Epithelial aryl hydrocarbon receptor regulates IL-22 producing colonic group 3 innate lymphoid cells to augment microbial metabolite mediated protection in colitis

Abstract

The intestinal barrier dysfunction is intimately associated with inflammatory bowel diseases (IBD) as the gut barrier provides the first line of protection to host from external factors. The pathogenesis of IBD is multifactorial resulting from combinations of genetic polymorphism, environmental factors, diet, altered microbiota and the immune system. Aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor which upon activation can regulate many pathophysiological functions like inflammation and gut barrier homeostasis. Recently, we identified that microbial metabolite Urolithin A (UroA) mitigated colitis in pre-clinical models through activation of AhR-dependent pathways at two distinct levels by preserving the gut barrier function and reducing systemic and acute inflammation. However, the interplay between the enhanced barrier function and reduction in inflammation and the requirement of specific cell types to mediate the UroA activities remains to be established. In the current study, we evaluated the UroA mediated cell specific requirement of AhR by using transgenic mice AhR fx -Villin Cre (AhR is deleted in intestinal epithelial cells) and AhR fx -LysM Cre (AhR is deleted in myeloid cells) mice. Our studies showed that UroA mediated activation of gut AhR is critical for regulation of intestinal homeostasis in dextran sodium sulphate (DSS) induced colitis. UroA also activated intestinal AhR dependent signaling to induce IL-22 production from type 3 innate lymphoid cells (ILC3). Further, our data from intestinal organoids revealed that AhR dependent-induction of IL-18 from intestinal epithelial cells is responsible for IL-22 production from immune cells. These studies revealed the novel findings that microbial metabolite mediated selective activation of AhR regulates the IL-18/IL-22-axis to maintain gut homeostasis and enhance gut barrier function to attenuate IBD pathogenesis. Current studies are supported by NIH/NIGMS COBRE project P20-GM125504-01 and JHFEREG from University of Louisville. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.