02301nas a2200313   4500000000100000008004100001260001500042100002300057700002000080700002000100700001800120700001900138700001800157700002600175700002300201700002700224700001400251700001500265700002500280700001900305700001600324700001700340245009700357856005800454300000900512490000700521520144500528022001401973       2019                            d  c2019-11-121 aClaudia Beaurivage1 aElena Naumovska1 aYee Xiang Chang1 aEdo D. Elstak1 aArnaud Nicolas1 aHeidi Wouters1 aGuido van Moolenbroek1 aHenriëtte L. Lanz1 aSebastiaan J. Trietsch1 aJos Joore1 aPaul Vulto1 aRichard A.J. Janssen1 aKai S. Erdmann1 aJan Stallen1 aDorota Kurek00aDevelopment of a Gut-on-a-Chip Model for High Throughput Disease Modeling and Drug Discovery  uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888156/  a56610 v203 aA common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators RELA and MYD88 through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.  a1422-0067