Inflammatory bowel disease risk and the environment: Where to next?

As the number of people diagnosed with inflammatory bowel disease (IBD) increases worldwide, with prevalent cases now estimated to be greater than five million, never has it been more important to understand the causes of IBD. While our medical therapies continue to palliate symptoms through the amelioration of inflammation, a cure for IBD remains elusive. This is despite enormous advances in our understanding of the genetics of IBD through the work of the international IBD genetics consortium and individual groups.1, 2 However, if we are to develop disruptive therapies that can cure or prevent IBD, we must develop a deeper understanding of the environmental aspects of IBD etiology. So, what is currently known about the etiology of IBD? The etiology of IBD is complex involving genes, the intestinal microbiome, and environmental factors. It is also becoming increasingly evident that these three domains of risk may influence each other significantly, rather than being independent of each other.3, 4 Genetics accounts for approximately one quarter of the attributable risk of developing IBD. As noted, this has proven to be fertile ground for researchers as our ability to interrogate the human genome has improved over the last two decades. However, the wave of research into the genetics of IBD has not been matched by increasing knowledge of environmental determinants of IBD. This is despite the acknowledged importance of the environment as a risk factor in a disease that has shown an exponential increase in incidence in just 50 years.5 So, how are we to examine the effect of the environment on the risk of developing IBD? Traditionally, case–control studies have been popular. The frequency of the environmental exposures of interest is compared between those with the disease (cases) and those without the disease (controls) with the direction and magnitude of association being expressed as odds ratios (OR) or hazard ratios with 95% confidence intervals (CIs). While popular and relatively quick to perform, case–control studies have a range of potential problems that may impact on their ability to identify environmental factors associated with the development of IBD. These include control ascertainment and matching, which are a large source of selection bias if performed incorrectly. Additionally, differential or non-differential information bias may be introduced when participants are asked to recall environmental exposure from the near or distant past. The likelihood of information bias occurring will often depend on the mode of data collection and the type of data being collected. For example, questionnaires rely on the recall of events that occurred in the distant past, while review of health records, which have been collected prospectively, may be more accurate. Likewise, events such as appendicectomy or tonsillectomy are more likely to be recalled accurately than dietary data from the distant past. Case–control studies in the domain of IBD are many and varied. These studies have been successful in further elucidating the mechanisms of disease propagation and identification of future therapeutic targets and may identify modifiable risk factors at both the personal and population level. Examples of the former include appendicectomy, which is associated with a 69% reduction in the risk of developing ulcerative colitis (UC)6 and is now being studied in multicentre randomized controlled trials to establish if appendicectomy may be of therapeutic benefit in UC. Examples of the latter would include the association of smoking and Crohn's disease (CD) and the fact that response to therapy is improved by smoking cessation7, 8 and the protective effect of breast feeding with respect to the subsequent development of IBD.9 Similar to appendicectomy, tonsillectomy involves the removal of a portion of mucosal-associated lymphoid tissue, and in its case, the region of tissue first exposed to environmental antigens as they enter the GI tract. It is therefore reasonable to hypothesize that the immunological effects of this may play a role in gut immune function. However, until now, the data regarding the association between tonsillectomy and IBD have been variable. In this edition of the Journal of Gastroenterology and Hepatology, Sun et al. have performed a meta-analysis of 23 observational studies (22 UC and 17 CD) in an attempt to draw more definitive conclusions as to the effect of tonsillectomy on the subsequent development of IBD.10 The results of this meta-analysis found a significant positive association between tonsillectomy and the subsequent development of CD (OR 1.37, 95% CI: 1.16–1.62) but no relationship between tonsillectomy and UC (OR 0.94, 95% CI: 0.84–1.05). This is in direct contrast to the consistent protective effect of appendicectomy in UC seen in many case–control studies.11 In the subgroup analyses, this association with CD was maintained when adjusted for smoking (five studies, pooled OR 1.66, 95% CI: 1.03–2.68) but was not statistically significant in studies, which adjusted for both smoking and appendicectomy (three studies, OR 1.71, 95% CI 0.62-4.69). Further subgroup analyses suggested a stronger relationship between tonsillectomy and CD in non-European (OR 1.52, 95% CI 1.2–1.91) versus European studies (OR 1.29, 95% CI 1.03–1.61), although this finding is limited by the fact that two of the non-European studies involved predominantly Caucasian populations. There was no statistically significant relationship between tonsillectomy and UC in any of the subgroups studied. The strengths of this study include the relatively high quality (18/23 studies scoring ≥7 on the Newcastle–Ottawa scale) and the absence of publication bias. However, it is particularly difficult to adjust for confounding variables, particularly as tonsillectomy may act as a surrogate marker for recurrent childhood infections and antibiotic use, both of which have been implicated in the development of IBD.9, 12, 13 With the environment remaining a compelling but elusive target for IBD research, how should we proceed? Case–control studies have served us well, but selection and information bias continue to prove problematic. It is likely that the key lies in prospective data collection using large cohort studies. However, the relative rarity of IBD as a diagnosis in a general population (0.5% prevalence at the most) means that very large cohorts are required. Investigators have addressed this recently with the initiation of the GEM (Genes, Environment and Microbiome) Project which is recruiting first-degree relatives of CD patients and following them prospectively.14 Those who develop CD are compared with those who do not with regard to multiple biologic, clinical, and demographic variables. Not only is this study attempting to include a wide range of biological samples, environmental data, and associated variables, but also the international collaborative approach being led by Canadian researchers is to be applauded. Such an approach may give insights into disease etiology through comparisons between different populations from around the world. While an enormous step forward, participants are recruited as young people when many relevant environmental exposures may have taken place. It seems likely that important exposures occur in childhood or earlier that may play an important role in the etiology of IBD. After the ground-breaking advances in the genetics of IBD, some of which have led to new therapies although the identification of cellular pathways associated with IBD, perhaps it is now time for research into the environment to come to the fore? Observations through studies like the GEM Project and other prospectively recruited cohorts with high-quality data are needed to enable the next round of environmental risk factor discovery to occur.

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