Urolithin A activates aryl hydrocarbon receptor-NLRP6-mediated pathways in intestinal epithelial cells to modulate mucosal immunity and strengthen gut barrier integrity.

The aryl hydrocarbon receptor (AHR) plays a central role in orchestrating gut barrier and mucosal immune functions in the pathogenesis of inflammatory bowel disease (IBD). Nevertheless, activation of the AHR by diverse ligands yields varied outcomes, and the downstream pathways responsible for these effects remain unknown. Here, we report that selective activation of AHR in mouse intestinal epithelial cells (IEC) by the microbial metabolite, urolithin A (UroA), triggers the Nod-like receptor pyrin domain-containing protein 6 (NLRP6) inflammasome, resulting in the release of interleukin (IL)-18 but not IL-1β. Further, we show that UroA-induced IL-18 in IECs is critical for IL-22, mucin 2 and REG3γ production, as well as protection against colitis. Moreover, UroA significantly upregulates IL-18 and IL-22 levels in IECs and type-3 innate lymphoid cells, respectively, in intestinal biopsies from patients with IBD patients. These results demonstrate that activation of AHR by UroA modulates intestinal barrier function through an NLRP6-IL-18-IL-22 pathway in both healthy and IBD conditions.