Antibiotic effects on gut microbiota modulate diet‐induced metabolic dysfunction‐associated steatohepatitis development in C57BL/6 mice

Abstract

AbstractThe potential involvement of the gut microbiota in metabolic dysfunction‐associated steatohepatitis (MASH) pathogenesis has garnered increasing attention. In this study, we elucidated the link between high‐fat/cholesterol/cholate‐based (iHFC)#2 diet‐induced MASH progression and gut microbiota in C57BL/6 mice using antibiotic treatments. Treatment with vancomycin (VCM), which targets gram‐positive bacteria, exacerbated the progression of liver damage, steatosis, and fibrosis in iHFC#2‐fed C57BL/6 mice. The expression levels of inflammation‐ and fibrosis‐related genes in the liver significantly increased after VCM treatment for 8 weeks. F4/80+ macrophage abundance increased in the livers of VCM‐treated mice. These changes were rarely observed in the iHFC#2‐fed C57BL/6 mice treated with metronidazole, which targets anaerobic bacteria. A16S rRNA sequence analysis revealed a significant decrease in α‐diversity in VCM‐treated mice compared with that in placebo‐treated mice, with Bacteroidetes and Firmicutes significantly decreased, while Proteobacteria and Verrucomicrobia increased markedly. Finally, VCM treatment dramatically altered the level and balance of bile acid (BA) composition in iHFC#2‐fed C57BL/6 mice. Thus, the VCM‐mediated exacerbation of MASH progression depends on the interaction between the gut microbiota, BA metabolism, and inflammatory responses in the livers of iHFC#2‐fed C57BL/6 mice.