Genes and environment: how will our concepts on the pathophysiology of IBD develop in the future?

Abstract

Inflammatory bowel disease (IBD) has long been known to arise from the interplay between host and environmental factors. From this, a picture is currently emerging in which IBD is likely the result of a continuum of diseases that range from mono- and oligogenically inherited familial forms at one extreme to sporadic forms at the other extreme, which are polygenic in origin and strongly influenced by environmental factors and especially those of infectious origin. The recent expansion of knowledge on the genetic underpinning of IBD has revealed several converging and inter-related functional host pathways that are central to the pathogenesis of these disorders. These include pathways such as autophagy, intracellular bacterial sensing and the unfolded protein response, which play specific roles at the interface between the host and the highly complex microbial communities within the intestines. As such they focus on the functional relationship between the intestinal epithelium and the unique microbial and immune environments along its luminal and abluminal surfaces. Thus, the genetic and environmental factors which are relevant to IBD seem to have the common property of influencing disease by virtue of their specific impact upon the functional relationship between these microbial communities and the intestinal immune system.

Fig. 1

The syndromic nature of IBD: a model.

Fig. 2

A ‘two-hit’ hypothesis for the pathogenesis of IBD. Genetic and environmental factors are risk factors for IBD as they determine the composition and function of the microbiota and the immune responsiveness of the host to microbial factors. NSAIA = Nonsteroidal anti-inflammatory agents.

Fig. 3

The immunogenetic relationship between the processes of the UPR in response to ER stress, autophagy and intracellular (myco)bacterial and viral sensing. Genetic factors in gray type (red in the color version) are those specific for CD, those in bold type (blue in the color version) are observed in UC and CD, and those in normal-weight black type have only been determined to date in animal models.