title: Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4.
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.
authors: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Madhukumar
authors: M
authors: Venkatesh
authors: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Subhajit
authors: S
authors: Mukherjee
authors: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Hongwei
authors: H
authors: Wang
authors: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Hao
authors: H
authors: Li
authors: Department of Pathology, Montefiore Medical Center, Bronx, NY 10467, USA.
authors: Katherine
authors: K
authors: Sun
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors: Alexandre P
authors: AP
authors: Benechet
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors: Zhijuan
authors: Z
authors: Qiu
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors: Leigh
authors: L
authors: Maher
authors: Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Matthew R
authors: MR
authors: Redinbo
authors: Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
authors: Robert S
authors: RS
authors: Phillips
authors: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors: James C
authors: JC
authors: Fleet
authors: Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors: Sandhya
authors: S
authors: Kortagere
authors: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Paromita
authors: P
authors: Mukherjee
authors: Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
authors: Alessio
authors: A
authors: Fasano
authors: 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.
authors: Jessica
authors: J
authors: Le Ven
authors: 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.
authors: Jeremy K
authors: JK
authors: Nicholson
authors: 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.
authors: Marc E
authors: ME
authors: Dumas
authors: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA. Electronic address: kkhanna@uchc.edu.
authors: Kamal M
authors: KM
authors: Khanna
authors: Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: sridhar.mani@einstein.yu.edu.
authors: Sridhar
authors: S
authors: Mani
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000276:immunology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018938:Caco-2 Cells; D002460:Cell Line; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000276:immunology; D000077297:Pregnane X Receptor; D034622:RNA Interference; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011987:Receptors, Steroid / Q000235:genetics / Q000276:immunology*; D015427:Reperfusion Injury / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D019108:Tight Junctions / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D017252:CD3 Complex; D007211:Indoles; D008070:Lipopolysaccharides; C000625852:NR1I2 protein, human; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C015292:indolepropionic acid; D007213:Indomethacin