Yin, Yuhan and Sichler, Anna and Ecker, Josef and Laschinger, Melanie and Liebisch, Gerhard and Hoering, Marcus and Basic, Marijana and Bleich, Andre and Zhang, Xue-Jun and Kuebelsbeck, Ludwig and Plagge, Johannes and Scherer, Emely and Wohlleber, Dirk and Wang, Jianye and Wang, Yang and Steffani, Marcella and Stupakov, Pavel and Gaertner, Yasmin and Lohoefer, Fabian and Mogler, Carolin and Friess, Helmut and Hartmann, Daniel and Holzmann, Bernhard and Hueser, Norbert and Janssen, Klaus-Peter (2023) Gut microbiota promote liver regeneration through hepatic membrane phospholipid biosynthesis. JOURNAL OF HEPATOLOGY, 78 (4). ISSN 0168-8278, 1600-0641
Full text not available from this repository. (Request a copy)Abstract
Background & Aims: Hepatocyte growth and proliferation depends on membrane phospholipid biosynthesis. Short-chain fatty acids (SCFAs) generated by bacterial fermentation, delivered through the gut-liver axis, significantly contribute to lipid biosyn-thesis. We therefore hypothesized that dysbiotic insults like antibiotic treatment not only affect gut microbiota, but also impair hepatic lipid synthesis and liver regeneration.Methods: Stable isotope labeling and 70% partial hepatectomy (PHx) was carried out in C57Bl/6J wild-type mice, in mice treated with broad-spectrum antibiotics, in germ-free mice and mice colonized with minimal microbiota. The microbiome was analyzed by 16S rRNA gene sequencing and microbial culture. Gut content, liver, blood and primary hepatocyte organoids were tested by mass spectrometry-based lipidomics, quantitative reverse-transcription PCR (qRT-PCR), immunoblot and immunohistochemistry for expression of proliferative and lipogenic markers. Matched biopsies from hyperplastic and hypoplastic liver tissue of patients subjected to surgical intervention to induce hyperplasia were analyzed by qRT-PCR for lipogenic enzymes.Results: Three days of antibiotic treatment induced persistent dysbiosis with significantly decreased beta-diversity and richness, but a massive increase of Proteobacteria , accompanied by decreased colonic SCFAs. After PHx, antibiotic-treated mice showed delayed liver regeneration, increased mortality, impaired hepatocyte proliferation and decreased hepatic phospholipid synthesis. Expression of the lipogenic enzyme SCD1 was upregulated after PHx but delayed by antibiotic treatment. Germ-free mice essentially recapitulated the phenotype of antibiotic treatment. Phospholipid biosynthesis, hepatocyte proliferation, liver regen-eration and survival were rescued in gnotobiotic mice colonized with a minimal SCFA-producing microbial community. SCFAs induced the growth of murine hepatocyte organoids and hepatic SCD1 expression in mice. Further, SCD1 was required for proliferation of human hepatoma cells and was associated with liver regeneration in human patients. Conclusion: Gut microbiota are pivotal for hepatic membrane phospholipid biosynthesis and liver regeneration.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TANDEM MASS-SPECTROMETRY; CHAIN FATTY-ACIDS; LIPID EXTRACTION; FERMENTATION; CELLS; Liver regeneration; intestinal microbiome; microbiota; microbial metabolites; lipidomics |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 12:29 |
| Last Modified: | 30 Jan 2024 12:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60475 |
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