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J Clin Invest. 2017 Jun 30;127(7):2829-2841. doi: 10.1172/JCI90562. Epub 2017 May 22.

Intestinal fungi contribute to development of alcoholic liver disease.

Author information

1
Department of Medicine, UCSD, La Jolla, California, USA.
2
Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan.
3
Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
4
Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA.
5
Department of Surgery, UCSD, La Jolla, California, USA.
6
J. Craig Venter Institute, La Jolla, California, USA.
7
Institute of Systems Biology and Bioinformatics, National Central University, Taoyuan City, Taiwan.
8
Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
9
Department of General, Visceral and Transplantation Surgery, Hospital of the LMU Munich, Munich, Germany.
10
Department of Pediatrics, UCSD, La Jolla, California, USA.
11
Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
12
Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
13
Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
14
Aberdeen Fungal Group, Medical Research Council Centre for Medical Mycology, University of Aberdeen, Aberdeen, United Kingdom.
15
Liver Center, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
16
Saint Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
17
J. Craig Venter Institute, Rockville, Maryland, USA.

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.

PMID:
28530644
PMCID:
PMC5490775
DOI:
10.1172/JCI90562
[Indexed for MEDLINE]
Free PMC Article

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