Autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease (CD)1. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity causes Paneth cell dysfunction2,3. As Atg16l1HM mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells (IECs), whose human orthologue harbors rare inflammatory bowel disease (IBD) risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis4. Unresolved ER stress is a common feature of IBD epithelium4,5, and several genetic risk factors of CD affect Paneth cells2,4,6-9. Here we show that impairment in either UPR (Xbp1ΔIEC) or autophagy function (Atg16l1ΔIEC or Atg7ΔIEC) in IECs results in each other’s compensatory engagement, and severe spontaneous CD-like transmural ileitis if both mechanisms are compromised. Xbp1ΔIEC mice exhibit autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased IEC death, inositol requiring enzyme 1α (IRE1α)-regulated NFκB activation and tumor necrosis factor signaling which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity and augmentation of autophagy in IECs ameliorates ER stress-induced intestinal inflammation and eases NFκB overactivation and IEC death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal CD as a specific disorder of Paneth cells.

BackgroundChronic enteropathy associated with SLCO2A1 gene (CEAS) is a hereditary disease caused by mutations in the SLCO2A1 gene and characterized by multiple small intestinal ulcers of nonspecific histology. SLCO2A1 is also a causal gene of primary hypertrophic osteoarthropathy (PHO). However, little is known about the clinical features of CEAS or PHO.MethodsSixty-five Japanese patients recruited by a nationwide survey of CEAS during 2012–2016 were enrolled in this present study. We reviewed the clinical information of the genetically confirmed CEAS patients.ResultsWe identified recessive SLCO2A1 mutations at 11 sites in 46 patients. Among the 46 patients genetically confirmed as CEAS, 13 were men and 33 were women. The median age at disease onset was 16.5 years, and parental consanguinity was present in 13 patients (28%). Anemia was present in 45 patients (98%), while a single patient experienced gross hematochezia. All patients showed relatively low inflammatory markers in blood tests (median CRP 0.20 mg/dl). The most frequently involved gastrointestinal site was the ileum (98%), although no patient had mucosal injuries in the terminal ileum. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO.ConclusionsThe clinical features of CEAS are distinct from those of Crohn’s disease. Genetic analysis of the SLCO2A1 gene is therefore recommended in patients clinically suspected of having CEAS.Electronic supplementary materialThe online version of this article (10.1007/s00535-017-1426-y) contains supplementary material, which is available to authorized users.

X-box–binding protein 1 suppresses tumor formation in the gut by regulating Ire1α and Stat3-mediated regenerative responses in the epithelium as a consequence of ER stress.