[Genetics of inflammatory bowel disease]

Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from an inappropriate immune response towards the microbial flora in a genetically susceptible host. Several epidemiological and animal studies have demonstrated the essential role of the microbial flora in the triggering and perpetuation of intestinal inflammation. IBD are multigenic and heterogeneous diseases, and result from multiple low penetrant genes or group of genes. The genetic strategy for gene hunting in multigenic studies relies on two separate approaches. A candidate gene approach which is based on a robust biological hypothesis. A more systematic/global approach is either based on linkage studies (in late 90s) on IBD families or, since 2000 on gene arrays, the genome wide arrays (GWAS) on patients and controls. In 2001, the first CD susceptible gene, NOD2, was discovered, and found to be a pattern recognition receptor for bacteria, shedding light on the role of bacterial recognition in the triggering of the disease. Since 2000, GWAs have greatly accelerated the discoveries of new genes or signalling pathways in Crohn's disease and ulcerative colitis, confirming the importance of bacterial recognition, but also of bacterial defence (i.e. autophagy genes) as well as the role of the adaptive immune response (i.e. IL-23R/Th17 pathway). Despite the role of genetics in the development of IBD, changes in the development and composition of the microbial flora, known as dysbiosis, (possibly induced by our Western life style) must alter the development and function of the mucosal immune system, and leads to disease expression.