Challenges in IBD research: Updating the scientific agendas

Abstract

Substantial progress has been made since the first "Challenges in IBD Research" white paper was drafted in 1990. Advances in basics science - particularly in immunology, genetics, epithelial cell biology, signal transduction, molecular biology, and other areas - have added greatly to our understanding of disease pathogenesis and have identified many new targets for therapeutic intervention. One important realization that has emerged in the past few years is that a complex and active communication among the bacterial flora, epithelium, and immune cells exists in the intestine and that perturbation of these interactions can result in chronic intestinal inflammation. Thus, the major working hypothesis, particularly coming from basic research in experimental models, is that inflammatory bowel disease (IBD) is due to an abnormal cell-mediated immune reaction - primarily by CD4+ T cells - to the antigens and adjuvants of the enteric bacteria in genetically susceptible host. Consequently, many of the priorities and associated resources are directed at gaining a better understanding of the interactions between enteric bacteria and the host as well as the regulation of T-lymphocyte activation and differentiation. Powerful new technologies are now available to define the molecular and genetic basis of complex diseases such as ulcerative colitis and Crohn's disease. These technologies must be applied to clinical studies of patients, i.e., to define subsets of patients with common molecular and/or genetic features. One emerging theme of the 2002 meeting in Phoenix was that there must be closer integration of laboratory-based and clinical investigators to take advantage of these powerful new technologies. A second overriding theme was a focus on disease prevention by both laboratory-based and clinical investigators. One goal for basic research is the achievement of sufficient knowledge and understanding of disease pathogenesis to frame strategies to prevent the onset or recurrence of disease in genetically susceptible individuals, and one goal for clinical research is to develop better treatments for the prevention of relapse in patients who have achieved remission through medical therapy or surgery. Prevention of IBD will require the combined efforts of both laboratory-based and clinical investigators. Many worthy avenues of research were considered and discussed. The leading basic and clinical research priorities at the present time are the following: • Identification of major susceptibility genes for Crohn's disease and ulcerative colitis. While most of these efforst will involve the general population with IBD, efforts should be extended to other specific populations such as African-Americans, Hispanics, and Asians; different clinical populations such as individuals with childhood-onset disease and those with extraintestinal manifestations; and IBD associated with Mendelian disorders such as the Hermansky-Pudlak syndrome. • Development of surrogate markers of disease activity to serve as the primary end points for clinical trials, identifying subclinical stages of disease, and for determining the prognosis of patients. • Development of a detailed understanding of regulatory cells in the intestine - including their origin, localization, cell surface markers, activation requirements, antigens/adjuvants/ligands recognized by their receptors, mechanism and targets of their action, and influence of CARD15/NOD2 on their activities. These aspects must be defined both in experimental models and in patients with IBD. • Delineation of the functions of each IBD susceptibility gene such as CARD15/NOD2, the signaling pathways involved, and interactions with other susceptibility genes and chromosomal regions. • Randomized controlled trials of therapy in important human disease models of the evolution of IBD - such as prevention of disease relapse after surgery for Crohn's disease or prevention of pouchitis after colectomy for ulcerative colitis. These studies should be designed not only to answer important clinical questions, but also to allow assessment of the utility of potential surrogate markers, microarray studies of mRNA, proteomics, bacterial flora studies, etc. The information gleaned from the latter assays would allow definition of the natural history of disease in patients treated with placebo, which currently does not exist. • Identification of the microbial antigens and adjuvants that activate pathogenic T-cell responses in the intestine, as well as those that activated regulatory (anti-inflammatory) responses. Utilization of multiple experimental systems, particularly the selective microbial colonization of rodents with defined flora (gnotobiotes), to understand the complex interplay between the host and the microbial flora in the intestine. • Definition of rigorous, reproducible clinical descriptors for patients for use in a molecular classification of IBD. • Identification of novel epidemiologic and environmental risk factors for IBD, as well as further clarification and elaboration of the impact of smoking on Crohn's disease. • Indentification of the microbial populations in the intestine and their interactions (microbial ecology) to answer whether an "abnormal" or a "dysbiotic" bacterial flora stimulates IBD. Such studies should take advantage of new technologies such as 16s ribosomal DNA sequencing and microbial trait profiling (biochemical, gene expression markers), which allow analysis of these types of complex eco-systems.