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

Shun Takano, Koudai Kani, Kaichi Kasai, Naoya Igarashi, Miyuna Kato, Kana Goto, Yudai Matsuura, Mayuko Ichimura-Shimizu, Shiro Watanabe, Koichi Tsuneyama, Yukihiro Furusawa, Yoshinori Nagai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The 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.

Original languageEnglish
Pages (from-to)635-649
Number of pages15
JournalGenes to Cells
Volume29
Issue number8
DOIs
StatePublished - 2024/08

Keywords

  • antibiotics
  • bile acid
  • fibrosis
  • gut microbiota
  • macrophage
  • metabolic dysfunction associated steatohepatitis

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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