Future of IBD pathogenesis: how much work is left to do?

About one-half century ago inflammatory bowel disease (IBD) was a true “Cinderella” of the autoimmune/chronic inflammatory disease cluster, with probably the most inadequate and least dependable amount of information on what might be causing Crohn’s disease (CD) or ulcerative colitis (UC), what could be leading to them, and what the mechanisms underlying inflammatory tissue damage might be.1 This situation is dramatically reversed at the beginning of the 21st century, and it is fair to state that more progress has been achieved in IBD than in any other condition characterized by chronic inflammation of a specific target organ. At present, the IBD research community is satisfied, if not convinced, with the general notion that both CD and UC are closely related to 4 fundamental components that explain their pathogenesis: broad environmental changes, genetic predisposition, the enteric commensal flora, and the immune system.2,3 Progress in each of these areas has not been necessarily even, which is primarily due to logistic difficulties intrinsic to large-scale studies, limits on financial means, variable technological progress, and the availability of enough “hands and brains” to perform basic studies or implement laborious and time-consuming experiments at the bench. Let us briefly analyze each of the above 4 pathogenic components. To further expand our understanding of the contribution of environmental changes to IBD pathogenesis obviously cannot be done at the bench. To generate strong solid evidence in support of the “hygiene hypothesis,”4,5 which links environmental changes to an inappropriate immune reactivity at the systemic or intestinal levels, massive, expensive, longterm prospective studies of diverse populations in various parts of the world would be needed. No single investigator or even groups of investigators alone will ever be able to gather the financial and logistic resources needed to properly carry out these studies, which should be relegated to international governmental agencies. Since this is highly improbable to occur, the lack of adequate IBD epidemiologic studies will continue to hinder efforts to better understand the impact of the environment on the emergence of IBD worldwide. Quite an opposite situation has taken place in the field of IBD genetics. The recent development of technologies that can generate a comprehensive portrait of the human genome, methods that allow rapid sequencing of DNA from preselected and reasonably well-defined patient and control populations, coupled with the creation of genetic consortia in the USA, Europe, and elsewhere have allowed the performance of massive genome-wide association (GWA) studies.6 These are not necessarily “bench-based” activities, but combined they have yielded 2 critical pieces of information: the first is the discovery of novel, numerous, strong links between genetic variations and IBD, particularly in CD; the second is the essentially irrefutable proof that genetic predisposition is required to develop IBD.7 This is an excellent example of how long-held intuitions about disease mechanisms based only on clinical and laboratory experience are transformed into reality because of technological advances. While the progress in the field of IBD genetics has been impressive, as is often the case, new challenges are created by new knowledge. At the moment 30 genetic variations have been reported in IBD, but they explain 30% of all IBD cases. How many more variations are to be expected? If the ones described so far represent the most frequent because they are the easiest to detect by GWA, will we uncover an even greater number of variations in unyielding numbers of small subsets of CD and UC patients?8 If so, this is a disheartening and daunting perspective, and one that may keep investigators very busy for quite some time unless additional screening tools become available.9 The long-lasting emphasis put on immunological studies during several decades has caused the field of microbiology to be relatively neglected. Scientists are now suffering from this gap in knowledge, which has become far more acute after the discovery that that the human genome contains “only” 20,000 genes—instead of the predicted 100,000—and the realization that essential functions needed for health depend on complementary functions codified by genes of the human microbiota.10 This is particularly true in the gastrointestinal tract, whose function is almost entirely dependent on the presence of the enteric commensal flora. Lack of adequate knowledge of the enteric microbiota has become a pressing issue for IBD pathogenesis after the realization that gut flora appears to be the target of the aberrant immune response driving inflammation and tissue damage in the gut of CD and UC patients.11,12 To alleviate our ignorance, the recently established Human Microbiome Project and the increasingly widespread use of DNA-based rather than culture-based techFrom the Department of Gastroenterology & Hepatology, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20659 Published online in Wiley InterScience (www.interscience.wiley.com).