Tryptophan-derived metabolite, indole-3-propionic acid, promotes homeostasis and prevents inflammation of the intestinal mucosa

ROMAGNOLI PA; SHENK GK; PHAM QM; MAHER L; KHANNA KM

Washington

Congreso; 18th International Congress of Mucosal Immunology (ICMI 2017); 2017

Society for Mucosal Immunology

Signals provided by microbiota-derived metabolites can promote the homeostasis of the epithelial cell layer of the intestinal mucosa. These signals can shape immune responses to bacterial pathogens as well as to prevent dysregulated responses to microbiota that result in inflammatory bowel disease (IBD). We tested the hypothesis that a metabolite arising from the tryptophan metabolism of commensal bacteria, indole-3-propionic acid (IPA), provides signals that promote intestinal mucosa homeostasis and in turn control inflammation to prevent IBD. We investigated the effect of IPA in the intestinal mucosa using a mouse model of colitis caused by oral infection with Citrobacter rodentium. Remarkably, we found that IPA treatment prevents colitis in mice. Although most active indoles derived from the tryptophan metabolism act as ligands of the aryl hydrocarbon receptor (AHR), previous reports have suggested that IPA acts through the nuclear receptor pregnane X receptor (PXR), independently of AHR. Here, we investigated if the effect of IPA is mediated by the activation of PXR promoting the integrity of the epithelial barrier present in the gut mucosa. Indeed, we found that IPA did not protect against colitis in PXR deficient mice. Moreover, the absolute numbers of lymphocytes producing IL-17A and IFNγ are increased in the intraepithelial lymphocyte compartment of the colon after IPA treatment and that this effect is also dependent on the presence of PXR. In conclusion, we believe the discovery of metabolites like IPA that promote the maintenance of the intestinal mucosa will provide exciting new strategies to prevent and treat IBD.