Circadian disruption exacerbates MASH in mice by reducing intestinal Akkermansia muciniphila abundance via the FXR-CYP7A1-bile acid axis_Targeting Bile Acids

Circadian disruption has emerged as a significant public health issue and is increasingly recognized as a contributor to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms remain poorly understood. In this study, we established a mouse model combining continuous light exposure and a western diet to investigate how circadian disruption exacerbates metabolic dysfunction-associated steatohepatitis (MASH). Our results demonstrated that circadian disturbance aggravated hepatic inflammation, lipid accumulation, and intestinal barrier impairment. Through integrated 16S rRNA sequencing and metabolomic analyses, we identified a marked reduction in Akkermansia muciniphila abundance and an elevation in CDCA-3S. Supplementation with A. muciniphila, taurine, or the FXR agonist obeticholic acid restored microbial and metabolic homeostasis, subsequently alleviating MASH pathology. Mechanistically, our data suggest these beneficial effects may involve the FXR–CYP7A1 signaling pathway. Our findings indicate that circadian disruption aggravates MASH potentially through reducing A. muciniphila abundance in a process associated with the FXR–CYP7A1–bile acid axis , and highlight the potential of microbial and metabolic interventions as novel therapeutic strategies for individuals with sleep-related circadian disorders.