Abstract The intestinal epithelium is under continuous renewal via a tightly controlled process of cell proliferation and cell shedding. During infection and sepsis, the rate of cell shedding increases dramatically as a protective response. However, the mechanisms through which epithelial turnover rate is controlled in the gut remain elusive. Here we identify diet-mediated control of epithelial cell shedding as an important mechanism in defense against infectious disease. We show that abrogating vitamin A signaling by expressing a dominant negative retinoic acid receptor exclusively in intestinal epithelial cells (dnRARVillin-Cre) makes mice resistant to pathological epithelial cell shedding and cell death in an LPS model of sepsis. In a Salmonella infection model, dnRARVillin-Cremice had increased intracellular loads of the pathogen in the intestine as compared to control mice. This trend was observed even at early time points of the infection and was associated with drastically reduced epithelial cell shedding compared to dnRARfl/fl mice. Intestinal epithelium RNA-seq and protein analysis uncovered that levels of the pro-inflammatory cytokine IL-18 are severely reduced in epithelia of dnRARVillin-Cre mice. LPS and pathogen induced cell death were both rescued upon IL-18 reconstitution in dnRARVillin-Cre mice. Furthermore, even dietary vitamin A could modulate epithelial IL-18 expression. Our results thus reveal a novel mechanism whereby dietary vitamin A modulates cell shedding response in the epithelium via IL-18, affecting barrier function and infection susceptibility in the gut.