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

Area of Science:

• Hepatology
• Microbiology
• Metabolomics

Background:

• Circadian disruption is a known risk factor for metabolic dysfunction-associated steatohepatitis (MASH).
• Sleep disturbances can negatively impact metabolic health and liver function.

Purpose of the Study:

• To investigate the mechanistic link between circadian disruption and MASH.
• To identify microbial and metabolic targets for MASH intervention.

Main Methods:

• Utilized a mouse model with continuous light exposure and a western diet to mimic circadian disruption.
• Performed integrated 16S rRNA sequencing and metabolomics to analyze gut microbiota and metabolites.
• Assessed the efficacy of interventions including Akkermansia muciniphila, taurine, and obeticholic acid.

Main Results:

• Circadian disruption aggravated hepatic steatosis, inflammation, and intestinal barrier damage in mice.
• Observed a decrease in Akkermansia muciniphila and an increase in chenodeoxycholic acid 3-sulfate (CDCA-3S).
• Interventions with A. muciniphila, taurine, or obeticholic acid ameliorated MASH by restoring microbial and metabolic balance.

Conclusions:

• Circadian disruption exacerbates MASH through an FXR-CYP7A1-bile acid axis, leading to reduced A. muciniphila.
• Targeting the gut microbiome and bile acid metabolism offers potential therapeutic strategies for MASH.
• Microbial and metabolic interventions may be beneficial for sleep-related disorders contributing to MASH.