Corroborating the specific effect on small intestinal inflammation, IL-22 treatment also worsened spontaneous CD-like ileitis and epithelial cell death in Atg16l1ΔIEC/Xbp1ΔIEC mice, which coincided with increased mRNA levels of Tnf and Ifnb. Our observations thus indicate a tissue specific interplay of ATG16L1-dependent autophagy, necroptosis, and IL-22 signaling in the small intestinal mucosa, which is in agreement of Atg16l1’s role as a CD risk gene with a predominant ileal phenotype (Durães et al., 2013). Here, IFNB1 is linked to Crohn ileitis.