Butyrate ameliorates ulcerative colitis through targeting STING-dependent ER stress signaling and limiting CD4+ TRM T cells accumulation

This study aimed to investigate the role of butyrate in regulating STING-induced endoplasmic reticulum stress (ERS) and CD4 + tissue-resident memory (TRM) T cells responses during the progression of ulcerative colitis (UC). Our results demonstrated that butyrate significantly alleviated dextran sulfate sodium (DSS)-induced colitis, as evidenced by restored intestinal epithelial architecture, reduced inflammatory cytokine, and decreased CD4 + TRM T cells. These protective effects were likely mediated through modulation of the STING–ERS pathway. Using a CT26 cell model, we further confirmed that STING activation promotes ERS, leading to enhanced secretion of inflammatory factors and subsequent induction of CD4 + TRM T cells. Importantly, butyrate effectively suppressed this STING-initiated inflammatory cascade in intestinal epithelial cells (IECs). Our findings revealed a novel mechanism by which butyrate ameliorates UC through inhibition of the STING–ERS axis in IECs, highlighting its therapeutic potential for UC treatment.