Mechanisms of Disease: Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBDs), represented by Crohn disease and ulcerative colitis, are associated with major morbidity in Western countries and with increasing incidence in the developing world. Although analysis of the genome of patients with IBD, especially through genome-wide association studies, has unraveled multiple pathways involved in IBD pathogenesis, only part of IBD heritability has been explained by genetic studies. This finding has revealed that environmental factors also play a major role in promoting intestinal inflammation, mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the innate immune system should also be compromised. Finally, activation of the immune system depends on the working balance between effector and regulatory cells present in the intestinal mucosa, which have also been found to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation. In this article, we will review the mechanisms proposed to cause IBD from the genetic, environmental, intestinal barrier, and immunologic perspectives.