The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium , colonize the gut mucosa via attaching and effacin g lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses an d infiltration of immune cells. Inflammatory caspases such as caspase'1 and caspase '4/11 are crucial mediators of host defense and inflammation in the gut via their abili ty to process cytokines such as IL'1 ? and IL'18. Here we report that the effector NleF binds the catalytic domain of caspase'4 and inhibits its proteolytic activity. Following infect ion of intestinal epithelial cells (IECs) EPEC inhibited caspase'4 and IL'18 processing in an NleF 'dependent manner. Depletion of caspase'4 in IECs prevented the secretion of mature IL'18 in response to infection with EPEC@ nleF. NleF'dependent inhibition of caspase'11 in colons of mice prevented IL'18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild'type C. rodentium nor C. rodentium @ nleF triggered neutrophil infiltration or IL'18 secreti on in Cas11 or Casp1/11 deficient mice. Thus, IECs play a key role in modu lating early innate immune responses in the gut via a caspase'4/11 ' IL '18 axis, which is targeted by virulence factors encoded by enteric pathogens