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

By M. Venkatesh, Subhajit Mukherjee, Hongwei Wang, Hao Li, Katherine Y. Sun, A. Benechet, Zhijuan Qiu, Leigh Maher, M. Redinbo, Robert S. Phillips and 9 more. Immunity, 2014

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SUMMARY Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed 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 as a ligand for PXR in vivo, and IPA down-regulated enterocyte TNF–α while up-regulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2−/−) mice showed a distinctly “leaky” gut physiology coupled with up-regulation 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 which involves luminal sensing and signaling by TLR4.

Subfields: Molecular Biology, Nutrition and Dietetics, Surgery

View Paper: https://www.semanticscholar.org/paper/a7277f57d3d5880473d78dc1527138f4ba90be31

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Citations in the corpus

The Human Gut Microbiome – A Potential Controller of Wellness and Disease (2018, background): “…T-cells, in which the mechanisms underlie the restoration of therapeutic response to CTLA-4 blockade is suggested to be via induction of the IL-12-dependent TH1 immune response in tumor-draining lymph nodes, and stimulation of intratumoral dendritic cells (DCs) maturation (Vétizou et al., 2015).”
Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health (2017, background): “Bacterially produced indoles interactwith pregnaneX receptors (PXRs) and mediate a range of effects, including improvedmucosal homeostasis and barrier function, and as such represent a fascinating exampleof interkingdomcommunication (32).”
Understanding the Holobiont: How microbial metabolites affect human health and shape the immune system (2017, background): “…the combined knockout of Nr1i2 and the gene encoding the LPS sensor toll-like receptor 4 (Tlr4) can rescue the phenotype of Nr1i2 / mice, possibly because it counteracts the accelerated cell death of inflammatory monocytes observed in NR1I2-deficient mice (Qiu et al., 2016; Venkatesh et al., 2014).”
Human gut microbiota/microbiome in health and diseases: a review (2020, background): “Indole-3propionate Tryptophan metabolism Clostridium sporogenes Maintenance of intestinal barrier function and mucosal homeostasis (Venkatesh et al. 2014)”
Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to the Body (2021, background): “sporogenes can convert tryptophan into IPA, resulting in a protective effect against dextran sulfate sodium-induced acute UC (96).”
Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation. (2017, background): “sporogenes metabolizes tryptophan to indole-3-propionic acid (IPA), a metabolite that protects mice from DSS-induced colitis (Venkatesh et al., 2014).”
The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “IPA (tryptophan metabolism) Clostridium sporogenes Maintenance of intestinal barrier function and mucosal homeostasis (Venkatesh et al., 2014)”