Urbanization of society is an important risk factor for the development of IBD. This meta-analysis suggests that living in urban environments may increase the risk of developing CD and UC. Though, the strengths of association varied among the 40 studies due to heterogeneity between studies. The association between CD and urban environment persisted across a number of stratified analyses that explored clinical and study quality factors. In contrast, the association between UC and urban environment was weaker and less consistent upon sensitivity analyses. Publication bias was not observed suggesting that the association were likely not an artifact of unpublished studies.
Several theories may explain the increased incidence of IBD in urban societies. The Hygiene Hypothesis proposes that the lack of early childhood exposure to enteric pathogens with improved sanitation in urban cities increases the incidence of IBD
[5, 55]. The lack of exposure to enteric pathogens may lead to a greater susceptibility to develop an inappropriate immunologic response upon exposure to new antigens (e.g. gastrointestinal infection) later in life
. Other environmental risk factors of IBD that are more predominant in urban societies include smoking, lack of helminths exposure, and antibiotic use
[57–59]. Additionally, a recent study demonstrated that air pollution in urban cities was associated with IBD in children
. Urban occupations such as driving and manufacturing have also been reported as risk factors for IBD
. While a cohesive hypothesis that explains the environmental determinants of IBD has not been proven, this meta-analysis supports further research exploring the environmental risk factors of urbanization and IBD.
Heterogeneity was observed in both the CD and UC cohort studies, whereas statistically significant heterogeneity was not observed for the UC and CD case–control studies. This inconsistency was likely due to the large overall study population in the cohort studies, leading to an overpowered heterogeneity statistical test. In contrast, the case–control studies were small in total study population. Alternatively, differences in heterogeneity between studies may be explained by the difference in the study design and by the intrinsic biases associated with cohort and case–control studies that explore environmental risk factors of IBD.
When studies were stratified by region the association between UC and urban environment persisted only in non-European studies, whereas the association between CD and urban environment remained significant in most regions. Regional differences may be due to the fact that studies originated from countries that differed by ethnicity, prevalence of IBD, and rates of IBD susceptibility genes
[62, 63]. Alternatively, the small number of studies in each region made appropriate and meaningful inferences challenging. Furthermore, data was lacking for low prevalent regions (i.e. developing world) and thus we could not explore the urban/rural effect in these regions.
We explored whether the year of publication contributed to the heterogeneity observed between studies. For UC, only publications after 1999 were significant after pooling. This time stratified finding may be due to study design differences in more recent publications or the changing pattern of UC diagnosis. In contrast, the urban/rural relationship persisted across all time strata for CD, which suggested a greater strength of association for CD over UC.
The definition of an urban environment was a source of heterogeneity across studies. The studies that clearly defined this exposure included population estimates of the urban and/or rural areas; however, the inconsistency or lack of definitions made study comparisons challenging. We a priori selected the definition of urban as more than 10,000 people because this definition is consistent with census of populations in many Countries (e.g. United Kingdom
 and Canada
). When considering only studies that defined urban as >10,000, the association was no longer significant, which was likely due to the small number of studies with this definition (n = 2 for UC and n = 4 for CD). However, this finding may also reflect that the risk associated with urban society may be driven by greater population size (e.g. living in a metropolis) and/or by population density. Ideally, we would have investigated the potential for a dose response effect to explore whether the risk of IBD increased with increasing population sizes. However, few papers stratified their results by multiple levels of exposure; for example, Tsianos
 and Ladas
 stratified their analysis into urban, semi-rural, and rural. Future studies of the urban–rural association should explore the importance of a dose response effect, a threshold value of population size, and population density.
Heterogeneity between studies may have occurred due to the biases associated with cohort and case–control studies. For the case–control studies, a selection bias may have influenced the association if cases were selected by a different mechanism than controls. The controls were grouped into population- and hospital/clinic-based selection categories. For CD, only population-based controls demonstrated a significant association with urban environment; in contrast, the urban–rural association was insignificant in both control populations for UC. Additionally, inconsistency in timing of exposure (e.g. defining urban–rural status at time of diagnosis versus childhood) may have contributed to the heterogeneity between case–control studies. People in rural settings may have less access to health care leading to under diagnosis of IBD. Although the majority of the case–control studies were matched by age and gender, other potential confounders including socioeconomic status and smoking were often not considered. Finally, studies that used administrative databases to identify IBD patients likely introduced misclassification errors. Interpreting the results of meta-analysis should be cautious because pooling data does not address the intrinsic biases of observational studies.
Limitations in our systematic review should be considered. First, the number of studies included in the stratified analyses was small and may have been underpowered. Second, the quality of studies was not always optimal as was shown with the inconsistent definitions of urban/rural and time of exposure. Third, the included studies used population estimates as indicators for urban environment; however, other factors that contribute to an urban setting, such as socioeconomic characteristics, were not considered. Finally, due to the nature of observational studies, a temporal relationship could not be determined. Thus, urban environment cannot be conclusively established as a causal factor in IBD.