The fecal mycobiome in non-alcoholic fatty liver disease
Open accessAbstract
Background & aims Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis.Methods We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B.Results The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis.Conclusions Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH.Lay summary Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage.
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MASH dysbiosis incorporates an altered fungal flora, and antifungals have some efficacy in reducing disease severity and fibrosis in germ-free mice.
“MASH dysbiosis also incorporates an altered fungal flora, with some efficacy of antifungals in reducing disease severity and fibrosis in germ-free mice (209).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [209]
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- Authors
- Demir, M., Lang, S., Hartmann, P., Duan, Y., Martin, A., Miyamoto, Y., Bondareva, M., Zhang, X., Wang, Y., Kasper, P., Bang, C., Roderburg, C., Tacke, F., Steffen, H.-M., Goeser, T., Kruglov, A., Eckmann, L., Stärkel, P., Fouts, D. E., & Schnabl, B.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- University of Cologne (DE)
- University of California San Diego (US)
- Lomonosov Moscow State University (RU)
- Christian-Albrechts-Universität zu Kiel (DE)
- Düsseldorf University Hospital (DE)
- UCLouvain (BE)
- J. Craig Venter Institute (US)
- Corresponding author
- Schnabl, Bernd
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 76
- Issue
- 4
- Pages
- 788-799
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC8981795
- OpenAlex
- W4200510289
- Cited by
- 197
- References
- 22
- Citations by year
- 2026: 33 · 2025: 52 · 2024: 47 · 2023: 38 · 2022: 27
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Veterans Health Administration Biomedical Laboratory Research and Development (BX004594)
- Marga und Walter Boll-Stiftung (210-03-2016)
- Russian Science Foundation
- Universität zu Köln (160/2014)
- AASLD
- Automotive Research Center
- Biocodex Microbiota Foundation
- California Department of Fish and Game
- DFG (LA 4286/1-1)
- Université Catholique de Louvain (U01 AA026939-04S1, U01 AA026939, R01 AA020703, R01 AA024726)
- Fond National de la Recherche Scientific (T.0217.18)
- Russian Academy of Sciences (21-14-00223)
- NIH (U01 AA026939, R01 AA024726, R01 AA020703, K12 HD85036)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, gut-liver axis, Candida albicans, Mucor, Saccharomyces cerevisiae, liver fibrosis, gnotobiotic mouse model, amphotericin B, antifungal therapy
- MeSH terms
- Gastrointestinal Microbiome, Mycobiome, Animals, Feces, Humans, Liver, Saccharomyces cerevisiae, Mice, Non-alcoholic Fatty Liver Disease
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