Although precise causes are not yet defined, most investigators believe that IBD results from the combined effects of alterations in host interactions with intestinal microbiota, intestinal epithelial dysfunction, aberrant mucosal immune responses, and altered composition of the gut microbiome. This view is supported by epidemiologic, genetic, and clinical studies as well as data from laboratory models of IBD (
Fig. 15.27
Genetics. Risk for disease is increased when there is an affected family member, and in Crohn disease, the concordance rate for monozygotic twins is approximately 50%. By contrast, concordance of monozygotic twins for ulcerative colitis is only 16%, suggesting that genetic factors are less dominant in this form of IBD.
Molecular linkage analyses of affected families have identified NOD2 (nucleotide oligomerization binding domain 2) as a susceptibility gene in Crohn disease. NOD2 encodes a protein that binds to intracellular bacterial peptidoglycans and subsequently activates NF-κB. Some studies suggest that the disease-associated form of NOD-2 is ineffective at defending against intestinal bacteria. The result is that bacteria are able to enter through the epithelium into the wall of the intestine, where they trigger inflammatory reactions. It should, however, be recognized that disease develops in less than 10% of individuals carrying specific NOD2 polymorphisms, and these polymorphisms are uncommon in African and Asian patients with Crohn disease.
The search for IBD-associated genes using genome-wide association studies (GWAS) that assess single-nucleotide polymorphisms (SNPs) as well as high throughput sequencing and other approaches have yielded a rich harvest of over 200 genes associated with IBD. Among these, NOD2, discussed above, and two autophagy–related genes are of particular interest. They are ATG16L1 (autophagy-related 16–like-1) and IRGM (immunity-related GTPase M)
Barrier defects lead to influxBacteria genes. Both are part of the autophagosome pathway and, like NOD-2, are involved in host cell responses to intracellular bacteria, supporting the hypothesis that inadequate defense against luminal bacteria may be important in the pathogenesis of IBD. None of these genes is associated with ulcerative colitis.
Mucosal immune responses. Although the mechanisms by which mucosal immunity contributes to the pathogenesis of ulcerative colitis and Crohn disease are still being deciphered, immunosuppressive and immunomodulatory agents remain mainstays of IBD therapy. Polarization of helper T cells to the TH1 type is well recognized in Crohn disease, and some data suggest that TH17 T cells also contribute to disease pathogenesis. Consistent with this, certain polymorphisms of the IL-23 receptor confer protection from Crohn disease and ulcerative colitis (IL-23 is involved in the development and maintenance of TH17 cells). However, agents that block IL-17 or its receptor have provided no benefit, whereas an antibody that inhibits both TH1-and TH17-inducing cytokines is effective, suggesting that the two T cell subsets may have a synergistic role in the disease. Some data suggest that mucosal production of the TH2-derived cytokine IL-13 is increased in ulcerative colitis, and, to a lesser degree, Crohn disease.
Defects in regulatory T cells, especially the IL-10producing subset, are believed to underlie the inflammation especially in Crohn disease. Mutations in the IL-10 receptor are associated with severe, early-onset colitis. Thus, some combination of excessive immune activation by intestinal microbes and defective immune regulation likely is responsible for the chronic inflammation in both forms of IBD.