Journal
IMMUNITY
Volume 41, Issue 2, Pages 296-310Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2014.06.014
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Funding
- NIH [CA127231, CA161879, AI097375]
- Damon Runyon Foundation [CI 1502, P30CA013330]
- University of Connecticut Health Center
- European Commission FP7 grant METACARDIS [FP7-HEALTH-2012-INNOVATION-I-305312]
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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-alpha 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.
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