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

Microbiome. 2021 Apr 20;9(1):93. doi: 10.1186/s40168-021-01050-9.


Background: 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.

Results: 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 using antibiotics in Pxr+/+ vs Pxr-/- C57BL/6J littermate mice followed by hepatic transcriptomics revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis suggested that microbiota-PXR interaction controlled fatty acid and xenobiotic metabolism. We confirmed that antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in the liver from Pxr+/+ but not Pxr-/- male mice.

Conclusions: These findings identify PXR as a hepatic effector of microbiota-derived signals that regulate the host's sexually dimorphic lipid and xenobiotic metabolisms in the liver. Thus, our results reveal a potential new mechanism for unexpected drug-drug or food-drug interactions. Video abstract.

Keywords: Fatty acid metabolism; Gut microbiota; Liver; NR1I2; Pregnane X receptor; Transcriptomics; Xenobiotic metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Female
  • Gastrointestinal Microbiome* / genetics
  • Lipids
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnane X Receptor / genetics
  • Xenobiotics


  • Lipids
  • Nr1i2 protein, mouse
  • Pregnane X Receptor
  • Xenobiotics