Molecular systems in inflammatory bowel disease

Abstract Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory diseases of the intestine, which can begin at any age, even in children. Both diseases are commonly known as inflammatory bowel diseases (IBDs). They represent a major challenge, because their causation is unclear, and though there have been significant advances in medical treatment, it is still far from satisfactory, and many patients require major surgery. The clinical phenotype of the patients that respond to treatment compared to those that do not respond can be very similar prior to treatment, and therefore the need for biomarkers is to differentiate between these groups. The genomic portrait of IBD was built with the high-resolution detection of loci that individually have a very modest influence. There is evidence for over 200 distinct genetic loci; however, they are not associated with prognosis. More specifically, there are at least 30 distinct loci that are associated with the phenotype of CD, and 23 loci with UC. Moreover, the boundaries between CD and UC are blurred by the larger proportion of loci that are shared. There are also parallels and paradoxes vis-a-vis other diseases, such as inflammatory, autoimmune, infectious, and primary immunodeficiencies. The IBD-associated variants within the genes, such as NOD2, IL23R, ATG16L1, and CARD9, have the potential to adversely affect innate and adaptive immunity, as well as mucosal barrier integrity and autophagy. The functional insights have largely been derived from reductive approaches, such cell culture and animal models. Unusually severe perturbations of the biology have also been observed in exceedingly rare cases of the monogenic forms of the disease. The molecular systems approach is poised to transform our holistic perception of the polygenic interactions by integrating the multiomic approaches rather than deconstruct the biology albeit the one-dimensional view. New methodologies for mathematical modeling and the exponential increase in computational power have made the integrative approaches of molecular systems biology feasible. The unprecedented scale of the massive data combined with the discovery of new IBD-associated biomarkers is envisioned for prediction, prognosis, and the diagnosis of individuals that are susceptible. The new insights from unraveling the multitude of disease mechanisms are prerequisite for novel, personalized therapeutic strategies.