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

Microbiome

Arnaud Polizzi¹  Yannick Lippi¹  Sandrine Ellero-Simatos¹  Sandrine Bruel¹  Laurence Guzylack¹  Maïwenn Olier¹  Marine Huillet¹  Frederic Lasserre¹  Elodie Person¹  Sharon Ann Barretto¹  Marion Régnier¹  Vassilia Théodorou¹  Hervé Guillou¹  Anne Fougerat¹  Claire Naylies¹  Laila Mselli-Lakhal¹  Céline Lukowicz¹  Daniel Zalko¹  Laurence Gamet-Payrastre¹  Colette Bétoulières¹  Sarra Smati¹  Nicolas Loiseau¹  Walter Wahli² 

[1]Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France

[2]Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France

[3]Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 308232, Singapore, Singapore

[4]Center for Integrative Genomics, University of Lausanne, CH-1015, Lausanne, Switzerland

关键词: Gut microbiota;    Liver;    Pregnane X receptor;    NR1I2;    Xenobiotic metabolism;    Fatty acid metabolism;    Transcriptomics;   

DOI  :  10.1186/s40168-021-01050-9

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsBy 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.ConclusionsThese 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.6jaknk__LWi2dgNs2otrXUVideo abstract

【 授权许可】

CC BY