Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

It is well-known that the pregnane X receptor (PXR)/Nr1i2 isa critical xenobiotic-sensing nuclear receptor enriched in liver and intestine and is responsible for drug-drug interactions, due to its versatile ligand binding domain (LBD) and target genes involved in xenobi-otic biotransformation. PXR can be modulated by various xenobiot-ics including pharmaceuticals, nutraceuticals, dietary factors, and environmental chemicals. Microbial metabolites such as certain sec-ondary bile acids (BAs) and the tryptophan metabolite indole-3-pro-pionic acid (IPA) are endogenous PXR activators. Gut microbiome is increasingly recognized as an important regulator for host xenobi-otic biotransformation and intermediary metabolism. PXR regulates and is regulated by the gut-liver axis. This review summarizes recent research advancements leveraging pharmaco-and toxico-metage-nomic approaches that have redefined the previous understanding of PXR. Key topics covered in this review include: (1) genome-wide investigations on novel PXR-target genes, novel PXR-DNA interac-tion patterns, and novel PXR-targeted intestinal bacteria; (2) key PXR-modulating activators and suppressors of exogenous andendogenous sources; (3) novel bidirectional interactions between PXR and gut microbiome under physiologic, pathophysiological, pharmacological, and toxicological conditions; and (4) modifying factors of PXR-signaling including species and sex differences and time (age, critical windows of exposure, and circadian rhythm). The review also discusses critical knowledge gaps and important future research topics centering around PXR. SIGNIFICANCE STATEMENT This review summarizes recent research advancements leveraging O'mics approaches that have redefined the previous understand-ing of the xenobiotic-sensing nuclear receptor pregnane X receptor (PXR). Key topics include: (1) genome-wide investigations on novel PXR-targeted host genes and intestinal bacteria as well as novel PXR-DNA interaction patterns; (2) key PXR modulators including microbial metabolites under physiological, pathophysiological, pharmacological, and toxicological conditions; and (3) modifying factors including species, sex, and time.