(P19-016-25) Gut Microbiota Mitigates Liver Injury and Fibrosis via Activation of the CYP Eicosanoid Pathway

Objectives: Gut microbiota has been shown to play an important role in the progression of liver injury and fibrosis, but the specific microbial factors or pathways involved remain poorly defined. This study aims to investigate the role of gut microbial metabolites in activating liver protective mechanisms against injury and fibrosis.

Methods: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics to compare eicosanoid profiles in the livers of conventionally raised mice with those of germ-free or antibiotic-treated mice. We then assessed the roles of the microbiota-regulated eicosanoid pathway in the progression of chemically and surgically induced liver injury or fibrosis.

Results: LC-MS/MS-based lipidomics shows 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 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 and surgically induced liver injury or fibrosis. Conversely, activation of this axis through indole administration attenuates liver injury and fibrosis.

Conclusions: These findings demonstrate that the gut-liver-CYP axis plays a crucial role in the mechanisms by which gut microbiota interacts with the liver to influence host metabolism and disease progression.

Funding Sources: This research is supported by new faculty start-up grants from the National University of Singapore and the University of California Davis (to G.Z.), a new faculty start-up grant from China Agricultural University (to H.Y.), and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Z01 ES025034 (to D.C.Z).