A variant of the autophagy gene ATG16L1 is associated with Crohn’s disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.

自噬基因ATG16L1的变体与克罗恩氏病，炎性肠病（IBD）和同种异体造血干细胞移植受者的存活率低有关。我们证明了在肠道上皮中的ATG16L1对于预防Paneth细胞的丢失和在病毒触发的IBD和同种异体造血干细胞移植的动物模型中夸大的细胞死亡是必不可少的。缺乏ATG16L1的肠道类器官在Paneth细胞中重现了这种损失，并表现出TNFα介导的坏死性硬化，这是程序性坏死的一种形式。ATG16L1的这种细胞保护功能与自噬在促进线粒体体内稳态中的作用有关。最后，在病毒触发的IBD模型中，通过TNFα或RIPK1抑制的治疗性坏死性肾病改善了疾病。这些发现表明，