Phenotypic limts of pregnane x receptor (PXR) in the gut

Abstract

A breach in gut epithelial integrity has been linked not only to a heightened risk of inflammatory bowel disease (IBD), but also to a broad spectrum of human ailments. Studies on human twins and first-degree relatives have clearly demonstrated that environmental cues play an important role in determining gut barrier function. Recent literature suggests that orphan nuclear receptors may serve as a mechanistic link between host environment and gut immunity; however, the exact mechanism of how this occurs remains elusive.;One such receptor, pregnane x receptor (PXR) is most compelling in this function because of its large ligand binding pocket, thus allowing for far-ranging xenosensing. We have demonstrated that PXR is differentially expressed along the gut crypt-villus axis, with its highest expression in the differentiated villus cells. We observed that, Cdx2, a member of the caudal family of transcription factors, regulates expression of PXR by directly binding to its promoter. We have also shown that gut commensal-derived specific indole metabolite, indole 3-propionic acid (IPA), regulates epithelial barrier function through PXR action.;Ultra-structural examination of Pxr-/- mice showed significant defects in the gut epithelium. These defects in Pxr-/- mice resulted in a heightened sensitivity to develop gut barrier dysfunction to a wide range of toxic insults. The barrier defects observed in Pxr -/- mice resulted from an enhanced epithelium-specific toll-like receptor 4 (TLR4) expression and signaling. These barrier defects are corrected in Pxr-/-/Tlr4-/- double knockout mice. Indeed, the role of PXR in maintaining gut epithelial barrier is directly related to its ability to inversely regulate TLR4 mRNA stability. Furthermore, we have shown that PXR regulates TLR4 mRNA stability by directly binding to its 3'-untranslated region. These findings implicate that novel immune regulation strategies might involve PXR-RNA binding.;Overall, our studies implicate epithelial PXR as a central regulator of TLR4 mediated control of the gut barrier function. This regulation is intrinsically associated with IPA producing gut commensals. Since, gut barrier dysfunction is linked to multiple disease pathologies; search for newer effective treatment options to prevent gut barrier defects may have broader implications beyond IBD.