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. SYNOPSIS Inflammatory bowel disease (IBD) is a group of disorders that causes severe inflammation of the intestine. This study identified that vascular dysfunction in the small intestine results in classic features of IBD in mice. Adult mice lacking Caspase‐8 (Casp8) in endothelial cells (Casp8 ECko ) die within 3 weeks after tamoxifen treatment with severe intestine inflammation and mucosal hemorrhages, whereas all other organs are not affected. Casp8 ECko mice show lymphatic and blood vessel regression in the small intestine that can be prevented by co‐deletion of MLKL. Deletion of Casp8 solely in the blood endothelium (not in lymphatics) does not manifest bowel inflammation, suggesting that Casp8 is primarily required as a pro‐survival factor in the lymphatic vasculature. Disease development in Casp8 ECko mice is dependent on the presence of microbiota. Graphical Abstract Inflammatory bowel disease (IBD) is a group of disorders that causes severe inflammation of the intestine. This study identified that vascular dysfunction in the small intestine results in classic features of IBD in mice.