Pathogenesis of Inflammatory Bowel Disease: the Bacterial Connection

The inflammatory bowel diseases are complex, idiopathic disorders whose pathogenesis is beginning to be understood largely due to the generation and investigation of many experimental models over the past decade. In most of these models, the enteric microbial bacteria are obligatory for disease expression, and in most, CD4 T-cells are the effector cells mediating chronic intestinal inflammation. Thus these disorders appear to represent disorders of host microbial interactions in the intestine. One model, C3H/HeJBir mice that are a high susceptibility phenotype for spontaneous colitis, has been particularly informative regarding the ‘bacterial connection’ to IBD. C3H/HeJBir T-cells are highly reactive to enteric bacterial antigens, and such Th1 cells can mediate disease upon transfer to immunodeficient SCID recipients. Sera from C3H/HeJBir mice has been used to identify and clone 60 antigens that stimulate their pathogenic T-cells and B-cells. The adaptive response to the microbiota is thus highly selective, even in the setting of chronic intestinal inflammation. Interestingly enteric bacterial flagellins comprised the major group of these antigens, and about half of patients with Crohn’s disease have IgG antibodies to them as well. There are emerging data from both experimental models and humans that the innate immune system plays a major role in the host interaction with the microbiota and that defects in innate immune cells, such as epithelial cells, dendritic cells, and macrophages, direct and shape the abnormal Tcell and B-cell immune responses to enteric microbial antigens that result in IBD.