Berberine alleviates metabolic dysfunction-associated steatohepatitis by enhancing the abundance of Akkermansia muciniphila.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with intestinal barrier defects and gut microbiota dysbiosis. The gut commensal bacterium Akkermansia muciniphila (Akk) maintains intestinal barrier integrity and improves MASH-related metabolic syndromes. Berberine (BBR), a traditional Chinese medicine, shows promise in treating MASH. However, research on drugs that target Akk regulation and its underlying mechanisms remains limited. This study investigates the mechanisms by which BBR regulates Akk in MASH. We fed C57BL/6 J male mice a methionine-choline-deficient (MCD) diet for 6 weeks to establish the MASH mouse models. The gut microbiota was analyzed using 16S rRNA sequencing and bacterial quantification measured by qPCR analysis. An antibiotic cocktail (Abx) and fecal microbiota transplantation (FMT) were applied to modulate gut microbiota. Results showed that BBR reduced hepatic and colonic inflammation, preserved intestinal barrier integrity and prevented microbiota translocation into the liver. The 16S rRNA sequencing and qPCR analysis revealed a significant increase in Akk abundance in fecal samples following BBR treatment. Mechanistically, BBR did not promote Akk growth directly, but it reduced the bacterial load and enhanced MUC2 expression, thereby facilitating Akk colonization indirectly. While disruption of the gut microbiota by antibiotics treatment weakened the therapeutic effect of berberine on MASH, transplanting of the fecal microbiota from BBR-treated mice could mitigate MASH in antibiotic-treated mice. Finally, BBR and Akk exhibited synergistic therapeutic effects against MASH. Our study illustrated that BBR alleviates MASH mice by enhancing Akk abundance and restoring intestinal barrier integrity. BBR and Akk combination therapy would be a promising strategy for MASH prevention.