Mechanisms and Therapeutic Implications of the Pregnane X Receptor Targeting Indole Bacterial Metabolites in Inflammatory Bowel Disease
Technical Report,30 Sep 2017,29 Sep 2018
New York University School of Medicine New York United States
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This proposal addresses a significant medical problem, namely, infection triggered inflammation in the intestines technically called post-infectious inflammatory bowel disease in military personnel. Compromised gut barrier integrity is an important risk factor that contributes to the onset of IBD, especially post-infection. The environmental cues and its molecular controls regulating intestinal barrier function are poorly understood in homeostatic and pathophysiologic states like infection-induced IBD. Our studies show a novel direct link between intestinal microbial metabolism i.e. specific microbial metabolites and regulation of intestinal permeability via a pathway regulated by an orphan nuclear receptor, PXR, and TLR4. We demonstrate that in the small intestines which mirrors what happens in large intestines, where PXR is expressed in intestinal epithelial cells in a crypt-villus gradient, in homeostasis, dietary tryptophan-derived bacterial metabolites i.e. indoles and indole metabolites in particular indole 3 propionic acid or IPA tonically activate PXR and induce a down-regulation of the Toll-like Receptors, in particular TLR4, and its downstream signaling pathway. This results in modulating the abundance of TNF-alpha, which in turn modulates intestinal barrier function i.e. permeability. In the context of an inappropriate increase in inflammatory signals e.g., infection, suppression of PXR, andor excess loss of dietary modulators e.g., tryptophan, andor specific indole metabolizing bacteria e.g., antibiotics results in increased permeability, thus exacerbating underlying disease predisposition and pathology. In this model, restitution of signaling homeostasis, either by reconstituting intestinal loss of indole-metabolite producing bacteria andor PXR activating bacterial metabolites i.e. IPA, could result in abrogating pro-inflammatory signals and loss of barrier permeability in the context of intestinal inflammation.
- Medicine and Medical Research