Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4

Immunity. 2014 Aug 21;41(2):296-310. doi: 10.1016/j.immuni.2014.06.014. Epub 2014 Jul 24.

Abstract

Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2(-/-)) mice showed a distinctly "leaky" gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2(-/-)Tlr4(-/-) mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / genetics
  • Adherens Junctions / immunology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antibodies / immunology
  • CD3 Complex / immunology
  • Caco-2 Cells
  • Cell Line
  • Female
  • HEK293 Cells
  • Humans
  • Indoles
  • Indomethacin / pharmacology
  • Inflammation / immunology
  • Intestines / immunology*
  • Intestines / microbiology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Microbiota / immunology
  • Pregnane X Receptor
  • RNA Interference
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Steroid / genetics
  • Receptors, Steroid / immunology*
  • Reperfusion Injury / immunology
  • Signal Transduction / immunology
  • Tight Junctions / genetics
  • Tight Junctions / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibodies
  • CD3 Complex
  • Indoles
  • Lipopolysaccharides
  • NR1I2 protein, human
  • Nr1i2 protein, mouse
  • Pregnane X Receptor
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Steroid
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • indolepropionic acid
  • Indomethacin