Intestinal fungi contribute to development of alcoholic liver disease

• Published in: The Journal of clinical investigation 2017-06, Vol.127 (7), p.2829-2841
• Main Authors: Yang, An-Ming, Inamine, Tatsuo, Hochrath, Katrin, Chen, Peng, Wang, Lirui, Llorente, Cristina, Bluemel, Sena, Hartmann, Phillipp, Xu, Jun, Koyama, Yukinori, Kisseleva, Tatiana, Torralba, Manolito G, Moncera, Kelvin, Beeri, Karen, Chen, Chien-Sheng, Freese, Kim, Hellerbrand, Claus, Lee, Serene Ml, Hoffman, Hal M, Mehal, Wajahat Z, Garcia-Tsao, Guadalupe, Mutlu, Ece A, Keshavarzian, Ali, Brown, Gordon D, Ho, Samuel B, Bataller, Ramon, Stärkel, Peter, Fouts, Derrick E, Schnabl, Bernd
• Format: Article
• Language: English
• Subjects: Alcohol; Alcoholism; Animals; Antifungal agents; Bacteria; Bioinformatics; Biomedical research; Bone marrow; Candida - growth & development; Care and treatment; Cirrhosis; Cytokines; Death; Development and progression; Ethanol; Fungi; Gastrointestinal Microbiome; Health aspects; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Immune response; Intestine; Intestines - microbiology; Kupffer cells; Kupffer Cells - metabolism; Kupffer Cells - pathology; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Liver cirrhosis; Liver diseases; Liver Diseases, Alcoholic - genetics; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - microbiology; Liver Diseases, Alcoholic - pathology; Mice; Mice, Knockout; Microbiota (Symbiotic organisms); Mortality; Plasma
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI90562

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.