Ambient air pollution and inflammatory bowel disease—a narrative review

Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that affects the gastrointestinal tract, including Crohn’s disease (CD) and ulcerative colitis (UC) (1). Its etiology remains unknown, but it results from an exaggerated immune response to a trigger in susceptible individuals (2). Long-term or chronic exposure to air pollution has been linked to the development of respiratory diseases and other chronic inflammatory disorders, such as multiple sclerosis and rheumatoid arthritis. These conditions share certain epidemiological and pathogenic characteristics with IBD (3-5).

The incidence of IBD has significantly increased in developing countries over the past few decades, shedding light on the potential role of air pollution as an environmental trigger. Air pollution resulting from industrial progress interacts with susceptible host cells via various mechanisms. It can reversibly alter gene function without modifying the DNA sequence and may play a significant role in the induction or modification of IBD expression. Ambient air pollution exposure, especially during early life stages, may alter the microbiome’s composition and diversity, which could potentially heighten the probability of developing IBD in later stages of life (6).

The objective of this paper is to review air pollution as a potential risk factor for IBD development. We present this article in accordance with the Narrative Review reporting checklist (available at https://dmr.amegroups.com/article/view/10.21037/dmr-23-12/rc).

Methods

We searched PubMed, Embase, and Cochrane Library databases to identify studies published up to September 15, 2023. The search strategy was as follows: (pollution) AND (“inflammatory bowel disease” OR IBD OR Crohn OR “ulcerative colitis”).

Two authors conducted an independent screening of all studies identified through the database search, initially based on titles and abstracts. After removing duplicate records and unrelated studies based on the titles and abstracts, full texts of potentially relevant articles were reviewed for inclusion if they met the predefined criteria [(I) observational studies (case series, case reports and cohort studies), reviews, meta-analysis and other studies; (II) reporting data on air pollution and IBD; (III) written in English, Portuguese or Spanish]. We also analyzed references from relevant original articles and literature reviews to identify additional studies that were not encompassed in the initial database searches. Disagreements were resolved through consensus or by a third author. For all eligible studies, we provided a narrative analysis of the findings. The search strategy summary is described in Table 1.

Results

Air pollution is a complex mixture of heterogeneous substances. The most studied gases in its composition include carbon dioxide (CO₂), carbon monoxide (CO), ozone (O₃), nitric oxide (NO), nitrogen dioxide (NO₂)—often used as a proxy for air pollution related to traffic, nitrogen oxides (NO_x), sulfur dioxide (SO₂), volatile organic compounds, and par ticulate matter (PM) of varying sizes—for example, PM10 and PM2.5 (7,8).

Studies have demonstrated that inhaled PM pollutants are efficiently cleared from the lungs into the intestine through mucociliary transport (8). These ingested contaminants can have direct and indirect effects on intestinal epithelial cells. Directly, they can alter tight junction proteins, leading to increased production of reactive oxygen species and permeability. Indirectly, these pollutants interact with gut microbiota, resulting in the production of toxins that have further negative effects (9).

Air pollutants can decrease microbes’ diversity and composition, reducing butyrate and short chain fatty acids production and increasing toxic metabolites output (9). This results in a feedback loop, enhancing the deleterious damage of the gut epithelial cells and inducing a pro-inflammatory response with a T cell activation and a Th1, Th17 and Th2 response (9,10). Based on these findings and epidemiological data, researchers conducted studies to explore the association between air pollution and gastrointestinal diseases. The studies assessed not only the pollutant concentration but also the duration of exposure. Despite significant limitations in the results, an association was found between sudden spikes in air pollution and incidents of gastroenteritis (11), non-specific acute abdominal pain (12), and appendicitis (13).

The rising and changing epidemiology of IBD over time and geography, particularly in emerging countries, indicates a potential association of accelerated industrialization and urbanization and IBD expression (14). Industrialization and urbanization can have various consequences that could be considered as triggers for IBD, such as changes in diet, use of antibiotics, hygiene, exposure to microorganisms, and, perhaps most importantly, pollution of water and air (3,14).

Li et al. analyzed the association of various specific air pollutants with the risk of incident IBD, among middle and old aged adults in UK, using a Biobank. Result of their analysis showed that long-term exposure to several air pollutants was associated with the risk of incident UC but not CD (7). A subgroup analysis of the study showed that the connection between all air pollutants and the likelihood of incident UC was significant for non-smokers but not for current smokers (7). The observed outcomes may be accounted for by the impact of nicotine on the production of mucus in the colon, which in turn limits the activity of inflammatory mediators including thromboxane synthetase, cyclooxygenase, and lipoxygenase. Subsequently, there is a plausible link to reduced risk of inflammation and potential mitigation of the negative impact of air pollution on the digestive system (12).

In a case-control study from the UK, Kaplan et al. found that NO₂ was associated with a higher risk of UC in young individuals but highlighted the need for further studies in different sub-populations. The same study observed a higher risk of CD among participants aged <23 years who had postnatal NO₂ exposure (15). This theory of children being more susceptible to the adverse effects of air pollution than adults were further examined in a study conducted in Canada. The study established a correlation between exposure to O_x during childhood and the development of IBD before the age of 18 (16).

Although a link between air pollutants and CD was not observed, Li et al. discovered an association between the risk of CD and the interaction of PM10 and NO₂ in men (7).

In 2022, Adam et al. published a retrospective observational study on 8,136 patients and found a positive association between PM and the risk of autoimmune diseases. In particular, exposure to PM10 was associated with rheumatoid arthritis, while exposure to PM2.5 was associated with rheumatoid arthritis, connective tissue diseases and IBDs. It should be noted that PM2.5 molecules, given their smaller diameter, are less affected by rain and weather conditions than larger PM. In fact, PM2.5 concentrations tend not to fluctuate in response to rain and may represent a more accurate indicator of chronic exposure to air pollution than PM10 (17).

In 2010, Kaplan et al. published a study attempting to link air pollution and IBD. Their analysis revealed that individuals residing in areas with NO₂ concentrations in the highest quintile were more likely to develop CD before the age of 23 than those from areas in the lowest quintile. Additionally, the researchers observed a similar association with UC instead of CD when investigating exposure to SO₂ (15).

Some air pollutants may worsen the evolution and prognosis of IBD. In 2011, Ananthakrishnan et al. conducted an American ecological analysis, which indicated a significant correlation between countries with higher air pollution emissions and the number of hospitalizations for IBD in adults: for every 1-log increase in the density of total criteria pollutant emissions, there was a 40% increase in the rate of hospitalization (18).

In their study, Ding et al. explored whether daily exposure to PM, O₃ and CO was linked to the risk of IBD hospitalizations in two Chinese hospitals. Each increase of 10 mg/m³ of PM, O₃ and 0.1 mg/m³ of CO increased the risk of IBD, with the effect being stronger in hot seasons (19).

The most recent paper on this subject is a prospective cohort study published in 2023 by Chen et al., which analyzed the risk of enterotomy, gastrointestinal cancer and all-cause mortality in 4,708 patients with an average follow-up of 12 years. They found that each interquartile range increases in PM2.5 exposure was associated with an increased risk of enterotomy. An increased exposure to NO_x and NO₂ was also associated with increased all-cause mortality in IBD patients (20).

Several hypotheses have been proposed to explain the link between air pollution and IBD. These include the direct toxic effects of inhaled air pollution on epithelial cells, which can lead to gut microbiome disturbance, increased gut permeability, and immune response induction. Experimental data has shown that chronic exposure to PM can cause high levels of pro-inflammatory cytokines, as well as disruptions in microbiota composition and colon function in mice (3,8,21).

There are notable strengths in this review. We conducted an extensive literature review and could then offer insightful analysis and potential areas for further research on the topic. However, this study is also constrained by certain limitations, particularly those associated with conducting a narrative review, such as potential bias in the assessment of retrieved articles and interpretation of results. Despite all the epidemiological studies published to date on the relationship between air pollution and IBD, conflicting and inconsistent results persist, and significant knowledge gaps remain. Therefore, there is an urgent need for more prospective cohort studies to determine how air pollution affects IBD. The investigation should not only identify environmental factors associated with IBD, but also explore how these exposures are linked in terms of duration, frequency, and temporality, as highlighted by Vieujean et al. in their review about the impact of exposome on the epigenome in IBD (22).

Conclusions

The development of IBD is linked to a range of risk factors, including genetic susceptibility, diet, immune dysregulation, and environmental triggers. Although the effect of air pollution on IBD pathogenesis has yielded contradictory findings, its ability to increase pro-inflammatory cytokine expression, disrupt microbiota composition and colonic function suggests an increased risk of incident IBD. Several gaps still exist, indicating that additional prospective cohort studies are necessary to determine this association.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Patrick Varga-Weisz and Raquel Franco Leal) for the series “Evidence of Epigenetics in Inflammatory Bowel Diseases” published in Digestive Medicine Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dmr.amegroups.com/article/view/10.21037/dmr-23-12/rc

Peer Review File: Available at https://dmr.amegroups.com/article/view/10.21037/dmr-23-12/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dmr.amegroups.com/article/view/10.21037/dmr-23-12/coif). The series “Evidence of Epigenetics in Inflammatory Bowel Diseases” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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