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Inflammatory bowel disease (IBD) is a chronic condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis. By combining quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intracellular signaling, we identified epithelial mammalian target of rapamycin (mTOR) signaling as a potential driver of inflammation in a mouse model of colitis. A kinetic analysis of mTOR inhibition revealed that the pathway regulates epithelial differentiation, which in turn controls the cytokine milieu of the colon. Consistent with our in vivo analysis, we found that cytokine expression of organoids grown ex vivo, in the absence of bacteria and immune cells, was dependent on differentiation state. Our study suggests that proper differentiation of epithelial cells is an important feature of colonic homeostasis because of its effect on the secretion of inflammatory cytokines., Author summary Chronic inflammation of the gastrointestinal track is the common defect shared by inflammatory bowel diseases (IBDs), such as Crohn’s disease and ulcerative colitis, which affect many people around the world. However, the genetic and physiologic complexities of IBDs have made it difficult to identify therapeutically tractable drivers of disease that can alleviate the symptoms. We reasoned that this complexity is probably originated by a smaller number of dysregulated signaling pathways, and therefore, a “protein-centric” approach would be more suited to identify new therapeutic targets. To this end, in this study we profiled the expression and phosphorylation status of proteins that mediate signaling between and within cells in a mouse model of colitis. We found that hyperactivated mammalian target of rapamycin (mTOR) signaling interferes with the proper differentiation of epithelial cells, which promotes colitis by altering the epithelial inflammatory cytokine secretion in the colon.