Caspase‐8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice

The gut has a specific vascular barrier that controls trafficking of antigens and microbiota into the bloodstream. However, the molecular mechanisms regulating the maintenance of this vascular barrier remain elusive. Here, we identified Caspase‐8 as a pro‐survival factor in mature intestinal endothelial cells that is required to actively maintain vascular homeostasis in the small intestine in an organ‐specific manner. In particular, we find that deletion of Caspase‐8 in endothelial cells results in small intestinal hemorrhages and bowel inflammation, while all other organs remained unaffected. We also show that Caspase‐8 seems to be particularly needed in lymphatic endothelial cells to maintain gut homeostasis. Our work demonstrates that endothelial cell dysfunction, leading to the breakdown of the gut‐vascular barrier, is an active driver of chronic small intestinal inflammation, highlighting the role of the intestinal vasculature as a safeguard of organ function.