Interaction between susceptibility and environment: examples from the digestive tract

During the last few years a significant advance has been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). From twin studies it was evident that there is more that 50% concordance of Crohn's disease (CD) in monozygotic twin pairs, however it is only 3.6% among dizygotic twins. These data indicate that the genetic background may be responsible for 50% of the risk or 'susceptibility' to develop CD. Obviously it is not a sufficient condition as otherwise there would be 100% concordance of disease in monozygotic twin pairs. Environmental factors as well must play an important role. This is further supported by the fact that there is only low development in genetic risk factors over ten thousands of years. In contrast, the incidence of CD and ulcerative colitis (UC) has dramatically increased in Western countries in the last 100 years. This further supports the concept of a 'Western lifestyle factor(s)' that triggers chronic intestinal inflammation in a genetically susceptible host. The proof of the concept of a genetic susceptibility was achieved in 2001 with the discovery that NOD2 is the most important susceptibility gene for CD. The function of NOD2 has been investigated in detail. NOD2 is an intracellular 'alarm button', a receptor recognizing invading bacteria that entered the mucosal wall. NOD2 mutants associated with susceptibility to CD seem to be deficient in their recognition of bacterial wall products. In a genome-wide association study a disease association was found in the autophagy-related 16-like 1 gene (ATG16L1). The ATG16L1 gene encodes a protein in the autophagosome pathway that processes intracellular bacteria. Based on these findings, CD is now discussed as an impaired and inadequate immune reaction to the gut bacteria which are a part of our environment (or perhaps 'in-vironment'). In addition to NOD2 and ATG16L1, there are more 'innate' pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa. The 'environment concept' and the 'genetic concept' of IBD pathophysiology are converging. With the finding that most susceptibility genes for CD and UC are involved in innate immune mechanisms and the primary defense against bacteria entering the mucosa, for the first time a unifying concept of the 'genetic pathophysiology hypothesis' and the 'environment pathophysiology hypothesis' of IBD was possible. Bacteria are the link between the environment and mucosal defense system.