In addition, a higher induction was observed in the ileal samples. This would argue that the ileum rather lives on a higher basal ER stress, but can still induce strongly the gene response. It also highlights that if the inflammation of the tissue did not significantly increase the UPR, it is not because the tissue is unable to do so. Indeed if the UPR is more activated in basal state, removal of a protective arm would prevent ABT-199 proper re-establishment of homeostasis and could logically result in imbalance. This would be coherent with both our findings and the ones of Kaser . Moreover, in the study of Kaser, XBP1 was deleted exclusively in epithelial cells, pointing toward a defect in epithelial cells in IBD pathogenesis. In our study, we observed that HSPA5 located mainly in intestinal epithelial secretory cells which produce large amounts of proteins involved in mucosal defense. Regarding the activation of the PERK branch, transcript and protein levels of GADD34 in colonic IBD patients were similar to healthy controls, which would argue against an activation of the PERK pathway. In contrast, western blot analysis showed an increased concentration of pEIF2A in colonic inflammation. If pEIF2A would result from PERK activation, we would expect an induction of GADD34, which is the co-factor of protein phosphatase 1 in the dephosphorylation of pEIF2A . This would represent the canonical PERK pathway, where GADD34 promotes the return to homeostasis of the ER. As we do not observe a significant difference in GADD34, we could hypothesize that phosphorylation of EIF2A results from another pathway, such as protein kinase RNA-activated . Another possibility is that Toll-like-receptor signaling prevents induction of DNA damage inducible transcript 3 also known as C/EBP homologous , a downstream target of PERK . TLR engagement does not suppress phosphorylation of PERK or EIF2A, which are upstream of CHOP, but pEIF2A fails to promote translation of the CHOP activator ATF4. As CHOP is TWS119 responsible for GADD34 induction, this would also be inhibited even in a context where PERK is active. Given that multiple SNPs within XBP1 have been found to be associated with CD and UC, we should keep in mind that these SNPs could influence the regulation of genes involved in the UPR . It will be important to study the impact of XBP1 mutations on the IBD phenotype, but also on the full ER stress signatures in the gut.