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

Madhukumar Venkatesh, Subhajit Mukherjee, Hongwei Wang, Hao Li, Katherine Sun, Alexandre P. Benechet, Zhijuan Qiu, Leigh Maher, Matthew R. Redinbo, Robert S. Phillips, James C. Fleet, Sandhya Kortagere, Paromita Mukherjee, Alessio Fasano, Jessica Le Ven, Jeremy K. Nicholson, Marc E. Dumas, Kamal M. Khanna, Sridhar Mani

Research output: Contribution to journalArticle

255 Scopus citations

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 invivo, 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.

Original languageEnglish (US)
Pages (from-to)296-310
Number of pages15
JournalImmunity
Volume41
Issue number2
DOIs
StatePublished - Aug 21 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Venkatesh, M., Mukherjee, S., Wang, H., Li, H., Sun, K., Benechet, A. P., Qiu, Z., Maher, L., Redinbo, M. R., Phillips, R. S., Fleet, J. C., Kortagere, S., Mukherjee, P., Fasano, A., Le Ven, J., Nicholson, J. K., Dumas, M. E., Khanna, K. M., & Mani, S. (2014). Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4. Immunity, 41(2), 296-310. https://doi.org/10.1016/j.immuni.2014.06.014