The gut microbiota promotes liver regeneration through hepatic membrane phospholipid synthesis

Background & Aims Hepatocyte growth and proliferation is dependent on the synthesis of membrane phospholipids. Lipid synthesis, in turn, requires short chain fatty acids (SCFA) generated by bacterial fermentation, delivered through the gut- liver axis. We therefore hypothesized that dysbiotic insults like antibiotics treatment not only negatively affect gut microbiota, but also impair hepatic lipid synthesis and liver regeneration. Methods Stable isotope labelling and 70% partial hepatectomy (PHx) was carried out in C57Bl/6J wildtype mice, in mice treated with broad-spectrum antibiotics, in germfree mice and gnotobiotic mice colonized with minimal microbiota. Microbiome was analysed by 16S rRNA gene sequencing and microbial culture. Gut content, liver and blood were tested by lipidomics mass spectrometry, qRT-PCR, immunoblot and immunohistochemistry for expression of proliferative and lipogenic markers. Matched biopsies from hyperplastic and hypoplastic liver tissue of human patients subjected to portal vein embolization were analysed by qRT-PCR for lipogenic enzymes and results were correlated with liver volumetry. Results Three days of antibiotics treatment induced persistent dysbiosis with significantly decreased beta-diversity and richness, but massive increase of Proteobacteria, accompanied by decreased colonic SCFA. After PHx, antibiotics- treated mice showed delayed liver regeneration, increased mortality, impaired hepatocyte proliferation and decreased hepatic phospholipid synthesis. Expression of the key lipogenic enzyme SCD1 was upregulated after PHx, but delayed by antibiotics-treatment. Germfree mice essentially recapitulated the phenotype of antibiotics-treatment. Importantly, phospholipid synthesis, hepatocyte proliferation, liver regeneration and survival were rescued in gnotobiotic mice colonized with a minimal SCFA-producing microbial community. SCD1 was required for human hepatoma cell proliferation, and its hepatic expression was associated with liver regeneration and hyperproliferation in human patients. Conclusion Gut microbiota are pivotal for hepatic membrane phospholipid synthesis and liver regeneration. Lay Summary Gut microbiota affects the liver lipid metabolism through the gut-liver axis, and microbial metabolites promote liver regeneration. Perturbations of the microbiome, e.g., by antibiotics treatment, impair the production of bacterial metabolites, which serve as building blocks for new membrane lipids in liver cells. As a consequence, hepatocyte growth and proliferation, and ultimately, liver regeneration and survival after liver surgery is impaired. Highlights Partial hepatectomy in mice pretreated with antibiotics is associated with impaired hepatocyte proliferation and phospholipid synthesis, delayed liver regeneration and increased mortality The delay in liver regeneration and impaired lipogenesis upon antibiotics treatment is preceded by dysbiosis of gut microbiota, increase of Proteobacteria and decreased short-chain fatty acids in the gut Partial hepatectomy in germfree mice essentially phenocopies the detrimental effects of antibiotic treatment Liver regeneration and mortality, as well as phospholipid synthesis and hepatocyte proliferation in germfree mice are fully rescued upon colonisation with a minimal gut bacterial consortium capable of short-chain fatty acid production In human patients, the intrahepatic expression of lipid synthesis enzymes positively correlates with proliferation and liver regeneration in the clinic Thus, liver regeneration is affected by composition of gut microbiota Clinically, pre-operative analysis of the gut microbiome may serve as biomarker to determine the extent of liver resections