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

doi:10.1016/j.immuni.2014.06.014

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

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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, …

Immunity (Cambridge, Mass.), v 41(2), pp 296-310

21 Aug 2014

DOI: https://doi.org/10.1016/j.immuni.2014.06.014

PMID: 25065623

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Abstract

Adherens Junctions - genetics

Adherens Junctions - immunology

Animals

Anti-Inflammatory Agents, Non-Steroidal - pharmacology

Antibodies - immunology

Caco-2 Cells

CD3 Complex - immunology

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

Receptors, Steroid - genetics

Receptors, Steroid - immunology

Reperfusion Injury - immunology

RNA Interference

RNA, Messenger

RNA, Small Interfering

Signal Transduction - immunology

Tight Junctions - genetics

Tight Junctions - immunology

Toll-Like Receptor 4 - genetics

Toll-Like Receptor 4 - immunology

Tumor Necrosis Factor-alpha - biosynthesis

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.

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813 citations in Web of Science

823 citations in Scopus

Details

Title: Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4
Creators: Madhukumar Venkatesh - Albert Einstein College of Medicine
Subhajit Mukherjee - Albert Einstein College of Medicine
Hongwei Wang - Albert Einstein College of Medicine
Hao Li - Albert Einstein College of Medicine
Katherine Sun - Montefiore Medical Center
Alexandre P Benechet - University of Connecticut Health Center
Zhijuan Qiu - University of Connecticut Health Center
Leigh Maher - University of Connecticut Health Center
Matthew R Redinbo - University of North Carolina at Chapel Hill
Robert S Phillips - University of Georgia
James C Fleet - Purdue University West Lafayette
Sandhya Kortagere - Drexel University
Paromita Mukherjee - Albert Einstein College of Medicine
Alessio Fasano - Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
Jessica Le Ven - Imperial College London
Jeremy K Nicholson - Imperial College London
Marc E Dumas - Imperial College London
Kamal M Khanna - University of Connecticut Health Center
Sridhar Mani - Albert Einstein College of Medicine
Publication Details: Immunity (Cambridge, Mass.), v 41(2), pp 296-310
Publisher: Elsevier
Grant note: AI097375 / NIAID NIH HHS CA127231 / NCI NIH HHS R01 CA127231 / NCI NIH HHS R01 CA161879 / NCI NIH HHS R01 AI097375 / NIAID NIH HHS P30CA013330 / NCI NIH HHS P30 CA013330 / NCI NIH HHS CA161879 / NCI NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Microbiology and Immunology
Web of Science ID: WOS:000341455300016
Other Identifier: 991019167955004721

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Collaboration types: Domestic collaboration; International collaboration
Web of Science research areas: Immunology

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

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Abstract

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UN Sustainable Development Goals (SDGs)

InCites Highlights

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