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

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.

Authors

Madhukumar Venkatesh¹, Subhajit Mukherjee¹, Hongwei Wang¹, Hao Li¹, Katherine Sun², Alexandre P Benechet³, Zhijuan Qiu³, Leigh Maher³, Matthew R Redinbo⁴, Robert S Phillips⁵, James C Fleet⁶, Sandhya Kortagere⁷, Paromita Mukherjee¹, Alessio Fasano⁸, Jessica Le Ven⁹, Jeremy K Nicholson⁹, Marc E Dumas⁹, Kamal M Khanna¹⁰, Sridhar Mani¹¹

Affiliations

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: [email protected].
¹¹ Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: [email protected].

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding