In the paper by Wapenaar et al (see page 463) the authors have taken a fascinating approach to identifying shared mechanisms involved in the genesis of either coeliac disease or inflammatory bowel disease (IBD). 1 They argue that in these two prototypical inflammatory diseases of the intestinal mucosa there exists reasonable evidence for a defect in barrier function that appears to be required before the development of disease. Furthermore, as both diseases have strong genetic components they speculated that these syndromes might share common genetic defects in the control of intestinal barrier function. They used a genetic association analysis approach and through this identified two adapter protein coding genes that were associated with coeliac disease in patients from both Great Britain and The Netherlands. They went on to demonstrate that one of these genes was also associated with ulcerative colitis in a Dutch patient cohort. These observations are important not only for the conclusions reached in the paper but also in the broader context. Until recently, it was believed that IBD, such as Crohn’s disease, represented dysregulation of the adaptive immune system. Over the past decade, however, there has been increasing recognition of the importance of both epithelial barrier function and innate immunity in the genesis of intestinal inflammation. In the broadest sense these two factors could be argued to be different aspects of the same basic system. Within the gastrointestinal tract there is significant exposure to foreign compounds that can drive systemic inflammation through a variety of mechanisms. The gut has a tremendous number of defence mechanisms that have evolved to manage this ever-changing threat (fig 1). In general terms these include the ability to manage commensal flora in preference to pathogenic organisms, the secretion of toxic molecules such as defensins, the scavenging and binding of luminal organisms by specifically formulated mucins, the presence of regulated tight and adherens junctions between epithelial cells that regulate the passage of potentially pro-inflammatory molecules and the presence of both intra and extracellular pattern recognition molecules that can regulate immunological responsiveness to environmental stimuli. Finally, the adaptive immune system, which sits on top of this large defensive system, can fine tune the responses to a wide variety of environmental agents. It is an amazingly complex system that in most of us functions extremely well! Given the complexity of this defensive system, however, it is not at all surprising that defects in many of these important systems could ultimately lead to inflammatory disease. Furthermore, as the mucosal immune system is ‘‘educated’’primarily in the gut and these cells subsequently migrate elsewhere, it is perhaps not surprising that defects in these systems may lead to inflammatory disease that can be expressed at sites distant to the intestine. This is becoming increasingly apparent in human disease and in animal models of disease. It is beyond the scope of this commentary to review each aspect of mucosal defence exhaustively and there have been excellent reviews recently. 2 I would, however, like to discuss one aspect of gut barrier function; that being abnormal epithelial permeability and disease. The genetic abnormalities described in this paper would appear to fit most closely with this system. Abnormal permeability refers to a measurable increase in flux of small water-soluble compounds across the paracellular pathway of the small intestine. The rate of movement across this pathway is regulated primarily by the functional state of the tight and …