Gut Microbiota Protects Against Liver Injury and Fibrosis via Activation of the CYP Eicosanoid Pathway

Gut microbiota has been shown to play an important role in the pathogenesis of liver injury and fibrosis, but the specific microbial factors or pathways involved remain poorly defined. Here we show that specific gut microbial metabolites, notably indole, activate the cytochrome P450 (CYP) eicosanoid pathway in the liver and protect the liver against liver injury and fibrosis. Using LC-MS/MS-based lipidomics to compare conventionally raised mice with germ-free or antibiotic-treated mice, we show that the gut microbiota induces the CYP eicosanoid pathway in the liver. Furthermore, by administering exogenous indole or mono-colonizing germ-free mice with indole-producing Bacteroides thetaiotaomicron or a mutant strain lacking indole production, we demonstrate that gut bacteria-produced indole activates the liver's CYP eicosanoid pathway through pregnane X receptor-dependent mechanisms. Finally, we find that disruption of the microbiota-liver-CYP axis, through inhibition or genetic ablation of CYP monooxygenases, or antibiotic suppression of gut microbiota, exacerbates chemically or surgically induced liver injury or fibrosis. Conversely, activation of this axis through indole administration attenuates liver injury and fibrosis. Together, these results demonstrate that the microbiota-liver-CYP axis plays a key role in the mechanisms by which gut microbiota interacts with the liver to influence host metabolism and disease progression.