期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 7, 页码 2829-2841出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI90562
关键词
-
资金
- NIH [R01 AA020703, U01 AA24726, U01 AA021856, RC2 AA019405, R01 AA020216, R01 AA023417]
- Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [I01BX002213]
- DFG [HO/5690/1-1]
- Swiss National Science Foundation [P2SKP3_158649]
- Yale Liver Center NIH [P30 DK34989]
- National Institute on Alcohol Abuse and Alcoholism [U01 AA021908]
- Wellcome Trust
- MRC [MR/N006364/1] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [P2SKP3_158649] Funding Source: Swiss National Science Foundation (SNF)
- Medical Research Council [MR/N006364/1] Funding Source: researchfish
- Wellcome Trust [102705/Z/13/Z] Funding Source: researchfish
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 beta-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased beta-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that beta-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-1 beta 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.
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