Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum1. Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium2. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans3. However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood.Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.

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As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn’s disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn’s disease led to detection of intestinal mTNF+ immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF+ cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF+ cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn’s disease and autoimmune or inflammatory disorders.

Main Recommendations 1 ESGE suggests that high definition endoscopy, and dye or virtual chromoendoscopy, as well as add-on devices, can be used in average risk patients to increase the endoscopist’s adenoma detection rate. However, their routine use must be balanced against costs and practical considerations.Weak recommendation, high quality evidence. 2 ESGE recommends the routine use of high definition systems in individuals with Lynch syndrome.Strong recommendation, high quality evidence. 3 ESGE recommends the routine use, with targeted biopsies, of dye-based pancolonic chromoendoscopy or virtual chromoendoscopy for neoplasia surveillance in patients with long-standing colitis.Strong recommendation, moderate quality evidence. 4 ESGE suggests that virtual chromoendoscopy and dye-based chromoendoscopy can be used, under strictly controlled conditions, for real-time optical diagnosis of diminutive (≤ 5 mm) colorectal polyps and can replace histopathological diagnosis. The optical diagnosis has to be reported using validated scales, must be adequately photodocumented, and can be performed only by experienced endoscopists who are adequately trained, as defined in the ESGE curriculum, and audited.Weak recommendation, high quality evidence. 5 ESGE recommends the use of high definition white-light endoscopy in combination with (virtual) chromoendoscopy to predict the presence and depth of any submucosal invasion in nonpedunculated colorectal polyps prior to any treatment. Strong recommendation, moderate quality evidence. 6 ESGE recommends the use of virtual or dye-based chromoendoscopy in addition to white-light endoscopy for the detection of residual neoplasia at a piecemeal polypectomy scar site. Strong recommendation, moderate quality evidence. 7 ESGE suggests the possible incorporation of computer-aided diagnosis (detection and characterization of lesions) to colonoscopy, if acceptable and reproducible accuracy for colorectal neoplasia is demonstrated in high quality multicenter in vivo clinical studies. Possible significant risks with implementation, specifically endoscopist deskilling and over-reliance on artificial intelligence, unrepresentative training datasets, and hacking, need to be considered. Weak recommendation, low quality evidence.

Main RecommendationsESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and endoscopic performance measures. Strong recommendation, moderate quality of evidence, level of agreement 90 %.ESGE recommends performing esophagogastroduodenoscopy, small-bowel examination, and/or colonoscopy earlier than the planned surveillance procedure if a patient is symptomatic. Strong recommendation, low quality of evidence, level of agreement 100 %.