The pregnane X receptor drives sexually dimorphic hepatic changes in lipid and xenobiotic metabolism in response to gut microbiota in mice

The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion in Pxr+/+ vs Pxr-/- C57Bl6/J mice revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis revealed that microbiota-PXR interaction controlled fatty-acid and xenobiotic metabolism. Antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in livers from Pxr+/+ but not Pxr-/- male mice. These findings identify PXR as a hepatic effector of sexually dimorphic responses to microbiota-derived signals and reveal a potential new mechanism for unexpected drug-drug or food-drug interactions. Littermate Pxr+/+ and Pxr-/- male and female C57Bl6/J adult mice were treated or not with broad-spectrum antibiotics (ATB) in drinking water for 2 weeks to deplete the gut microbiota. 8 groups were compared: Pxr+/+ Control males, Pxr+/+ ATB males, Pxr-/- Control males, Pxr-/- ATB males, Pxr+/+ Control females, Pxr+/+ ATB females, Pxr-/- Control females, Pxr-/- ATB females.. Transcriptomic data were generated for 6 mice per group (3 per cage).