Circadian disruption exacerbates MASH by reducing Akkermansia muciniphila via the FXR-CYP7A1-bile acid axis.

Circadian disruption is a recognized risk factor for metabolic dysfunction-associated steatohepatitis (MASH). Using a mouse model combining continuous light exposure and a western diet, we found that circadian disruption exacerbated hepatic steatosis, inflammation, and intestinal barrier damage. Integrated 16S rRNA sequencing and metabolomics revealed a concurrent marked decrease in intestinal Akkermansia muciniphila abundance and an increase in chenodeoxycholic acid 3-sulfate (CDCA-3S). Interventions with A. muciniphila, taurine, or the farnesoid X receptor (FXR) agonist obeticholic acid restored microbial and metabolic balance, alleviating MASH. Mechanistically, circadian disruption suppressed hepatic FXR signaling, upregulated cytochrome P450 7A1 (CYP7A1), and promoted CDCA-3S accumulation, which was associated with A. muciniphila depletion. Thus, circadian disruption aggravates MASH via an FXR-CYP7A1-bile acid axis that reduces intestinal A. muciniphila, highlighting microbial and metabolic interventions as potential therapies for sleep-related disorders.