Intestinal barrier defects cause antigen translocation and immune dysregulation. The pyroptosis of colonic epithelial cells (CECs) disrupts the colonic barrier, and its inhibition might be a therapeutic approach for ulcerative colitis (UC), but the mechanisms are not fully understood. A DSS-induced UC model was established to assess the level of colonic epithelial cell pyroptosis. 16S rDNA sequencing and LC‒MS/MS were applied to screen potential candidate bacterial species and metabolites. The roles of target metabolites were evaluated in vivo using GSDMD-knockout mice. FHC cells treated with LPS + ATP were used as a cellular model of pyroptosis, and the underlying molecular mechanism was explored mainly by siRNA transfection and lentivirus infection. We found that DSS-treated mice exhibited increased levels of pyroptosis in the colon. Fecal microbiota transplantation (FMT) significantly suppressed mucosal inflammation and CEC pyroptosis, accompanied by increased levels of butyrate-producing bacteria and butyrate in feces. Butyrate treatment alleviated DSS-induced colitis in mice. Moreover, GSDMD knockout mitigated DSS-induced colitis in mice, whereas a butyrate intervention failed to further ameliorate colitis in GSDMD-knockout mice. Mechanistically, we found that butyrate significantly inhibited LPS + ATP-induced pyroptosis by activating its receptor, aryl hydrocarbon receptor (AhR), in FHC cells, while silencing AhR suppressed this effect. The overexpression of cGAS in FHC increased the level of pyroptosis, whereas the administration of butyrate inhibited the activation of the cGAS–STING pathway. Treatment with a cGAS inhibitor significantly reversed the increase in pyroptosis caused by AhR knockdown in pyroptotic FHC cells. Gut microbiota-derived butyrate levels were increased after FMT. Butyrate suppressed the proinflammatory cGAS–STING–NF-κB signaling axis via AhR to inhibit CEC pyroptosis and thereby alleviate UC.
Zou et al. (2026) studied this question.