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Demir M, Lang S, Hartmann P, et al. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol. 2021;doi: 10.1016/j.jhep.2021.11.029.
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. (2021). The fecal mycobiome in non-alcoholic fatty liver disease. Journal of hepatology, . https://doi.org/10.1016/j.jhep.2021.11.029
Demir, Münevver, et al. "The fecal mycobiome in non-alcoholic fatty liver disease." Journal of hepatology vol. (2021). doi: https://doi.org/10.1016/j.jhep.2021.11.029
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 HM, Goeser T, Kruglov A, Eckmann L, Stärkel P, Fouts DE, Schnabl B. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol. 2021 Dec 09; doi: 10.1016/j.jhep.2021.11.029. Epub 2021 Dec 09. PMID: 34896404.
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J Hepatol. 2021 Dec 09; doi: 10.1016/j.jhep.2021.11.029. Epub 2021 Dec 09.

The fecal mycobiome in non-alcoholic fatty liver disease.

Journal of hepatology

Münevver Demir, Sonja Lang, Phillipp Hartmann, Yi Duan, Anna Martin, Yukiko Miyamoto, Marina Bondareva, Xinlian Zhang, Yanhan Wang, Philipp Kasper, Corinna Bang, Christoph Roderburg, Frank Tacke, Hans-Michael Steffen, Tobias Goeser, Andrey Kruglov, Lars Eckmann, Peter Stärkel, Derrick E Fouts, Bernd Schnabl

Affiliations

  1. Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
  2. University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  3. Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
  4. Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  5. University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany.
  6. Belozerskiy Research Institute for Physical and Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, 119991, Russia; Chronic Inflammation Lab, German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany.
  7. Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
  8. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
  9. Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany; Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  10. St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
  11. Department of Genomic Medicine, J. Craig Venter Institute, Rockville, MD, USA.
  12. Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address: [email protected].

PMID: 34896404 DOI: 10.1016/j.jhep.2021.11.029

Abstract

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 NAFLD patients, 16 controls and 73 patients with alcohol use disorder (AUD). Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 NAFLD patients. 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 anti-fungal 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 NAFLD patients with advanced fibrosis as compared with AUD patients and advanced fibrosis. Plasma anti-C. albicans IgG was increased in NAFLD patients with advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis.

CONCLUSIONS: Non-obese NAFLD patients with more advanced disease have a different fecal mycobiome composition than non-obese NAFLD patients 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.

Published by Elsevier B.V.

Keywords: Fungi; NAFLD; NASH; gut pathogens; metagenomics; microbiome; microbiota

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