Dimethyl fumarate alleviated DSS-induced colitis by regulating Th17/Treg balance via suppressing JAK2/STAT3 and NF-κB signaling.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by immune dysregulation. Restoring Th17/Treg balance represents a promising therapeutic strategy for UC. Gut metabolism has been reported to critically regulates Th17 and Treg cell homeostasis. However, the role of fumarate in the pathogenesis of UC and the immunoregulatory effect of Dimethyl fumarate (DMF) in the treatment of UC remain unclear. Herein, results demonstrated decreased fumarate levels in colonic tissues of DSS-induced colitis mice, whereas DMF administration elevated colonic fumarate concentrations and relieved DSS-induced colitis by suppressing the inflammatory response and pro-inflammatory cytokines in vivo. Moreover, DMF treatment significantly decreased the frequency of Th17 cells, increased the frequency of Treg cells, thus improved Th17/Treg balance in vitro. Mechanistically, DMF significantly inhibited Th17 cell differentiation via interrupting JAK2/STAT3 and NF-κB signaling. Taken together, these results indicated that DMF alleviated DSS-induced UC by suppressing JAK2/STAT3 and NF-κB signaling to restore Th17/Treg balance. Furthermore, these findings preliminary demonstrate a role for fumarate in the pathogenesis of UC and suggest that DMF treatment leading to fumarate accumulation is a potential metabolic mechanism for colitis mitigation. Collectively, DMF-mediated immunometabolic reprogramming constitutes a novel strategy for UC immunotherapy.