Pregnane X receptor is a sexually dimorphic hepatic effector of gut microbiota involved in the host's lipid and xenobiotic metabolism. PXR-gut microbiota interaction

The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathological states. However, hepatic sensors and effectors of microbial signals are not well defined. By comparing publically available transcriptomics studies in the liver from conventional vs. germ-free mice, we identified the pregnane X receptor (PXR, NR1I2) as strongly affected by the absence of gut microbes. Microbiota depletion in Pxr+/+ vs Pxr-/- C57Bl6/J mice further revealed that the vast majority of microbiota-sensitive genes were PXR-dependent in the liver from males, but not in females. Pathway enrichment analysis highlighted that the microbiota-PXR interaction controlled both fatty acid and xenobiotic metabolism. Antibiotic treatment decreased hepatic triglyceride content and hampered xenobiotic metabolism in livers from Pxr+/+ but not Pxr-/- male mice. These findings identify PXR as a sexually dimorphic hepatic effector for microbiota-derived signals and highlight a potential new mechanism for unexpected drug-drug or food-drug interactions.