Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression

Recent studies suggest that mitochondrial dysfunction promotes progression to non-alcoholic steatohepatitis (NASH) by aggravating the gut-liver status. However, the underlying mechanism remains unclear. Herein, we hypothesized that enhanced mitochondrial activity might reshape a specific microbiota signature that, when transferred to germ-free (GF) mice, could delay NASH progression. WT and methylation-controlled J protein knock-out (MCJ-KO) mice were fed for 6 weeks with either control or a choline-deficient, L-amino acid-defined, high-fat diet (CDA-HFD). One mouse of each group acted as a donor of caecal microbiota to GF mice, who also underwent the CDA-HFD model for 3 weeks. Hepatic injury, intestinal barrier, gut microbiome and the associated faecal metabolome were then studied. Following 6 weeks of CDA-HFD, the absence of MCJ, an inhibitor of mitochondrial complex I activity, reduced hepatic injury and improved gut-liver axis in an aggressive NASH dietary model. This effect was transferred to GF mice through caecal microbiota transplantation. We suggest that the specific microbiota profile of MCJ-KO, characterised by an increase in the faecal relative abundance of Dorea and Oscillospira genera and a reduction in AF12, Allboaculum and [Ruminococcus], exerted protective actions through enhancing short-chain fatty acids, NAD+ metabolism and sirtuin activity, subsequently increasing fatty acid oxidation in GF mice. Importantly, we identified Dorea genus as one of the main modulators of this microbiota-dependent protective phenotype. Overall, we provide evidence for the relevance of mitochondria-microbiota interplay during NASH, and that targeting it could be a valuable therapeutic approach.