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HIGHLIGHT PUBLICATIONS IN CLINICAL PRACTICE M Ines Pinto-Sanchez, MD, MSc Commentary on: Development of Celiac Disease Therapeutics: Report of the Third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics Workshop. By Leffler D et al. Gastroenterology 2016. http://www.ncbi.nlm.nih.gov/pubmed/27456385 The only currently available treatment for CD is lifelong adherence to a gluten-free diet (GFD), which entails the avoidance any products containing even traces of wheat, rye, and barley. It is well known that in celiac patients the lack of treatment may lead to anemia, osteoporotic fractures and small-bowel lymphoma. Even though the risk of complications is predictable, more than half of celiacs find difficulties following a strict GFD. Therefore, there is an unmet medical need of alternative treatments options beyond GFD. In this report, worldwide renowned experts in the field of celiac disease discussed at the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3) workshop, how to define target populations for pharmacologic therapies, as well as measuring clinical benefit in celiac disease trials to support marketing approval. Persistently symptomatic and newly diagnosed patients, as well as children with CD who are affected by neurodevelopmental or behavioral conditions may potentially benefit from a future medication. There were 3 sessions in the workshop to discuss how to define clinical benefit in clinical trials, as the definition may differ according to patients, physicians and the FDA. From the perspective of celiac patients, they were more interested in therapies that protect against gluten cross contamination, and that prevent them to develop symptoms while eating at home or outside home. Gastroenterologists were looking not only on symptomatic improvement but an expansion to other objective measures. There was consensus among patients and clinicians at the workshop that diarrhea and abdominal pain will be central patient-reported outcomes for research studies involving therapies. The FDA’s view usually includes survival within the definition of clinical benefit, however, in celiac disease this is not a pragmatic end point. Therefore, health-related quality of life was proposed as a measurement of clinical benefit. There are many research studies ongoing investigating the effect of non-dietary therapies in celiac disease, however, the efficacy of treatment will depend on how the outcome is measured. There are many obstacles in clinical research, including the absence of a precedent product approval for celiac disease, difficulties in defining target populations for pharmacologic therapy, clinical end points, measurement tools, clinical and meaningful differences in responder criteria, lowest effective dose, and translation to the pediatric population. Future studies will benefit from collaboration between patients, physicians, industry and regulatory bodies. HIGHLIGHT PUBLICATION IN BASIC RESEARCH Heather Galipeau, PhD Comment on: Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. By Caminero et al. http://www.ncbi.nlm.nih.gov/pubmed/27373514 Intestinal dysbiosis has been described in celiac disease, but a clear microbial signature, and the pathophysiological significance is still unclear. Intestinal bacteria are able to degrade gluten invitro, which is highly resistant to degradation by human digestive enzymes. In the recently published article by Caminero et al, the authors demonstrate that opportunistic pathogens and commensal bacteria differentially participate in gluten metabolism in vivo, influencing the end products of gluten metabolism and immunogenic potential of the generated peptides. Using Pseudomonas aeruginosa, an opportunistic pathogen that was only isolated from the duodenum of celiac disease patients, Caminero et al show that P. aeruginosa, through its elastase activity, degrades gluten to produce immunogenic gluten peptides that can stimulate gluten-specific T cells from HLA-DQ2.5 celiac disease patients. Moreover, these P. aeruginosadigested gluten peptides were able to translocate across the small intestinal barrier more efficiently than those peptides digested by human proteases. On the other hand, Lactobacillus spp, isolated from the duodenum of healthy controls, degraded gluten peptides produced by both P. aeruginosa and human proteases to non-immunogenic gluten peptides. Thus, there are distinct patterns in gluten breakdown products generated by the opportunistic pathogen P. aeruginosa and Lactobacillus spp that are associated with increased or decreased immunogenicity. The authors describe an important mechanism through which opportunistic pathogens may modify the pool of gluten peptides in the small intestine, generating immunogenic peptides that can translocate the intestinal barrier and increase susceptibility to celiac disease in genetically susceptible individuals. Importantly, this microbe-gluten-host interaction may apply to other opportunistic pathogens that are present in celiac disease patients and may be a target for therapeutic interventions.