Introduction
Inflammatory bowel disease (IBD) is a disabling intestinal condition of unclear etiology affecting over two million people in Europe alone [
1]. Both Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of IBD, are thought to result from a complex interplay between the immune system and gut microbiota in genetically susceptible individuals [
2]. Yet, the changing epidemiology of IBD supports a key role for environmental factors in the development of this chronic disorder [
3].
The incidence of IBD in Western countries has increased over the last century but currently appears relatively stable, whereas a rapid disease emergence is observed in developing nations, where IBD was formerly uncommon [
4,
5]. Consequently, industrialization and westernization of lifestyle have been linked to the etiology of CD and UC [
3,
6,
7]. Although various risk factors, such as diet [
8], have previously been proposed, these do not fully explain the increase in the incidence of IBD and other environmental changes must therefore be involved [
9].
Air pollution is associated with industrialization and consists of a complex mixture of different substances, such as particulate matter (PM). Although air pollution has mainly been associated with cardiorespiratory disorders [
10], limited experimental and epidemiological data suggest that air pollutants may also exert deleterious gastrointestinal effects [
11]. Potential mechanisms by which air pollutants may cause intestinal injury are thought to include direct adverse effects on epithelial cells, alterations in immune responses, or modulation of the gut microbiota [
11‐
14].
Epidemiological studies examining the relationship between air pollution and IBD are scarce. In a case–control study from the UK, children and young adults, but not older individuals, living in areas with high-level exposure to nitrogen dioxide (NO
2) and sulfur dioxide had an increased risk of developing CD and UC, respectively, indicating possible age-related effects [
15]. However, this study was based on regional air pollution estimates, limiting exposure assessment. Therefore, we aimed to investigate the association between residential exposure to ambient air pollution and IBD in a nested case–control study within a multicenter European cohort. Based on previous studies, we hypothesized that air pollution exposure increases the risk of developing CD and UC.
Results
A total of 38 CD cases (median age at diagnosis 56.2 years, 76.3 % female) and 104 UC cases (median age at diagnosis 55.2 years, 70.2 % female) with air pollution measures were identified (Table
2). The median time between recruitment and diagnosis was 4.5 years [interquartile range (IQR) 2.3–6.8 years] and 3.8 years (IQR 2.1–6.4 years) for CD and UC, respectively. Fourteen CD cases (36.9 %) had ileal disease. Left-sided colitis (involvement limited up to the splenic flexure) was the commonest disease phenotype in UC cases (
n = 45, 43.6 %). Air pollution estimates were available for 100, 90, 83, 70, and 27 % of controls from the Dutch Prospect cohort, the British cohort, the Dutch MORGEN cohort, the Danish cohort, and the French cohort, respectively. The distribution of air pollutant concentrations and traffic indicators for all IBD cases and controls per individual cohort is presented in Supplementary Tables 1–5. These tables show that within cohorts, pollution distributions were generally very similar between cases and controls and that in some cohorts, the concentration ranges of especially PM
2.5 and PM
10 were very small. The correlations between these estimates are presented in Supplementary Tables 6–10.
Table 2
Characteristics of inflammatory bowel disease cases and controls
Female, n (%) | 29 (76.3) | 116 (76.3) | 73 (70.2) | 292 (70.2) |
Age (years) at recruitment, median (IQR) | 50.9 (44.7–60.9) | 50.3 (44.5–59.0) | 50.7 (43.2–56.1) | 50.9 (43.2–56.6) |
Age (years) at diagnosis, median (IQR) | 56.2 (49.7–63.6) | – | 55.2 (48.1–60.9) | – |
Distribution of Crohn’s disease, n (%) |
L1, ileal | 14 (36.9) | – | – | – |
L2, colonic | 13 (34.2) | – | – | – |
L3, ileocolonic | 10 (26.3) | – | – | – |
+ L4, upper gastrointestinal disease | 1 (2.6) | – | – | – |
Unknown | 0 (0.0) | – | – | – |
Distribution of ulcerative colitis, n (%) |
E1, ulcerative proctitis | – | – | 25 (24.3) | – |
E2, left-sided colitis | – | – | 45 (43.6) | – |
E3, extensive colitis | – | – | 26 (25.2) | – |
Unknown | – | – | 7 (6.8) | – |
Smoking status at recruitment, n (%) |
Never smoker | 13 (34.2) | 52 (34.2) | 36 (34.6) | 180 (43.3) |
Former smoker | 10 (26.3) | 54 (35.5) | 34 (32.7) | 118 (28.4) |
Current smoker | 15 (39.5) | 44 (28.9) | 33 (31.7) | 116 (27.9) |
Unknown | 0 (0.0) | 2 (1.3) | 1 (1.0) | 2 (0.5) |
Highest educational level at recruitment, n (%) |
Primary school | 4 (10.5) | 29 (19.1) | 15 (14.4) | 61 (14.7) |
Technical school | 17 (44.7) | 38 (25.0) | 36 (34.6) | 128 (30.8) |
Secondary school | 10 (26.3) | 39 (25.7) | 22 (21.2) | 91 (21.9) |
Higher education | 7 (18.4) | 45 (29.6) | 27 (26.0) | 116 (27.9) |
Not specified | 0 (0.0) | 1 (0.7) | 4 (3.8) | 14 (3.4) |
Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 6 (1.4) |
No statistically significant associations were detected between air pollution exposure and either CD (Table
3) or UC (Table
4), apart from a positive association for total traffic load on all major roads within a 100-m buffer [OR 1.58 (95 % CI 1.00–2.49) per 4,000,000 motor vehicles m per day] in the crude analysis of UC. The effect sizes were largely similar for the univariable and multivariable analyses and for CD and UC. In the crude analysis of CD and UC combined, residential exposure to PM
2.5 was inversely associated with IBD, with an OR of 0.28 (95 % CI 0.08–0.94) per 5 μg/m
3 (Table
5). A positive association was found for total traffic load on all major roads [OR 1.60 (95 % CI 1.06–2.43) per 4,000,000 motor vehicles × m per day]. These associations remained statistically significant with similar effect sizes after adjusting for smoking status and educational level in the multivariable analysis. Additionally, PM
10 concentrations were inversely associated with IBD in the multivariable model, with an OR of 0.25 (95 % CI 0.08–0.78) per 10 μg/m
3. Excluding data of the French cohort, which had the lowest proportion of IBD cases (
n = 15) and controls with air pollution measures (
n = 20), did not affect the direction of the effect sizes materially (data not shown). The associations for PM
2.5 per cohort are presented in Supplementary Fig. 1. In the analysis based on tertiles, significant inverse associations were detected for PM
2.5 (
p
trend = 0.01) and PM
coarse (
p
trend = 0.04) in IBD (Supplementary Table 11). Air pollution estimates back-extrapolated to the baseline year of each participant were generally higher than those during 2008–2011. Although no statistically significant associations were found, the sensitivity analyses for IBD for back-extrapolated concentrations of NO
2, NO
x
, PM
2.5 absorbance and PM
10 showed similar effect sizes as for nonback-extrapolated concentrations, apart from PM
2.5 absorbance (Table
5).
Table 3
Association between air pollution exposure and Crohn’s disease (n = 38 cases)
NO2
| 1.25 (0.68–2.30) | 1.13 (0.59–2.16) |
NO
x
| 1.26 (0.75–2.12) | 1.17 (0.67–2.03) |
PM2.5
| 0.29 (0.03–2.71) | 0.12 (0.01–1.77) |
PM2.5 absorbance
| 0.59 (0.11–3.03) | 0.34 (0.04–3.05) |
PM10
| 0.45 (0.07–2.90) | 0.10 (0.01–1.37) |
PMcoarse
| 1.07 (0.17–6.55) | 0.59 (0.07–4.98) |
Traffic intensity on the nearest roadb
| 1.18 (0.82–1.70) | 1.16 (0.79–1.71) |
Traffic intensity on major roads within 100-m bufferb
| 1.92 (0.64–5.82) | 1.81 (0.50–6.47) |
Table 4
Association between air pollution exposure and ulcerative colitis (n = 104 cases)
NO2
| 1.03 (0.73–1.46) | 0.99 (0.70–1.41) |
NO
x
| 1.06 (0.79–1.43) | 1.03 (0.76–1.38) |
PM2.5
| 0.27 (0.06–1.17) | 0.23 (0.05–1.02) |
PM2.5 absorbance
| 1.19 (0.48–2.96) | 1.20 (0.48–2.98) |
PM10
| 0.34 (0.09–1.27) | 0.28 (0.07–1.07) |
PMcoarse
| 0.38 (0.11–1.35) | 0.31 (0.09–1.10) |
Traffic intensity on the nearest roadb
| 1.08 (0.90–1.29) | 1.06 (0.88–1.27) |
Traffic intensity on major roads within 100-m bufferb
| 1.58 (1.00–2.49) | 1.55 (0.97–2.46) |
Table 5
Association between air pollution exposure and inflammatory bowel disease (n = 142 cases)
NO2
| 1.08 (0.80–1.46) | 1.05 (0.77–1.42) |
NO
x
| 1.11 (0.86–1.43) | 1.08 (0.83–1.40) |
PM2.5
| 0.28 (0.08–0.94) | 0.24 (0.07–0.81) |
PM2.5 absorbance
| 0.99 (0.45–2.17) | 1.03 (0.45–2.34) |
PM10
| 0.37 (0.13–1.09) | 0.25 (0.08–0.78) |
PMcoarse
| 0.52 (0.19–1.45) | 0.42 (0.14–1.20) |
Traffic intensity on the nearest roadb
| 1.09 (0.93–1.28) | 1.07 (0.92–1.26) |
Traffic intensity on major roads within 100-m bufferb
| 1.60 (1.06–2.43) | 1.60 (1.04–2.46) |
Back-extrapolated NO2
| 1.14 (0.78–1.66) | 1.07 (0.73–1.59) |
Back-extrapolated NO
x
| 1.15 (0.86–1.55) | 1.10 (0.81–1.49) |
Back-extrapolated PM2.5 absorbance
| 0.46 (0.07–3.10) | 0.40 (0.06–2.78) |
Back-extrapolated PM10
| 0.20 (0.02–2.22) | 0.17 (0.02–2.01) |
Discussion
In this European multicenter study, no consistent association between residential exposure to ambient air pollution and the risk of IBD was found. The effect sizes were mostly similar for CD and UC separately. Individuals with IBD were less likely to have higher exposure levels of PM2.5 and PM10, whereas a positive association was observed for total traffic load on all major nearby roads. Other air pollutants were mostly positively but not statistically significantly associated with IBD. Although not reaching statistical significance, the effect sizes were broadly similar when back-extrapolating air pollutant concentrations to the participants’ baseline year.
Numerous studies have confirmed the association of ambient air pollution with a variety of diseases, and several underlying biological mechanisms have been proposed [
10,
17,
24,
25]. The link between air pollution and intestinal health is, however, less well established with a few studies showing positive associations with colorectal cancer, appendicitis, and nonspecific abdominal pain [
26‐
30]. In this respect, the adverse effects of smoking [
31,
32], which may have some resemblance with air pollution, may help indicate the potential impact of air pollution exposure. It is hypothesized that exposure to air pollutants may contribute to the development of intestinal disorders, including IBD, through diverse biological mechanisms. First, ingestion of air pollutants by inhalation or contaminated foods may have direct toxic effects on epithelial cells, which may induce proinflammatory responses and increase gut permeability [
11]. Second, various studies have shown that air pollution exposure may result in systemic inflammatory effects, such as changes in circulating cytokines, including tumor necrosis factor alpha [
33]. Notably, air pollution has also been related to immunologically mediated disorders that may share some epidemiological and pathogenic aspects with IBD [
34]. For instance, exposure to PM
10 has been associated with an increased risk of relapse in multiple sclerosis [
35], whereas traffic exposure has been found to be positively associated with incident rheumatoid arthritis [
36]. Third, it is thought that air pollution may modulate the microbial composition of the gut [
14], as recently exemplified in two studies in which PM exposure in mice led to significant alterations in the microbiota and induced acute and chronic intestinal inflammatory responses [
12,
13].
To date, very few epidemiological studies explored the effects of air pollution in IBD. In a nested case–control study from the UK, in the whole population, no significant association between air pollution and incident IBD was found [
15]. However, children and young adults living in areas with higher levels (within the upper three quintiles) of NO
2 and sulfur dioxide, respectively, were more likely to develop CD [OR 2.31 (95 % CI 1.25–4.28) for individuals aged ≤23 years] and UC [OR 2.00 (95 % CI 1.08–3.72) for individuals aged ≤25 years]. Land-use regression models for more refined exposure assessments could not be incorporated in this study. An ecological analysis from the US related hospitalizations for IBD to air pollution emissions from an emission inventory, but was unable to estimate air pollution concentrations [
37]. In our study, which included mainly middle aged to elderly people, we observed opposing associations. This could indicate that different pollutants have differential effects in specific groups. For example, younger people (with a developing immune system) might be more susceptible to air pollutants as compared to older people. Importantly, children and young adults are also likely to spend more time outdoors and near their home, which may increase and better reflect true personal exposure. Exposure assessment may therefore be more accurate in these individuals. There were no statistically significant associations for CD and UC separately, which presumably resulted from the relatively small numbers of cases. Disease-specific results may exist, as previously observed, for example, in the opposing associations for smoking between CD and UC [
22], although the effect sizes were mostly similar for both forms of IBD in our study. We observed inverse associations for some pollutants, which appeared largely consistent across centers and in the analyses using pollution exposure as continuous and categorical variables. It remains unclear whether these associations reflect a true causal relationship or that these pollutants are a proxy for other variables. Interestingly, in the earlier mentioned study, PM
10 and NO
2 concentrations were inversely associated with CD in individuals aged 44–57 years with ORs of 0.48 (95 % CI 0.29–0.80) and 0.56 (95 % CI 0.33–0.95), respectively [
15], demonstrating that inverse associations have previously been observed in older patients in another population using a different methodological approach. Overall, despite previous data suggesting that air pollutants may negatively impact IBD, no coherent associations have currently been confirmed to draw firm conclusions on the putative adverse effects of air pollution exposure in CD and UC, indicating the need for further research.
This study had several strengths. First, the multicenter design enabled us to explore the association between air pollution and IBD in several European countries. Second, a significant advantage over previous studies was the use of land-use regression models to accurately determine small-scale variations in residential exposure to air pollution and traffic intensity for each participant according to a highly standardized protocol. Third, both cases and controls were drawn from the same baseline population, thereby reducing the risk of selection bias. Fourth, to ensure case ascertainment all diagnoses were confirmed by local physicians and participants with indeterminate or microscopic colitis were excluded. Fifth, the number of cases was similar to what was expected, which reduces the likelihood of follow-up bias [
38].
Despite nesting in a well-characterized cohort, the limited sample size was an important drawback and our study may have been underpowered to detect statistical differences. Therefore, we chose to evaluate outcomes for CD and UC separately and for total IBD. Furthermore, air pollution estimates were assessed only at the residential address of each participant and not, for example, at their working address, where individuals may also be exposed. This could have resulted in misclassification of exposure. Moreover, air pollution was measured after diagnosis, which was a general issue in epidemiological studies using ESCAPE exposure data, such as in a previous study linking air pollution to mortality [
17]. However, previous studies show that spatial air pollution contrasts remain stable over long periods of time and are well predicted with land-use regression models [
39‐
43]. Using back-extrapolation, we evaluated the association for some pollutants at the baseline year of each participant, with effect sizes being broadly similar to the main analyses. It has been estimated that most of the participants did not move after enrollment [
17], but exact data on moving were unavailable for all centers. The majority of cases developed IBD over the age of 50 years, indicating late-onset IBD, whereas CD and UC commonly present at an earlier age. This limited the opportunity to study age-specific effects, and the results may therefore not be generalizable to the whole IBD population as other phenotypes may have different environmental influences. Considering the limited sample size and multiple comparisons, we cannot entirely exclude that our results are due to chance findings. Finally, although we were able to either match or adjust for potential confounders, such as center and smoking, residual confounding (by unknown risk factors) could not be fully excluded in this observational study.
To conclude, we were unable to demonstrate a consistent association between residential exposure to ambient air pollution and IBD risk in this European multicenter cohort.
Acknowledgments
J.L.O. was supported by an unrestricted research grant from Dr. Falk Pharma. The coordination of the European Prospective Investigation into Cancer and Nutrition (EPIC) study was financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer (IARC). The national cohorts were supported by the Danish Cancer Society (Denmark); Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, French Institute of Health and Medical Research (INSERM) (France); Dutch Ministry of Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (the Netherlands); Cancer Research UK C8221/A19170, Medical Research Council MR/M012190/1 (UK). The European Study of Cohorts for Air Pollution Effects (ESCAPE) study has received funding from the European Community’s Seventh Framework Program (FP7/2007-2011) under Grant Agreement No. 211250.