The cause of chronic inflammation manifestations such as inflammatory bowel disease (IBD) is still not yet fully understood. Evidence however points to the convergence of environmental factors, genetic factors, intestinal microbiota and the immune response at the intestinal epithelial surface that consequently leads to a breakdown of barrier function in IBD. An increasing number of theories implicate a dysfunctional intestinal epithelial surface in the pathogenesis of IBD and progression to complicated disease, which contributes significantly to the IBD burden. As yet, the significance of the intestinal epithelial surface in IBD manifestation and progression has not been explored using a systems biology approach, that compares the mucosa of healthy patients to those with IBD. In the context of dyregulation of the epithelial barrier, there is a scarcity of publications that explore the contribution of proteins- the effectors of the cells and RNA message in the pathways affected by CD and in particular the localization of inflammatory response. We aim to evaluate the functional pathways of chronic inflammation at the intestinal epithelial surface using a combination of transcriptomic and proteomic analyses on intestinal epithelial tissue samples from paired inflamed and non-inflammed Crohn’s disease (CD) and healthy control subjects. Concordance of several biological pathways from both data sets was found to be altered in CD patients’ epithelia when compared to healthy controls. This information could be helpful in identifying novel therapeutic targets that aim to restore barrier function at the intestinal epithelial surface and to guide therapy.