The 48 national member societies and 17 specialist member societies which operate under the umbrella of United European Gastroenterology (UEG) increasingly develop clinical practice guidelines for both national and international implementation. The methodologies and strategies used in these guidelines vary considerably. The UEG Quality of Care Taskforce aimed to provide a framework for quality guidelines in order to assist member societies in the process of developing guidelines, and to provide a tool for readers of guidelines to critically appraise their quality. We outline the steps necessary to begin the guideline development process, how to build working groups, how to search for evidence, how to grade the quality of the evidence, how to reach consensus on statements and how to write the guideline document. We believe that using this framework will increase the potential to produce a high-quality guideline which is transparent, independent, reproducible and implementable.

Background and aims Inflammatory Bowel Disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC) are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural Killer (NK) cells play a pivotal role in the dynamic interaction between the innate and adaptive immune response. There is an increasing appreciation for the key role immunometabolism plays in the regulation of NK cell function, yet little remains known about the metabolic profile, cytokine secretion and killing capacity of human NK cells during active IBD. Methods PBMC were isolated from peripheral blood of patients with moderate to severely active IBD and healthy controls. NK cells were stained with a combination of cell surface receptors, intracellular cytokines, proteins and analyzed by flow cytometry. For measurements of NK cell cytotoxicity, the calcein-AM release assay was performed. Metabolic profile was analyzed by extracellular flux analyzer. Results NK cells from IBD patients produce large quantities of pro-inflammatory cytokines, IL-17A and TNF-α ex vivo but have limited killing capability. Furthermore, patient NK cells have reduced mitochondrial mass and oxidative phosphorylation. mTORC1, an important cell and metabolic regulator, demonstrated limited activity in both freshly isolated cells and cytokine stimulated cells. Conclusions Our results demonstrate that circulating NK cells of IBD patients have an unbalanced metabolic profile, with faulty mitochondria and reduced capacity to kill. These aberrations in NK cell metabolism may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients.

The HIF hydroxylase enzymes (PHD1‐3 and FIH) are cellular oxygen‐sensors which confer hypoxic‐sensitivity upon the hypoxia‐inducible factors HIF‐1α and HIF‐2α. Microenvironmental hypoxia has a strong influence on the epithelial and immune cell function through HIF‐dependent gene expression and consequently impacts upon the course of disease progression in ulcerative colitis (UC), with HIF‐1α being protective while HIF‐2α promotes disease. However, little is known about how inflammation regulates hypoxia‐responsive pathways in UC patients. Here we demonstrate that hypoxia is a prominent microenvironmental feature of the mucosa in UC patients with active inflammatory disease. Furthermore, we found that inflammation drives transcriptional programming of the HIF pathway including downregulation of PHD1 thereby increasing the tissue responsiveness to hypoxia and skewing this response toward protective HIF‐1 over detrimental HIF‐2 activation. We identified CEBPα as a transcriptional regulator of PHD1 mRNA expression which is downregulated in both inflamed tissue derived from patients and in cultured intestinal epithelial cells treated with inflammatory cytokines. In summary, we propose that PHD1 downregulation skews the hypoxic response toward enhanced protective HIF‐1α stabilization in the inflamed mucosa of UC patients.