Symbiotic bacterial metabolites regulate GI barrier function via PXR and TLR4 (MUC4P.852)

Intestinal microbial metabolites affect mucosal integrity through incompletely characterized mechanisms. Here we identify microbial specific indoles that regulate intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, serves as a ligand for PXR and down-regulates enterocyte TNF-α while up-regulating junctional protein-coding mRNAs. Pxr-/- mice exhibit a distinctly “leaky” gut physiology coupled with up-regulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier are corrected in Pxr-/-/Tlr4-/- double-knockout mice. To validate that IPA drives the anti-inflammatory response directly via PXR, we exposed intestinal commensal-depleted Pxr+/+ and Pxr-/- mice to live (IPA-producing) or heat-killed (non-IPA producing) C. sporogenes preceding indomethacin exposure (toxic small intestinal injury model). There was a significant reduction in histologic injury and mucosal myeloperoxidase (MPO) enzyme activity. The intestinal mucosa exposed to live (as opposed to heat-killed) C. sporogenes had significant induction of PXR target gene (Ugt1a1). These effects were absent in Pxr-/- mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway which involves luminal sensing and signaling by TLR4.