Symbiotic Bacterial Metabolites Regulate Gastrointestinal Barrier Function Via the Xenobiotic Sensor PXR and Toll-like Receptor 4

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2014 Jul 29

PMID 25065623

Citations 481

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Intermittent fasting inhibits platelet activation and thrombosis through the intestinal metabolite indole-3-propionate.

Qi Z, Zhou L, Dai S, Zhang P, Zhong H, Zhou W Life Metab. 2025; 4(2):loaf002.

PMID: 40078933 PMC: 11897983. DOI: 10.1093/lifemeta/loaf002.

Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication.

Shin H, Bang Y Immune Netw. 2025; 25(1):e10.

PMID: 40078785 PMC: 11896664. DOI: 10.4110/in.2025.25.e10.

Deciphering respiratory viral infections by harnessing organ-on-chip technology to explore the gut-lung axis.

Koceva H, Amiratashani M, Akbarimoghaddam P, Hoffmann B, Zhurgenbayeva G, Gresnigt M Open Biol. 2025; 15(3):240231.

PMID: 40037530 PMC: 11879621. DOI: 10.1098/rsob.240231.

Gut Microbiome Regulation of Gut Hormone Secretion.

Chao J, Coleman R, Keating D, Martin A Endocrinology. 2025; 166(4).

PMID: 40037297 PMC: 11879239. DOI: 10.1210/endocr/bqaf004.

The Inflammatory Mechanism of Parkinson's Disease: Gut Microbiota Metabolites Affect the Development of the Disease Through the Gut-Brain Axis.

Gao A, Lv J, Su Y Brain Sci. 2025; 15(2).

PMID: 40002492 PMC: 11853208. DOI: 10.3390/brainsci15020159.

References

Yamaguchi A, Hori O, STERN D, Hartmann E, Ogawa S, Tohyama M . Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylation. J Cell Biol. 1999; 147(6):1195-204. PMC: 2168098. DOI: 10.1083/jcb.147.6.1195. View

Cassol E, Misra V, Holman A, Kamat A, Morgello S, Gabuzda D . Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors. BMC Infect Dis. 2013; 13:203. PMC: 3655873. DOI: 10.1186/1471-2334-13-203. View

Zhou C, Tabb M, Nelson E, Grun F, Verma S, Sadatrafiei A . Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest. 2006; 116(8):2280-2289. PMC: 1501109. DOI: 10.1172/JCI26283. View

Watkins R, Wisely G, Moore L, Collins J, Lambert M, Williams S . The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science. 2001; 292(5525):2329-33. DOI: 10.1126/science.1060762. View

Abreu M, Vora P, Faure E, Thomas L, Arnold E, Arditi M . Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol. 2001; 167(3):1609-16. DOI: 10.4049/jimmunol.167.3.1609. View

Mayer E . Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011; 12(8):453-66. PMC: 3845678. DOI: 10.1038/nrn3071. View

Leavy O . Mucosal immunology: the 'AHR diet' for mucosal homeostasis. Nat Rev Immunol. 2011; 11(12):806. DOI: 10.1038/nri3115. View

Asquith M, Powrie F . An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J Exp Med. 2010; 207(8):1573-7. PMC: 2916138. DOI: 10.1084/jem.20101330. View

Lee K, Kim S, Kim E, Ha E, You H, Kim B . Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila. Cell. 2013; 153(4):797-811. DOI: 10.1016/j.cell.2013.04.009. View

10.

Maloy K, Powrie F . Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011; 474(7351):298-306. DOI: 10.1038/nature10208. View

11.

Fasano A, Shea-Donohue T . Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005; 2(9):416-22. DOI: 10.1038/ncpgasthep0259. View

12.

Wikoff W, Anfora A, Liu J, Schultz P, Lesley S, Peters E . Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009; 106(10):3698-703. PMC: 2656143. DOI: 10.1073/pnas.0812874106. View

13.

Chen H, Yang J, Zhang M, Zhou Y, Shen T, Chu Z . Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol. 2010; 299(6):G1287-97. DOI: 10.1152/ajpgi.00196.2010. View

14.

Dong F, Zhang L, Hao F, Tang H, Wang Y . Systemic responses of mice to dextran sulfate sodium-induced acute ulcerative colitis using 1H NMR spectroscopy. J Proteome Res. 2013; 12(6):2958-66. DOI: 10.1021/pr4002383. View

15.

Wang H, Venkatesh M, Li H, Goetz R, Mukherjee S, Biswas A . Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. J Clin Invest. 2011; 121(8):3220-32. PMC: 3148718. DOI: 10.1172/JCI41514. View

16.

Clemente J, Ursell L, Parfrey L, Knight R . The impact of the gut microbiota on human health: an integrative view. Cell. 2012; 148(6):1258-70. PMC: 5050011. DOI: 10.1016/j.cell.2012.01.035. View

17.

Martin F, Wang Y, Sprenger N, Yap I, Rezzi S, Ramadan Z . Top-down systems biology integration of conditional prebiotic modulated transgenomic interactions in a humanized microbiome mouse model. Mol Syst Biol. 2008; 4:205. PMC: 2516362. DOI: 10.1038/msb.2008.40. View

18.

Weiser M . Intestinal epithelial cell surface membrane glycoprotein synthesis. II. Glycosyltransferases and endogenous acceptors of the undifferentiated cell surface membrane. J Biol Chem. 1973; 248(7):2542-8. View

19.

Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C . Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol. 2011; 8(1):36-45. DOI: 10.1038/nchembio.741. View

20.

Gupta N, Thaker A, Kanuri N, Riehl T, Rowley C, Stenson W . Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity. Inflamm Bowel Dis. 2011; 18(7):1214-20. PMC: 3235239. DOI: 10.1002/ibd.21849. View