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.

Figure 1.. Mechanisms involved in the pathogenesis of Inflammatory Bowel Disease.

IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. Abbreviations: GWAS, Genome-wide association studies; IBD, Inflammatory Bowel Diseases.

Figure 2.. The intestinal mucosa in the normal bowel and IBD.

Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELMβ proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. From the innate immune system perspective, the IBD mucosa has been shown to exhibit: a decrease in colonic macrophages expressing CD14, defective CX3CR1 antigen presentation by dendritic cells; and impaired Autophagy. Lastly, while leukocyte migration via integrin cellular adhesion molecules (CAMs) interactions also occurs in the normal mucosa, the balance between Effector and regulatory T cells (T-reg) appears to be disturbed in the IBD mucosa, resulting in uncontrolled activation of different T-cell lineages that migrate to the inflamed intestine.