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

Abstract

It is well-known that the pregnane X receptor (PXR/Nr1i2) is a critical xenobiotic-sensing nuclear receptor enriched in liver and intestine and is responsible for drug-drug interactions (DDI), due to their versatile ligand binding domain (LBD) and target genes involved in xenobiotic biotransformation. PXR can be modulated by various xenobiotics including pharmaceuticals, nutraceuticals, dietary factors, and environmental chemicals. Microbial metabolites such as certain secondary bile acids (BAs) and the tryptophan metabolite indole-3-propionic acid (IPA) are endogenous PXR activators. Gut microbiome is increasingly recognized as an important regulator for host xenobiotic biotransformation and intermediary metabolism. PXR regulates and is regulated by the gut-liver axis. This review summarizes recent research advancements leveraging pharmaco-and toxico-metagenomic 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 interaction patterns, and novel PXR-targeted intestinal bacteria; 2) key PXRmodulating activators and suppressors of exogenous and endogenous sources; 3) novel bidirectional interactions between PXR and gut microbiome under physiological, pathophysiological, pharmacological, and toxicological conditions; and 4) modifying factors of PXR-signaling including species-and sex difference, 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.

Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals’ Health and Disease

“…Moreover, IPA acts as a ligand of the aryl hydrocarbon receptor (AhR) present in colonic epithelial cells, activation of which is associated with anti-inflammatory and anticancer effects [119] Interestingly, it has been observed that in patients suffering from colitis serum, IPA concentration decreases significantly [28]. Apart from being an AhR ligand, IPA can also produce its biological action by activating the pregnane X receptor (PXR) present in colonic, liver endothelial and muscle cells [23,119,120]. Complex laboratory techniques allow testing the function of GBB by measuring its permeability to specific substances, including Fluorescein Isothiocyanate-Dextran (FITC-Dextran).…”

Indole-3-propionic Acid Attenuates HI-Related Blood–Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway

“…After all, the liver and small intestine are PXR-enriched sites. 20,30,49 In summary, IPA has played a BBB protective role in the neonatal rat model of HI brain injury. IPA can attenuate inflammation by inhibiting NF-κB signaling.…”

“…IPA is an endogenous activator that can activate the Pregnane X receptor (NR1I2, PXR). 20,21 Moreover, PXR has been approved to play an anti-inflammatory role by inhibiting the actions of the NF-κB signaling pathway 22−24 and hypoxia can potently inhibit the expression of PXR. 25 Therefore, we hypothesize that PXR is involved in the protective effect of IPA on BBB.…”

“…To further explain the regulatory effect of IPA on NF-κB signaling, we next aimed to study the PXR signaling pathway, as previously it had been reported that IPA is an endogenous activator that can activate the PXR. 20,21 IPA activates PXR in the vascular endothelium of mice and increases PXR mRNA expression in aortic segments. 21 An intestinal barrier function study also showed that IPA activates PXR in mice.…”

“…PXR, a ligand-activated transcription factor, is a member of the NR1I subfamily of the nuclear receptor superfamily. The effects of PXR were initially studied in the liver and the small intestine, which showed enrichment of PXR. ,, The mechanism of interaction between PXR and NF-κB has been reported to explain the potentially anti-inflammatory effects of PXR. However, these studies mainly focus on intestinal inflammation.…”