Mucosal barrier dysfunction to luminal microbes plays a crucial role in the development of intestinal inflammation in inflammatory bowel disease (IBD). Recently, intestinal epithelial cell (IEC) death resulting from a form of innate immune activation called pyroptosis was proposed as a possible cause of this barrier defect. We hypothesize that inhibition of IEC pyroptosis and prevention of associated barrier defects is a potential mechanism of action for mesalamine. The aim of this study was to determine the effect of mesalamine on recombinant caspase-1 enzyme activity, in vitrocell and spheroid IEC culture model undergoing pyroptosis and in IBD patients treated with mesalamine.