The inflammatory bowel diseases (IBDs), represented mainly by ulcerative colitis and Crohn disease but also including noninfectious inflammations of the bowel, have posed an enigma to gastroenterologists and immunologists alike since their first modern descriptions some 75–100 years ago. Powerful new investigative techniques, however, are gradually leading to an increased understanding of the major pathophysiologic processes underlying these diseases, enabling in turn the development of powerful new therapies.
Idiopathic IBDs such as Crohn disease and ulcerative colitis occur in clinically immunocompetent individuals whose characteristic symptoms and signs arise from a robust, cytokine-driven (yet noninfectious) inflammation of the gut (1
). Crohn disease is associated with excess IL-12/IL-23 and IFN-γ/IL-17 production that affects the small bowel and colon with discontinuous ulceration and full thickness bowel wall inflammation often including granulomas. Patients report gastrointestinal symptoms of abdominal pain, diarrhea, and rectal bleeding as well as systemic symptoms of weight loss, fever, and fatigue. Crohn disease patients can also develop obstructing strictures of the bowel and inflammatory connections (fistulae) between segments of bowel or between the bowel and skin and other organs. In comparison, ulcerative colitis is associated with excess IL-13 production, primarily affecting the colon, with a continuous inflammation of the mucosa nearly always involving the rectum and extending proximally (2
). The symptoms are similar to Crohn disease, although fistula development does not occur. Usually both conditions are chronic and relapsing, though ulcerative colitis is curable by surgical removal of the colon (surgery for Crohn disease treats bowel blockage, fistula complications, and intractable bleeding and pain but is not used for cure) (3
). Medical therapy relies on classic antiinflammatory and immunosuppressant drugs: corticosteroids, mesalamine compounds, azathioprine, and derivatives of the latter. The evidence for their utility and mechanism of action has been described elsewhere (4
). Suffice it to say here, that these agents vary in their ability to induce and maintain control of symptoms as well as in their tolerability and toxicities. Newer biological drugs such as anti–TNF-α antibodies targeting the general inflammatory cytokine, TNF-α, have added greatly to our ability to control IBD, but even this therapy is limited by lack or loss of efficacy and associated toxicities (7
). Emerging therapies for IBD are focusing on major effector cytokines as they are identified in ongoing investigations (8
), for instance using an anti–IL-12p40 antibody to neutralize the effects of IL-12 and IL-23 in Crohn disease (10
). Moreover, the occurrence of IBDs in immunodeficient states (such as chronic granulomatous disease [ref. 11
] and common variable immunodeficiency [ref. 12
]) and genetic syndromes (such as Hermansky-Pudlak syndrome [ref. 13
]) and following immunotherapies such as anti–CTLA-4–blocking antibody (14
) suggests that many components of the immune response have a role in IBD susceptibility.
Most students studying the pathogenesis of IBD have adopted the view that the disease is due to a dysfunctional interaction between bacterial microflora of the gut and the mucosal immune system. In one version of this view, the microflora are both qualitatively and quantitatively normal and the disease defect lies within the mucosal immune system. In this case, the normal state of immunologic tolerance to microbial antigens in the GI tract is disturbed either by the presence of a defective mucosal effector T cell population that overreacts to usual microbial antigens or, alternatively, by the presence of a defective mucosal Treg cell population that underreacts to usual microbial antigens such that even normal effector T cells are not properly modulated. In a second and opposing version of this view, a fundamental abnormality exists in the gut microflora, either in the number or type of organisms that comprise the population or in the extent to which the organisms confront on the mucosal immune system. This again results in a loss of tolerance, since the microflora are subsequently able to induce a normal immune system to respond excessively to microbial antigens. Here we attempt to marshal the available evidence supporting each of these theories so as to decide which of them (if not a combination of both) best explains IBD.