Epithelial autophagy dampens chronic intestinal inflammation

Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract, thought to arise from an imbalanced immune response to the microflora. Intestinal epithelial cells (IECs) form the physical and chemical barrier separating the microflora from the mucosal immune cells and are a key player in maintaining homeostasis as well as modulating the immune response. Recent genome-wide association studies (GWAS) linked polymorphisms in the autophagy genes ATG16L1 and IRGM with susceptibility to inflammatory bowel disease (IBD). We sought to investigate the role of Atg16l1/ autophagy within the intestinal epithelium during chronic colitis.

We employed a tissue-specific Atg16l1-deficient transgenic mouse strain in a Helicobacter hepaticus driven model of chronic colitis. In parallel, we studied the response of the IECs towards inflammatory mediators in an ex vivo organoid system.

Mice lacking Atg16l1 in IECs (Atg16l1^Δvillin) were more susceptible to development of chronic colitis. However, despite severely aggravated pathology in Atg16l1^Δvillin mice, we did not observe elevated adaptive immune responses in the lamina propria, but found elevated levels of epithelial derived chemokines. In accordance, genome-wide RNA sequencing of organoids stimulated with inflammatory cytokines revealed increased activation of Atg16l1-deficient IECs compared to wt IECs.

These findings suggest that the IBD susceptibility gene ATG16L1 actively regulates the proinflammatory response in the epithelium and thereby dampens chronic intestinal inflammation.