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

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

Author information

1
Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2
Department of Pathology, Montefiore Medical Center, Bronx, NY 10467, USA.
3
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
4
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
5
Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
6
Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
7
Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
8
Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
9
Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK.
10
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA. Electronic address: kkhanna@uchc.edu.
11
Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: sridhar.mani@einstein.yu.edu.

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.

PMID:
25065623
PMCID:
PMC4142105
DOI:
10.1016/j.immuni.2014.06.014
[Indexed for MEDLINE]
Free PMC Article
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