Death in the intestinal epithelium—basic biology and implications for inflammatory bowel disease

<jats:p>Every 4–5 days, intestinal epithelial cells (<jats:styled-content style="fixed-case">IEC</jats:styled-content>) are terminated as they reach the end of their life. This process ensures that the epithelium is comprised of the fittest cells that maintain an impermeable barrier to luminal contents and the gut microbiota, as well as the most metabolically able cells that conduct functions in nutrient absorption, digestion, and secretion of antimicrobial peptides. <jats:styled-content style="fixed-case">IEC</jats:styled-content> are terminated by apical extrusion—or shedding—from the intestinal epithelial monolayer into the gut lumen. Whether death by apoptosis signals extrusion or death follows expulsion by younger <jats:styled-content style="fixed-case">IEC</jats:styled-content> has been a matter of debate. Seemingly a minor detail, <jats:styled-content style="fixed-case">IEC</jats:styled-content> death before or after apical extrusion bears weight on the potential contribution of apoptotic <jats:styled-content style="fixed-case">IEC</jats:styled-content> to intestinal homeostasis as a consequence of their recognition by intestinal lamina propria phagocytes. In inflammatory bowel disease (<jats:styled-content style="fixed-case">IBD</jats:styled-content>), excessive death is observed in the ileal and colonic epithelium. The precise mode of <jats:styled-content style="fixed-case">IEC</jats:styled-content> death in <jats:styled-content style="fixed-case">IBD</jats:styled-content> is not defined. A highly inflammatory milieu within the intestinal lamina propria, rich in the proinflammatory cytokine, <jats:styled-content style="fixed-case">TNF</jats:styled-content>‐α, increases <jats:styled-content style="fixed-case">IEC</jats:styled-content> shedding and compromises barrier integrity fueling more inflammation. A milestone in the treatment of <jats:styled-content style="fixed-case">IBD</jats:styled-content>, anti‐<jats:styled-content style="fixed-case">TNF</jats:styled-content>‐α therapy, may promote mucosal healing by reversing increased and inflammation‐associated <jats:styled-content style="fixed-case">IEC</jats:styled-content> death. Understanding the biology and consequences of cell death in the intestinal epithelium is critical to the design of new avenues for <jats:styled-content style="fixed-case">IBD</jats:styled-content> therapy.</jats:p>