Debate session: So what causes inflammatory bowel disease? It's all in the environment.

Abstract

The past decade has witnessed a revolution in our understanding of the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Significant strides have been made in our understanding of the genetic architecture of these complex diseases, yet the exact cause of IBD remains unclear.1 The relative contribution of genetic and non-hereditary factors in disease pathogenesis also remains to be well established. Considerable lines of evidence suggest that environmental factors may play a dominant role in the pathogenesis of IBD such that these diseases may even be considered “environmental” in origin.2, 3 First, despite significant progress through international collaborative genetic consortia, genetic polymorphisms explain very little of the occurrence of IBD.4, 5 In twin studies, summarized in an elegant review by Brant et al., even in monozygotic twins, the concordance of CD and UC remain only 30% and 15%, respectively, suggesting that genetics incompletely explain disease variance.6 Three large global pooled analyses from genetic consortia have increased the number of risk single nucleotide polymorphisms for CD and UC to 174 and 164 loci, respectively. However, all risk loci together explain only 13% and 8% of the variance of disease. In addition, each single nucleotide polymorphism itself confirms only modest elevated risks with odds ratio for most being between 1.02 and 1.32.7 Further, epidemiologic trends globally have demonstrated that there has been a 2–3 fold increase in the incidence of CD and UC between 1940 and 2010.8, 9 These findings have been demonstrated not just from population-based cohorts in North America and Europe but also from Asian populations where IBD was previously considered very rare.10 In addition, second-generation immigrants from families that have migrated from a region of low incidence to a high IBD incidence country have a risk of IBD that is similar to that of their country of residence and higher than that of their country of origin.11 The temporal changes in IBD incidence also parallel the many epidemiologic trends noted globally with decreasing consumption of dietary fiber, increased consumption of sugars, fats, and processed food, and changes in lifestyle and the external environment. Together, these factors strongly support that the environment plays an important role in the pathogenesis of IBD. Emerging data from prospective cohort studies in the United States and Europe have demonstrated an association between various environmental factors and risk of CD or UC.3 These include an association of higher incidence of CD with lower intake of dietary fiber,12 low vitamin D levels, nonsteroidal anti-inflammatory drug intake, and stress, while a higher intake of n-3 containing PUFA13 is associated with reduced risk of UC. These epidemiologic observations are also supported by various mechanistic studies demonstrating the biological plausibility of these associations exerting an influence on intestinal inflammation by alteration of the microbiome and/or immunologic responses. The final piece of evidence in support for IBD being an environmental disease is that changing behavior alone through either diet modification (exclusive enteral nutrition) or smoking cessation14 has been associated with an improvement in disease course like that observed with certain pharmacologic therapies. Thus, there is now a wealth of evidence from clinical observations, epidemiologic studies, and laboratory experiments that suggests a strong effect of the external environment on IBD pathogenesis and subsequent course.