Taurodeoxycholate ameliorates DSS-induced colitis in mice

Abstract

BackgroundInflammatory bowel disease (IBD) is typically managed using medications such as 5-aminosalicylic acid (5-ASA), glucocorticoids, anti-TNFα Ab, or anti-IL-12/23 Ab. However, some patients do not respond well to these treatments or frequently experience relapses. Therefore, alternative therapeutic options are needed. Since the activation of the inflammasome is crucial to the pathogenesis of IBD, inhibiting the inflammasome may be beneficial for patients. Materials and methodsWe tested the efficacy of taurodeoxycholate (TDCA), which is a known G-protein coupled receptor 19 (GPCR19) agonist, in a mouse colitis model induced by dextran sodium sulfate (DSS). ResultsIn the mouse colitis model, TDCA prevented loss of body weight, shortening of the colon, production of pro-inflammatory cytokines, infiltration of pro-inflammatory cells, and mucosal ulceration in the colon. In vitro, TDCA inhibited the activation of NF-κB in bone marrow-derived macrophages (BMDMs) by activating the cAMP-PKA axis. TDCA downregulated the expression of purinergic receptor P2X7 (P2X7R) and enhanced the colocalization of P2X7R with GPCR19, and inhibited the Ca2+ mobilization of BMDMs when stimulated with ATP or BzATP, which plays a pivotal role in activating the NLRP3 inflammasome (N3I) via P2X7R. TDCA inhibited the oligomerization of NLRP3-ASC and downregulated the expression of NLRP3 and ASC, as well as suppressed the maturation of pro-caspase-1 and pro-IL-1β. TDCA also increased the percentage of M2 macrophages while decreasing the number of M1 macrophages, Th1, Th2, and Th17 cells in the colon. ConclusionTDCA ameliorated DSS-induced colitis in mice, possibly by inhibiting both the priming phase (via the GPCR19-cAMP-PKA-NF-κB axis) and the activation phase (via the GPCR19-P2X7R-NLRP3-Caspase 1-IL-1β axis) of N3I signaling.