PXR: More Than Just a Master Xenobiotic Receptor

Oladimeji, Peter; Chen, Taosheng

doi:10.1124/mol.117.110155

Cited by 125 publications

(111 citation statements)

References 117 publications

(138 reference statements)

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“…The well-known host xenobiotic-sensing nuclear receptors PXR and CAR are highly expressed in the liver and intestine. Upon ligand activation, PXR and CAR up-regulate certain drug-metabolizing enzymes and e ux transporters as a compensatory mechanism against xenobiotic insult [16,17]. PXR and CAR share many target genes, such as the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) in humans [18].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

Little

Dutta

et al. 2020

Preprint

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Background: Pharmacological activation of the host xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding the physiological functions of PXR and CAR on the gut microbiome, which is an important regulator for the host immune surveillance and bile acid (BA) metabolism. We examined the gut microbiome composition and BA metabolites in high vs. low PXR/CAR-expressing mice, and in mice that are deficient in PXR, CAR, or both, at two developmental ages. We also utilized humanized PXR transgenic (hPXR-TG) mice to compare the species-specific effect of PXR on the gut microbiome. Results: We discovered bivalent hormetic functions of PXR and CAR in modulating the richness of the gut microbiome and inflammatory biomarkers: the high PXR/CAR expressers had higher microbial richness, pro-inflammatory bacteria (distinct taxa in Helicobacteraceae and Helicobacter), and fecal pro-inflammatory cytokines, suggesting higher immune surveillance to prevent the colonization of harmful bacteria. Interestingly, the absence of PXR or CAR also increased the microbial richness, and absence of both receptors synergistically increased the microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria (Helicobacteraceae and Helicobacter). Most notably, deficiency in both PXR and CAR markedly increased the relative abundance of Lactobacillus, which is capable of bile salt hydrolase (BSH) activity. This corresponded to a decrease in major primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice, including a higher representation of Prevotella. hPXR-TG mice also had higher 12-OH BAs but lower 6-OH BAs, suggesting PXR’s species-specific role in modulating host hepatic BA synthesis. Conclusions: This study is the first to show that the host PXR and CAR profoundly influence the composition of the gut microbiome and its BA metabolites, with a bivalent hormetic relationship between PXR/CAR levels and microbial richness, unveiling the involvement of PXR/CAR-microbiome interactions in host immune surveillance and BA metabolism.

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Section: Introductionmentioning

confidence: 99%

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

Little

Dutta

et al. 2020

Preprint

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“…Understanding the functional properties of NRs that have a known nominal ligand, as in the case with steroid and vitaminactivated receptors, has increased significantly due to the development of synthetic ligands with agonistic or antagonistic properties. However, with the identification of NRs with no known nominal ligands over recent decades, an increasing number of studies have attempted to elucidate their physiological functions (Banerjee, Robbins, & Chen, 2015;Mullican, Dispirito, & Lazar, 2013;Oladimeji & Chen, 2018). These so-called orphan NRs tend to possess much broader ligand selectivity, such ligands including numerous xenobiotics (Ihunnah, Jiang, & Xie, 2011).…”

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confidence: 99%

The constitutive androstane receptor and pregnane X receptor in the brain

Torres-Vergara

Espinoza

et al. 2020

British J Pharmacology

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Since their discovery, the orphan nuclear receptors constitutive androstane receptor (CAR;NR1I3) and pregnane X receptor (PXR;NR1I2) have been regarded as master regulators of drug disposition and detoxification mechanisms. They regulate the metabolism and transport of endogenous mediators and xenobiotics in organs including the liver, intestine and brain. However, with proposals of new physiological functions for NR1I3 and NR1I2, there is increasing interest in the role of these receptors in influencing brain function. This review will summarise key findings regarding the expression and function of NR1I3 and NR1I2 in the brain, hereby highlighting the need for further research in this field.

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“…PXR is another xenobiotic receptor that is also found to exert many homeostatic functions, specifically in immunity, cell proliferation, and cell motility, [ 98–100 ] in addition to its involvement in metabolism of drugs and xenobiotic molecules. [ 101 ] PXR has been shown to modulate intestinal epithelial barrier integrity, [ 89,102 ] which suggests that microbial metabolites may affect intestinal homeostasis through PXR.…”

Section: Gut Microbial Metabolites and Intestinal Stem Cell Activitiesmentioning

confidence: 99%

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

2020

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Microorganisms that colonize the gastrointestinal tract, collectively known as the gut microbiota, are known to produce small molecules and metabolites that significantly contribute to host intestinal development, functions, and homeostasis. Emerging insights from microbiome research reveal that gut microbiota‐derived signals and molecules influence another key player maintaining intestinal homeostasis—the intestinal stem cell niche, which regulates epithelial self‐renewal. In this review, the literature on gut microbiota‐host crosstalk is surveyed, highlighting the effects of gut microbial metabolites on intestinal stem cells. The production of various classes of metabolites, their actions on intestinal stem cells are discussed and, finally, how the production and function of metabolites are modulated by aging and dietary intake is commented upon.

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PXR: More Than Just a Master Xenobiotic Receptor

Cited by 125 publications

References 117 publications

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

The constitutive androstane receptor and pregnane X receptor in the brain

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

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