analysis of F4/80 (red) and IL-1β (green) (representative liver sections); nuclei are blue. (D–F) C57BL/6 mice underwent transplantation of WT or Clec7a–/– bone marrow (Clec7aΔBM) and were fed an oral control diet (n = 5) or ethanol diet (n = 8–10). (D) Hepatic expression of Il1b mRNA. (E) Hepatic levels of IL-1β protein. (F) Immunofluorescence analysis of F4/80 (red) and IL-1β (green) (representative liver sections); nuclei are blue. Arrowheads indicate double-positive cells. Scale bars: 50 μm. Unpaired Student’s t test. *P < 0.05.