Hepatic cytochrome P450 2E1 (CYP2E1) is an important P450 enzyme involved in the metabolism of numerous xenobiotics. Notably, it contributes to the metabolic activation of many pro-carcinogenic and toxic compounds, thereby playing a critical role in human health and disease development. Previous studies suggest that gut microbiota modulate hepatic CYP2E1 expression; however, the microbiota’s effects are inconsistent, and the underlying mechanisms remain unknown. Here, we show that the gut microbiota suppress hepatic CYP2E1 expression, at least in part, through the gut microbial metabolite indole-3-propionic acid (IPA). Hepatic CYP2E1 expression was significantly increased in germ-free and antibiotic-treated mice compared with conventionally raised mice, indicating that the gut microbiota reduce hepatic CYP2E1 expression. Furthermore, we found that IPA, a gut microbial metabolite, accumulates at high levels in the livers of conventionally raised mice but is barely detectable in germ-free or antibiotic-treated mice. Finally, IPA treatment reduced CYP2E1 expression both in liver cells and in mice. Collectively, these findings demonstrate that the gut microbiota suppress hepatic CYP2E1 expression, at least in part, through microbial metabolites, particularly IPA. These findings suggest a novel mechanism by which the gut microbiota regulate host metabolism and human health.
