Antibiotic-mediated microbiota depletion limits IgA-related fibrogenesis in metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) is the fastest-growing cause of hepatocellular carcinoma (HCC). Due to the direct connection between the gut and the liver, the intestinal microbiota is suspected to be involved in inflammatory and metabolic processes during MASH development. Therefore, in this study we aimed to investigate the role of the gut microbiota in a mouse model of MASH-to-HCC transition.

C57Bl/6 mice were fed a choline-deficient high fat diet (CD-HFD) for 6 or 12 months to induce MASH and MASH-to-HCC progression, and the microbiota was depleted using broad-spectrum antibiotics (ABx). Microbiota composition and liver pathogenesis were analyzed by shotgun metagenomic sequencing, serology, immunohistochemistry, RNA sequencing and metabolomics.

We showed that IgA from gastrointestinal B cells was sufficient to induce fibrosis through IgA-dependent activation of hepatic FCGR1+cells. Furthermore, we found that the role of B cells in MASH was independent of the gut microbiota since germ-free mice were not protected from MASH development. However, therapeutic ABx-mediated microbiota depletion significantly reduced fibrosis development during MASH progression without affecting obesity, steatosis and T-cell infiltration. ABx treatment also significantly decreased hepatic myeloid cell activation and intestinal and systemic IgA, leading to reduced activation of hepatic FCGR1+cells. Moreover, ABx treatment was associated with significant metabolic changes compared to non-treated CD-HFD mice.

Our results demonstrate that the intestinal microbiota promotes MASH progression through IgA-mediated fibrogenesis. Furthermore, our data suggest that certain immunological features of MASH occur independent of the microbiota while metabolic processes regulated by the microbiota might be involved in the pathogenesis.

Publication History

Article published online:
20 January 2025