Demir, Munevver ORCID: 0000-0002-7050-797X, Lang, Sonja, Hartmann, Phillipp ORCID: 0000-0003-3658-3335, Duan, Yi, Martin, Anna, Miyamoto, Yukiko, Bondareva, Marina ORCID: 0000-0001-7893-0580, Zhang, Xinlian, Wang, Yanhan, Kasper, Philipp ORCID: 0000-0002-6218-2239, Bang, Corinna, Roderburg, Christoph, Tacke, Frank, Steffen, Hans-Michael, Goeser, Tobias, Kruglov, Andrey ORCID: 0000-0002-4597-2087, Eckmann, Lars, Starkel, Peter, Fouts, Derrick E. and Schnabl, Bernd (2022). The fecal mycobiome in non-alcoholic fatty liver disease. J. Hepatol., 76 (4). S. 788 - 801. AMSTERDAM: ELSEVIER. ISSN 1600-0641

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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 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 antiC. 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. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Demir, MunevverUNSPECIFIEDorcid.org/0000-0002-7050-797XUNSPECIFIED
Lang, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, PhillippUNSPECIFIEDorcid.org/0000-0003-3658-3335UNSPECIFIED
Duan, YiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miyamoto, YukikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bondareva, MarinaUNSPECIFIEDorcid.org/0000-0001-7893-0580UNSPECIFIED
Zhang, XinlianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, YanhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kasper, PhilippUNSPECIFIEDorcid.org/0000-0002-6218-2239UNSPECIFIED
Bang, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roderburg, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tacke, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steffen, Hans-MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goeser, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kruglov, AndreyUNSPECIFIEDorcid.org/0000-0002-4597-2087UNSPECIFIED
Eckmann, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Starkel, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fouts, Derrick E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnabl, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-694111
DOI: 10.1016/j.jhep.2021.11.029
Journal or Publication Title: J. Hepatol.
Volume: 76
Number: 4
Page Range: S. 788 - 801
Date: 2022
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 1600-0641
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PERITONITIS; MICROBIOTA; FUNGIMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69411

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