Microbial metabolite Urolithin A induces expansion of Regulatory T Cells in aryl hydrocarbon receptor (AhR)-dependent manner

Abstract

Abstract Intestinal inflammation and loss of gut barrier integrity contribute to severity of inflammatory bowel diseases (IBD). Gut microbiota and their metabolites play an important role in maintenance of immunological balance within the gut. Previously, our group demonstrated that treatment with Urolithin A enhanced gut barrier function by inducing junctional proteins and blocked LPS-induced inflammation. Moreover, treatment with this microbial metabolite mitigated colitis in pre-clinical models. In the current study, we identified novel function for Urolithin A, where treatment with Urolithin A significantly expanded FoxP3+ T regulatory cells (Tregs) both ex vivo and in vivo models. Urolithin A failed to induce Treg expansion in AhR−/− mice suggesting Urolithin A mediates its activities through AhR. Moreover, treatment with Urolithin A mitigated murine model of dextran sulfate sodium (DSS)-colitis and enhanced Treg cell population compared to vehicle treatment. These results suggest that Urolithin A offers multi-pronged beneficial activities on gut epithelial layer (enhanced barrier function), macrophages (down regulation of inflammatory cytokines) and expansion of Treg cells to protect against colitis.