We found that small-molecule inhibitors targeting NLRP3 and Caspase-8 rescued the inflammatory phenotype observed in the AIEC/piroxicam group, indicating an indispensable role of Caspase-8 and NLRP3 in AIEC/NSAID-induced inflammation and in IBD-pathogenesis. Here, NLRP3 is linked to inflammatory bowel disease.