Microbiome.: co-auth.: W.Wahli

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

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

Sharon Ann Barretto # 1Frederic Lasserre # 1Marine Huillet 1Marion Régnier 1Arnaud Polizzi 1Yannick Lippi 1Anne Fougerat 1Elodie Person 1Sandrine Bruel 1Colette Bétoulières 1Claire Naylies 1Céline Lukowicz 1Sarra Smati 1Laurence Guzylack 1Maïwenn Olier 1Vassilia Théodorou 1Laila Mselli-Lakhal 1Daniel Zalko 1Walter Wahli 1 2 3Nicolas Loiseau 1Laurence Gamet-Payrastre 1Hervé Guillou 1Sandrine Ellero-Simatos 4

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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.