Commensal metabolite indol-3-propionic acid promotes gut barrier function by regulating IL-22 production during intestinal inflammatory conditions

Abstract

Abstract Microbiota-derived metabolites provide signals to maintain homeostasis of the epithelial cell layer in the intestinal mucosa that in turn shape immune responses to bacterial pathogens. In contrast, disruption of these signals can result in dysregulated responses to microbiota that cause inflammatory bowel diseases (IBD). Here we tested the hypothesis that a metabolite produced via tryptophan metabolism by commensal bacteria, Indol-3-propionic acid (IPA), promotes immune homeostasis and gut barrier function in the intestinal mucosa during inflammatory conditions and prevents IBD. We investigated the effect of IPA on the intestinal mucosa using a model of colitis caused by oral infection with Citrobacter rodentium (Crod). Remarkably, we observed that IPA treatment results in protection of mice from colitis. Our studies show that IPA treatment results in increased expression of IL-22 by intraepithelial lymphocytes (IELs) of the small intestine (S). In fact, most of the IL-22 observed at 4 days following oral Crod infection is produced by IELs from small intestines. Since we have previously shown that IPA is a potential ligand of the nuclear receptor pregnane X receptor (PXR), which contributes to the maintenance of the intestinal barrier function, we further investigated if IPA protects by activating PXR or other pathways in the gut mucosa. Indeed we discovered an increase in the absolute numbers of IL-17A and IFNγ producing lymphocytes from the IEL compartment of the colon by the IPA treatment and this effect was dependent on PXR expression. In conclusion, we believe the discovery of metabolites like IPA that promotes the repair of the intestinal epithelial cell layer can provide new strategies to prevent and treat IBD.