Unravelling the pathogenesis of inflammatory bowel disease
Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.
The major forms of idiopathic IBD, ulcerative colitis and Crohn’s disease are chronic inflammatory disorders of the gastrointestinal tract that have been empirically defined by clinical, pathological, endoscopic and radiological features. The onset of IBD typically occurs in the second and third decades of life and a majority of affected individuals progress to relapsing and chronic disease. Family aggregation has long been recognized. First-degree relatives of affected individuals have a relative risk of fivefold or greater. The inheritable component seems stronger in Crohn’s disease than in ulcerative colitis. It is of interest that in several countries with historically low rates of IBD, a pattern of rising incidence in the past one to two decades, particularly for Crohn’s disease, has occurred, suggesting that environmental factors are also involved.
Recent studies indicate that the outcome of microbe–host-cell interaction may depend on the competence of the host response rather than the intrinsic invasiveness of the bacteria per se. If the mechanisms for intracellular inhibition and killing are diminished, persistent survival may stimulate progressive inflammation. A better definition of disease, coupled with host gene expression profiles, metabolomic profiling of microbes and metagenomic approaches may help narrow the microbial factors central to disease pathogenesis.
Unravelling the pathogenesis of inflammatory bowel disease
Nature 448, 427-434 (26 July 2007)
