Henrik Olstrup1*
Hani A. S. Mohamed2Julie Honoré2Jörg Schullehner2,3
Torben Sigsgaard2,3Bertil Forsberg1
Anna Oudin1,4
- 1Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
- 2Department of Public Health, Aarhus University, Aarhus, Denmark
- 3The Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark
- 4Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
This systematic literature review investigates the relationship between air pollution exposure and inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC). Despite the growing concern over air pollution's impact on various health outcomes, studies specifically addressing effects on the digestive system, particularly IBD, are relatively rare. This review aims to synthesize the current knowledge on this topic, focusing on the mechanisms underlying these associations and the role of different air pollutants. Following PRISMA guidelines, a systematic literature search of PubMed and Web of Science databases was conducted, yielding 13 epidemiological studies and six mechanistic (toxicological) studies meeting the inclusion criteria. The epidemiological studies examined associations between IBD and various air pollutants, including PM2.5 (particles with an aerodynamic diameter smaller than, or equal to, 2.5 µm), PM10 (particles with an aerodynamic diameter smaller than, or equal to, 10 µm), PM2.5–10 (coarse particles with an aerodynamic diameter in the range of 2.5–10 µm), BC (black carbon), NO2 (nitrogen dioxide), NO (nitrogen monoxide), NOx (nitrogen oxides), N2O (nitrous oxide), CO (carbon monoxide), SO2 (sulfur dioxide), VOC (volatile organic compounds), O3 (ozone), Ox (oxidant capacity), and traffic load. Study methodologies varied among these 13 epidemiological studies, including four cohort studies, two ecological studies, three case-control studies, two studies using two-sample Mendelian randomization, and two longitudinal time-series studies. Eight studies investigated associations with Crohn's disease and ulcerative colitis separately, while five studies analyzed IBD as a whole without distinguishing between CD and UC. Eleven studies found statistically significant associations between air pollution exposure and IBD, although inconsistent results were found in several of these studies. A total number of six mechanistic (toxicological) studies were retrieved. Among these six studies, five were using particulate matter as exposure metric, and one was based on NO2 and O3 as exposure metrics. With a combination of animal, human, and in vitro studies, the results in terms of biological mechanisms indicate that air pollution exposure influences the composition of the gut microbiome, altering metabolic functions within the gut, and creates immunological reactions with inflammation contributing to the development of IBD. Consequently, the results suggest a link between air pollution exposure and both the onset and exacerbation of IBD. However, differences in study design, exposure assessment, and pollutant types make it challenging to draw any firm conclusions. Moreover, the lack of multi-pollutant models in most epidemiological studies makes it difficult to estimate the individual effect of specific air pollutants. This review highlights the need for further research utilizing robust study designs and standardized exposure assessment methods to better understand the impact of air pollution on IBD. By elucidating these associations, policymakers and healthcare professionals can develop effective strategies to mitigate the adverse effects of air pollution on digestive health.
1 Introduction
Exposure to air pollution has, in a wide range of studies, been shown to have detrimental health effects. According to the World Health Organization, ambient (outdoor) air pollution is estimated to have caused around 4.2 million premature deaths worldwide in 2019 (1). Moreover, ambient PM2.5 was the fifth-ranking risk factor of preterm mortality in 2015 (2). In epidemiological studies focusing on health outcomes associated with air pollution exposure, increased mortality has often been used as a metric. Harmful health effects in terms of increased mortality associated with exposure to air pollution have been shown in several studies focusing on both short- and long-term relationships. Long-term mortality effects associated with air pollution have been shown for both NO2 (3–6) particulate matter (7), and O3 (6, 8) although the results for O3 are less clear and consistent. Likewise, associations between short-term exposure to air pollutants and mortality have been shown for NO2 by Wang et al. (9), for O3 by Vicedo-Cabrera et al. (10), and for PM10 and PM2.5 by Orrelano et al. (11). Moreover, cardiovascular and respiratory outcomes as well as cancer can be captured by calculating cause-specific mortality. Associations between air pollution exposure and cardiovascular mortality and respiratory mortality (less clear for respiratory mortality though) have been shown in a systematic review by Hoek et al. (12), and for cancer mortality in a meta-analysis of cohort studies by Kim et al. (13). However, many other health outcomes associated with air pollution exposure are more difficult to capture using mortality as a metric (14).
Neurodegenerative and psychiatric disorders as well as immune-mediated disorders have been shown to be associated with air pollution exposure, but are less well captured by mortality. When considering neurodegenerative disorders, associations between air pollution have been shown for both dementia (15–17), Parkinson's disease (18–21), and multiple sclerosis (22–24). Regarding psychiatric disorder, an association between air pollution exposure and depression has been shown by Borroni et al. (25). Moreover, a potential link between particulate matter and depression, anxiety, and suicide was suggested in a systematic review and meta-analysis by Braithwaite et al. (26).
Other immune-mediated diseases, including autoimmune diseases, have also been shown to be influenced by air pollution exposure (27). Regarding rheumatic diseases, effects from air pollution exposure were demonstrated for both systemic autoimmune rheumatic diseases (SARD) by Celen et al. (28) and Sun et al. (29), and for rheumatic arthritis (RA) by Di et al. (30) and by Essouma and Noubiap (31). Associations between air pollution exposure and RA are also supported by both toxicological, clinical, in vitro and in vivo studies (32–35).
Studies on the effects of air pollution exposure on the digestive system are not as abundant as many of the outcomes mentioned above. Inflammatory bowel disease (IBD) constitutes an umbrella term for some different types of inflammatory conditions in the gut. The two main types of IBD referred to are Crohn's disease (CD) and ulcerative colitis (UC). Both these conditions affect the bowel, but they manifest differently with different mechanisms of emergence (36), and exhibit clear differences in terms of bacterial composition in the gut (37). Ulcerative colitis is an inflammatory disorder of the colonic mucosa, which generally manifests in a continuous manner through part of, or the entire large intestine (38). Crohn's disease (Morbus Crohn) constitutes a relapsing systemic inflammatory disease, which can potentially manifest in parts of the whole gastrointestinal tract, and with extraintestinal manifestations and associated immune disorders (39). The prevalence of IBD has increased worldwide during the last decades (40), and this increase has been particularly marked in the Western world (41, 42), however, newly industrialized countries whose societies have become more westernized also show a sharp increase in the incidence of IBD (43). The burden and costs related to IBD are significant. In Europe during 2020, the direct health care costs associated with IBD per patient and year are estimated to be approximately €3,500 in CD and €2,000 in UC, and with indirect costs of approximately €1,900 per patient yearly related to work productivity loss (44). A total number of 2.5‒3 million people in Europe are estimated to be affected by IBD, with a direct healthcare cost of €4.6‒€5.6 billion Euros per year (45). In the U.S., the total annual health care expenditures for gastrointestinal diseases during the year 2015 were $135.9 billion, of which the costs for IBD were estimated to be $7.2 billion (46).
The associations between environmental factors, including air pollution exposure, and IBD have been addressed in a number of review studies (47–59). Although the mechanisms behind IBD are not fully understood, the current opinion on the mechanisms behind IBD suggests that environmental factors, a dysregulated gut microbiota, and certain genes interact in terms of disease onset (47–49, 52, 54, 56–58, 60–65). A dramatic increase in the incidence of IBD has been observed during the past few decades, suggesting that environmental factors constitute an increasingly critical role in the development of these disorders (48, 57, 66, 67).
When focusing more specifically on the effects of air pollution exposure on IBD, several studies suggest that there is a relationship (47, 48, 53). Plausible mechanisms mediating the effects of air pollution exposure on the gastrointestinal tract could include direct effects on epithelial cells, systemic inflammation and immune activation, and modulation of the intestinal microbiota (48). The gut is exposed to particles in the inhaled air as most of these inhaled particles are removed from the lungs to the gastrointestinal tract via mucociliary clearance (50), alternatively from swallowing of air or from foods coated with airborne particles (68). It has also become evident that there exists a “crosstalk” between the respiratory and gastrointestinal tracts, which is commonly referred to as the gut-lung axis (51). Alterations in the gut microbiota as a result of exposure to NO2 and O3 have been demonstrated on humans by using whole-genome sequence analysis (69). Other than IBD, there are also associations between air pollution exposure and other disorders of the gastrointestinal tract. Associations between air pollution exposure and IBS (irritable bowel syndrome) have been shown (70–72). Short-term air pollution exposure may trigger non-specific abdominal pain in young individuals (73), peptic ulcers (74–76), appendicitis (77–79), and finally, acute effects of air pollution on enteritis were shown by Xu et al. (80).
The goal of this review was to update the current state of knowledge regarding the effects of air pollution exposure on IBD including the intestinal mechanisms that may underlie these associations, and the importance of various kinds of air pollutants.
2 Materials and methods
2.1 Literature search and selection criteria
The elaboration of this systematic review was based on the guidelines presented in PRISMA (Preferred Reporting System for Systematic Reviews and Meta-Analysis) (81–83). The main issue was to find out if exposure to air pollution is associated with an increased risk of inducing and/or exacerbating IBD. A systematic literature search was conducted using PubMed and Web of Science. The search terms “air pollution”, “environmental factors”, “environment” “inflammatory bowel disease”, “IBD”, “exposomes”, “Crohn's disease”, and “ulcerative colitis” were used to identify and select relevant studies. In addition, the reference lists of the retrieved studies were searched to identify additional relevant articles on air pollution as a risk factor for IBD.
Boolean operators were generated based on different search terms related to “IBD” and “air pollution” in “title” and “abstract” with the following main search string:
“((inflammatory bowel disease[Title/Abstract] OR IBD[Title/Abstract] OR crohns disease[Title/Abstract] OR morbus crohn[Title/Abstract] OR ulcerative colitis[Title/Abstract] OR colitis[Title/Abstract]) AND (exposure[Title/Abstract] OR exposome[Title/Abstract] OR environmental factors[Title/Abstract] OR environment[Title/Abstract] OR environmental pollution[Title/Abstract])) AND (air pollution[Title/Abstract] OR nitrogen dioxide[Title/Abstract] OR nitrogen oxide[Title/Abstract] OR carbon monoxide[Title/Abstract] OR sulfur dioxide[Title/Abstract] OR volatile organic compounds[Title/Abstract] OR particulate matter[Title/Abstract] OR black carbon[Title/Abstract] OR elemental carbon[Title/Abstract] OR ozone[Title/Abstract])”.
Two researchers (H.A.S.M. and H.O.) independently screened the studies generated with this search string for potential relevance for further analysis. In a first step, each record's title and abstract underwent a screening process. If the reviewers disagreed during this initial stage, the study went on to a full-text screening phase. During the full-text screening, only those studies that passed the initial review were evaluated in detail.
The following inclusion criteria:
1. Epidemiological studies using prospective and retrospective cohort study designs, longitudinal study designs, case-control and nested case-control study designs, and ecological study designs;
2. Apart from epidemiological studies, other relevant studies including toxicological, clinical, in vitro and in vivo studies analyzing the relationships between air pollution and IBD, and the potential underlying mechanisms behind these relationships;
3. Studies assessing the impact of ambient air pollution on any of the different population groups;
4. A description of the method for assigning exposure had to be present;
5. Studies on associations between short- and long-term exposure to outdoor air pollution and incidence of IBD (Crohn's disease and ulcerative colitis separately or altogether);
6. Providing information on population characteristics;
7. Epidemiological studies reporting the effect estimates in terms of relative risks (RR), odds ratios (OR), incidence rate ratios (IRR), or hazard ratios (HR) with 95% confidence intervals (CI);
8. Studies written in English language.
The following exclusion criteria:
1. Review studies, meta-analyses, and other studies not reporting original research results;
2. Studies investigating the associations between IBD and pollutants other than ambient air like smoking (both passive and active) and pollutants originating indoors;
3. Health outcome was ascertained by self-diagnosis;
4. Not peer reviewed studies like conference abstracts, theses, and preprints;
5. Studies written in other than English language.
2.2 Selected studies and synthesis
All epidemiological studies selected based on the above mentioned criteria were further evaluated based on their quality. The factors that were used to evaluate the quality consist of exposure assessment, magnitude of effect, consistency of results, adjustments of confounders, and the study design. A quality score from 1 to 4 was used in order to create an average value based on these factors. The few toxicological studies that were selected were not evaluated in the same way as the epidemiological studies, but rather presented to clarify the biological mechanisms behind air pollution exposure and IBD.
Although the focus of this literature review is on air pollution exposure and IBD, other environmental factors as well as genetic factors have been addressed in the Discussion section. The reason for that is to also have a certain focus on the complex interplay between several environmental factors and genes where air pollution is one of many important factors regarding the onset and exacerbation of IBD.
3 Results
3.1 Literature search procedure
This literature search was conducted according to a complete “Preferred Reporting Items for Systematic Reviews and Meta-Analysis” (PRISMA) checklist (83). “Title” and “abstract” were screened using different search terms related to “IBD” and “air pollution”. The search procedure is presented in Figure 1.
Figure 1. The search and selection procedure performed in PubMed and Web of Science.
3.2 Summary of studies retrieved from PubMed and web of science divided into epidemiological studies and toxicological (mechanistic) studies
Table 1 summarizes the epidemiological studies selected for this systematic literature review, and Table 2 presents the corresponding toxicological studies. In order to make a fair synthesis of the epidemiological studies, the quality of evidence for a potential causal link between air pollution exposure and IBD was evaluated based on a number of factors (101) (see Table A2 in Appendix A). A quality score from 1‒4, presented in Table A1 (Appendix A), was used in order to create an average value based on the factors presented in Table A2. Factors that increase the score include consistent results, a large magnitude of the effect, and detailed adjustments of confounders. Factors lowering the grade include limitations in study design or execution (risk of bias) and inconsistency of results. The evaluation from very low (1) to high (4), with a description of the assessment criteria, is presented in a Table A1, Appendix A.
Table 1. Summary of epidemiological studies analyzing the associations between air pollution exposure and IBD.
Table 2. Summary of the toxicological studies analyzing the biological mechanisms behind air pollution exposure and the intestinal physiology including IBD.
3.3 Interpretation of the results
Based on both the epidemiological and the toxicological studies, the findings from this systematic literature review suggest that air pollution exposure could influence the onset and worsening of IBD. The quality score of the epidemiological studies in the range of 2.2–3.7 indicates a relatively high quality level of the included studies. However, variations in study design across the included epidemiological studies pose challenges in drawing definitive conclusions. Despite this, the analysis reveals both short- and long-term impacts on IBD associated with various air pollutants, affecting both Crohn's disease and ulcerative colitis, and plausible biological mechanisms are supported by the toxicological studies. However, the lack of multi-pollutant models in most of the epidemiological studies makes it difficult to distinguish the individual effect of specific air pollutants.
4 Discussion
4.1 The link between environmental factors and IBD
4.1.1 Air pollution and IBD based on study design and pollutants
This comprehensive literature review encompassed 13 epidemiological studies, each examining distinct air pollutants in relation to IBD. Among these, PM2.5 was the focus of twelve studies, followed by NO2 in eight studies, and PM10 in eight studies, among others. Eight studies investigated associations with Crohn's disease and ulcerative colitis separately, while five studies analyzed IBD as a whole without distinguishing between CD and UC. Study methodologies varied, including four cohort studies, two ecological studies, three case-control studies, two studies using two-sample Mendelian randomization, and two longitudinal time-series studies. Despite methodological differences, a number of consistent associations between air pollution exposure and IBD were observed. For example, one cohort study linked IBD to PM2.5 exposure (84), while another associated ulcerative colitis with exposure to multiple pollutants such as PM10, PM2.5, PM2.5–10, NO2, and NOx (91). Ecological studies also identified associations between PM2.5 and a combination of pollutants including N2O, NO2, VOC, CO, SO2, O3, and PM2.5 (85, 92). The six toxicological studies (69, 96–100) do not have as much variation in terms of air pollutants; five studies have focused on particles (96–100), and one study is based on NO2 and O3 (69). However, with a combination of animal, human, and in vitro studies, the results in terms of biological mechanisms indicate that air pollution exposure influences the composition of the gut microbiome, altering metabolic functions within the gut, and creates immunological reactions with inflammation contributing to the development of IBD.
4.1.2 Genes, air pollutants, and other environmental factors affecting IBD
During the past few decades, the incidence and prevalence of IBD has increased rapidly in the industrialized countries (41, 102–106), which cannot be explained through genetic mechanisms (103, 107–110). This increase in IBD has been particularly noticeable in many developing countries where IBD has previously been relatively uncommon (111). Additionally, when immigrants from countries with little occurrence of IBD move to countries with a higher occurrence, the risk of developing IBD levels with the country they have moved to rather than the country they have moved from (112–115). However, a complex interplay between epigenetic mechanisms in terms of DNA methylation, histone modification, and alterations in the expressions of microRNAs could explain the link between genetic and environmental factors regarding the onset of IBD (54). Nevertheless, certain genes are involved in the pathogenesis of IBD, with more than 200 risk genes being identified (116, 117). Possible genetic mechanisms involve dysregulation of innate immune response to the microbiome, increased permeability across the intestinal mucosa, and dysregulation of the adaptive immune system (118–120). However, these risk genes explain less than 30% of the susceptibility to the development of IBD, suggesting environmental factors as the key in the pathogenesis of IBD (117, 121), and where a large proportion of the cases of IBD may be preventable through lifestyle modifications (122, 123).
The impact of environmental factors on IBD are reflected by geographical variations, with a higher incidence of IBD among people living in urban environments compared to those living in rural environments (124–126), as well as a higher incidence of IBD among those living in densely populated areas (127). Living in green and blue spaces as well as in natural environments may also constitute protective factors regarding the development of IBD (128). However, a higher incidence of IBD in rural agricultural areas has been shown for northern France by Declercq et al. (129). Urbanization including changes in diet, use of antibiotics, hygiene status, microbial exposures, and pollution have all been suggested as potential environmental risk factors for IBD (130). In addition to air pollution, water pollution has been shown to have some impact on the development of IBD, with increased risks associated with drinking water containing certain metals and disinfectants (131).
The use of some pharmaceuticals, most commonly used in the industrialized world, may have an impact on the IBD incidence. Non-steroidal anti-inflammatory drugs (NSAIDs) have, despite their anti-inflammatory effects, been shown to be able to contribute to the exacerbation of IBD (132), and effects in terms of gastrointestinal toxicity (dyspepsia, gastroduodenal ulcers, and gastrointestinal bleeding and perforation) have been shown in association with the use of NSAIDs (133). An increased risk of developing IBD associated with antibiotic consumption has also been shown (134), with the highest risk increase linked to the antibiotics affecting the gut microbiota (135). Moreover, exposure to oral contraceptives has been shown to increase the risk of developing IBD (136, 137), where estrogen can potentially affect the gut microbiota, the intestinal wall barrier function, and possibly cause micro-ischaemia within the vasculature of the gut (138).
When considering dietary intake and the risk of IBD, there is a general pattern with a decreased risk associated with high fruit, vegetable, fiber, and omega-3 fatty acid intake, and an increased risk associated with total fat, animal fat, polyunsaturated fatty acid, omega-6 fatty acid, and refined sugar intake (139–145). Vitamin D has also been shown to constitute an important risk factor, with higher plasma concentrations of vitamin D linked to a reduced risk of developing IBD (146). High prevalence of vitamin D deficiency among people with IBD has also been shown, with some evidence of a latitude-dependent effect, and with higher incidence at northern latitudes, possibly reflecting the role of sun exposure (147, 148).
Stress and high mental load are also well-known risk factors for the development and exacerbation of IBD (149–153). More specifically, stress is defined as an acute threat to the body's homeostasis, which can give rise to a number of physiological changes in the intestine including changes in gastrointestinal secretion, increased intestinal permeability, decreased mucosal blood flow, and negative effects on the microbiota, of which all affect the risk of IBD (152–154).
When considering IBD incidence and educational level, the associations point in different directions. A Swedish study by Li et al. (155) found a decreased risk of IBD-related hospitalizations among higher educated groups, while a Norwegian study by Aamodt et al. (124) found a higher incidence rate of IBD in the municipalities with the highest level of education when compared to the municipalities with the lowest level of education. When comparing IBD diagnoses between men and women based on two cohorts, there were some differences in the age of onset and disease location, but there were no large sex-related differences regarding therapeutic management or IBD-specific healthcare costs (156).
When considering air pollution exposure and IBD, it is only one of many interacting environmental factors mentioned above that can influence the onset and exacerbation of IBD. Despite air pollution being an important risk factor in the development and pathogenesis of IBD, its interaction with other environmental factors also needs to be addressed in terms of their impact and how the burden of IBD can be reduced.
4.1.3 The biological mechanisms behind air pollution exposure and induction or exacerbation of IBD
According to the toxicological studies presented in Table 2, it was found that exposure to air pollution affected both the gut microbiota and the metabolic processes in the intestine. However, the mechanisms of how air pollution exposure affect the intestinal physiology and pathology are not fully understood. Nevertheless, there are several potential mechanisms of how air pollution exerts its effects on IBD. In general, air pollution and its components can alter the host's mucosal defenses and trigger immune responses (47). Inhaled air pollutants reach the gut via mucociliary clearance from the lungs. Potential mechanisms of how air pollution exposure affects the gut physiology include direct effects on epithelial cells, systemic inflammation and immune activation, and modulation of the intestinal microbiome (48). An increased thrombotic tendency and imbalances in prostaglandin synthesis have also been proposed as possible mechanisms (55). Impact on the intestinal microbiome associated with air pollution exposure has been suggested as a very conceivable mechanism. The lipid metabolism within the intestine is controlled by the gut microbiota, and intestinal redox lipids might be important in terms of both systemic and intestinal inflammation (50). A crosstalk between the respiratory and gastrointestinal tracts occurs via the bloodstream and the lymphatic system, commonly referred to as the gut-lung axis, where these two organs communicate via microbial secretions, metabolites, immune mediators, and lipid profiles (51).
In comparison with healthy individuals, a less diverse microbiome and imbalances between different bacterial strains has been shown in those diagnosed with IBD (157), and different epigenetic profiles between inflamed and non-inflamed colonic segments have also been shown (158). Accordingly, an association between air pollution exposure and changes in the composition of the gut microbiota has been shown in several studies, although the pattern is not completely clear, and the mechanisms behind it are not fully understood (59, 159). Alterations in the gut microbiome as a result of exposure to air pollution have been shown for particulate matter in both epidemiological and experimental studies (97–100, 160–165), for NOx and O3 in one experimental study by Fouladi et al. (69), and for traffic-related air pollution (NOx) in one epidemiological study by Alderete et al. (166). Alterations and dysfunctions of the microbiome have been shown among people with IBD, and this in turn results in shifts in oxidative stress pathways with decreased carbohydrate metabolism and amino acid biosynthesis during tissue damage (167).
Although the etiology of IBD is multifactorial, involving both environmental, genetic, epigenetic, and immunological factors, oxidative stress constitutes an inherent part of any one of them. Air pollution entering the gastrointestinal tract can have a direct effect on the intestinal epithelium by oxidizing intestinal lipids (50). Consequently, redox equilibrium is crucial in order to maintain cell homeostasis within the gastrointestinal tract (168, 169), and increased levels of reactive oxygen species in combination with decreased levels of antioxidants contribute to the disease pathogenesis of IBD (170). Oxidative stress causes damages to the mucosal layer of the gastrointestinal tract with subsequent bacterial invasion, which in turn causes immune responses and initiates IBD (169). Particulate matter has been shown to induce oxidative stress in human cells, with subsequent chronic inflammation (171). Exposure to PM2.5 has also been shown to increase the concentrations of oxidized low density lipoproteins, as shown in a clinical study in China by Qin et al. (172). Consequently, and with respect to the close relationship between the gut microbiota and lipid metabolism, air pollution exposure can cause an increase in oxidized lipids with subsequent pathological systemic effects (50).
Changes in the intestinal barrier function have been associated with IBD (173). Exposures to particulate matter and ozone have been shown to change the intestinal permeability by breaking the intercellular barriers (68, 99, 174). The intestinal mucosal barrier maintains a delicate balance between absorbing important and essential nutrients, but also has the function of preventing the influx of harmful substances and form a defense against them. IBD is incidentally associated with disruptions of essential elements of the intestinal barrier, which creates dysfunctions of gut permeability (175).
To sum up, the mechanisms behind air pollution exposure and the onset or exacerbation of IBD are very complex, and all details are not fully understood. The mechanisms constitute a combination of several interrelated and interacting factors where microbial composition, oxidative stress, lipid metabolism, and gut permeability play significant roles (Figure 2). Altered composition and decreased diversity of bacterial species can cause changes in the gut metabolism with changes in fatty acid production, and with the creation of toxic and inflammatory substances. Increased oxidative stress can be caused by air pollution exposure itself, or secondarily to that followed by altered metabolism caused by changes in the composition of the gut microbiota. Increased production of radicals and oxidative stress can cause increased gut permeability, which in turn promotes the influx of toxic substances with inflammatory responses from macrophages and the release of cytokines (99).
Figure 2. An illustration describing the biological mechanisms behind exposure to particulate matter and the accompanying pathophysiological mechanisms of the gut [adapted from Salim et al. (99)]. The development of IBD as a result of exposure to particulate matter is caused by several factors: (1) Changes in the composition of the microbiome, with a decrease in beneficial short-chained fatty acids and an increase in toxic metabolites, when particles are metabolized by the gut microbiota. (2) Reactive oxygen species interact with the tight junctions of the epithelial cells resulting in increased permeability and leaky gut syndrome. (3) Immunological effects in terms of production of pro-inflammatory cytokines with further breakdown of epithelial cells and systemic inflammation.
4.1.4 The effects of smoking on IBD in relation to the effects of ambient air pollution
Although there are clear indications that outdoor air pollution is associated with the induction and exacerbation of both CD and UC, the impact of tobacco smoke on IBD is complex. Smoking may be able to impact the pathogenesis of IBD through several direct and indirect effects including oxidative stress, impairment of intestinal barrier and immune cell function, epigenetic changes, and dysregulation of the microbiota (176). In general, smoking is unfavorable for CD, but beneficial for UC (108, 177–181). Current smoking is associated with an increased risk of CD, but former smoking is associated with an increased risk of UC (182, 183). Current smoking is furthermore protective against the development of UC (183). However, passive smoking during childhood has not been shown to increase the risk of developing either CD or UC in adulthood (184).
The role of smoking in the pathogenesis of IBD is complex. Nicotine is considered to play an important role. Tobacco smoke modulates nicotinic acetylcholine receptors by activating a cholinergic anti-inflammatory pathway among smokers who have UC. Contrarily, with regard to CD, nicotine can exacerbate the condition as nicotine will increase the inflammatory response of macrophages infected with certain types of bacteria, and with a reduced cellular apoptosis in macrophages exposed to nicotine (185).
The potential role of carbon monoxide exposure as beneficial on the pathogenesis of IBD could also explain the positive effect of smoking on UC. Carbon monoxide (CO) is produced as a result of incomplete combustion of tobacco, and smokers usually have a significant proportion of carbon monoxide bound to the hemoglobin (186). Apart from being inhaled from tobacco smoke, CO is endogenously and physiologically produced in cells during the degradation of heme (a ring-shaped iron-containing component of hemoglobin) under the influence of the enzyme heme oxygenase (187, 188). Heme oxygenase is generated by the enteric microbiota, and the pathway involving heme oxygenase and CO can affect the balance between pro-inflammatory and anti-inflammatory cytokine expressions. The heme oxygenase and CO-pathway also includes antimicrobial effects regulating the intestinal immune homeostasis (189). The action of CO involves the activating of heme-containing proteins resulting in the promotion of autophagy, a decreased generation of reactive oxygen species, and the promotion of adaptive responses and cell survival (190). Besides, tangible therapeutic effects of CO on both inflammation and arthritis have been shown by Takagi et al. (191). In summary, CO has the potential to exert anti-inflammatory and tissue-protective effects (190).
Regarding IBD and ambient air pollution exposure, no protective effects have been demonstrated in the epidemiological studies reviewed. Unlike tobacco smoke, outdoor air pollution does not contain nicotine, and CO is emitted along with a variety of other air pollutants, which makes it unlikely that CO in ambient air could exert any notable anti-inflammatory effects.
4.1.5 Environmental factors including air pollution and pediatric IBD
The effects of air pollution on pediatric IBD need to be addressed separately. The incidence of IBD is rising worldwide, with a particularly prominent increase among children (53, 192–199). Even though the incidence of IBD varies around the world, there is an increasing trend of pediatric IBD (particularly evident for CD) in both developed and developing countries (194). However, Northern Europe and North America have the highest incidence and prevalence of pediatric-onset IBD, while Southern Europe, Asia, and the Middle East have the lowest incidence and prevalence (200). Despite an increasing trend of pediatric IBD in developed countries, the corresponding trend for adult IBD in developed countries seems to have stabilized in recent times according to some studies (105). However, the genetic risk factors associated with pediatric IBD are largely similar to those associated with adult-onset IBD (201). Nevertheless, childhood-onset IBD might be etiologically different from adult-onset IBD. When comparing the phenotypic characteristics between those two, childhood-onset IBD was shown to be characterized by more extensive intestinal involvement and rapid early progression in comparison with adult-onset IBD (202). When comparing the vulnerability to environmental pollutants among children and adults, several factors are important to take into account: their relatively much smaller body volume, the way they interact with the environment, and their dynamic developmental physiology are decisive in terms of differences in susceptibility between adults and children (203). Moreover, the fetal gut is generally thought to be sterile, but starts to develop during the neonatal period during the influence of early-life exposures (204). Since the initial colonization of the gut microbiome is determined early in life, early-life environmental exposures can cause various pathological changes (193). Observational studies have also shown that there are associations between the living conditions during childhood and the risk of developing IBD later in life (205).
Apart from an increased risk for a child to develop IBD later in life if the mother was diagnosed with IBD, or having different types of illnesses during the first year of life (206, 207), or being hospitalized for gastrointestinal infections during childhood (208), the importance of several environmental factors regarding pediatric IBD is confirmed through several studies (193). The use of antibiotics in early age is a well-known risk factor developing IBD (209–212). An increased risk of pediatric IBD has also been shown in association with the use of antibiotics during pregnancy (213). The “hygiene hypothesis” means that growing up in cleaner environments can alter the balance of the immune system, with an increased risk of developing immunological conditions including IBD. The “hygiene hypothesis” is based on the assumption that exposure to harmless microorganisms decreases the risk of developing immune-mediated diseases, possibly leading to less induction of dendritic cell maturation and the regulation of T lymphocytes (58). The impact of exposure to microorganisms is supported by the fact the H. pylori infection in early childhood has been shown to decrease the risk of developing IBD (214). Additionally, the impact of childhood hygiene on the risk of developing IBD is supported by studies on several markers of hygiene, with an increased risk associated with fewer family members (215, 216), an increased risk of CD associated with living in households with hot-water tap and separate bathrooms (217), and a decreased risk of IBD associated with growing up with pets and having contact with farm animals (215, 218–220). However, the use of agricultural pesticides has been shown to increase the risk of developing pediatric IBD (92).
Other identified risk factors for pediatric IBD include low fruit intake, low physical activity, birth by caesarean section, exposure to antibiotics, appendectomy, age above 10 years, and frequent gastroenteritis admissions according to a multicenter case-control study in Saudi Arabia (221). Moreover, gluten introduction in early age (222), as well as high sugar intake and stressful life events (208) have been shown to increase the risk of developing pediatric IBD. Finally, when comparing the incidence and phenotypic expression of IBD in the South Asian pediatric population with the domestic pediatric population, a significantly higher incidence and different phenotypic expression was shown in Canada by Pinsk et al. (223), and in New Zealand by Rajasekaran et al. (224), suggesting potential effects of migration, environment, and lifestyle factors.
In contrast to risk factors, there are also a number of identified factors that are protective regarding the development of pediatric IBD. Based on studies performed in Canada, protective factors regarding the development of IBD with respect to childhood exposure include living in rural households (225). A decreased risk of developing CD among children living in relatively more deprived areas has been shown in Scotland (192). Breastfeeding is another protective factor regarding the development of both pediatric-onset and adult-onset IBD, as shown by systematic reviews (226–228), possibly reflecting the role of breast milk on the process of colonization of the gut microbiota and pathological imprinting early in life (229). Vitamin D supplementation may also have a beneficial effect on pediatric IBD, with significantly decreased markers of inflammation, which was shown when two groups of children with IBD were compared, one of which received vitamin D supplementation (230). Moreover, appendectomy has been shown to reduce the risk of developing UC according to a meta-analysis by Koutroubakis et al. (231). Finally, when measuring exposure to residential greenspace among children using a normalized difference vegetation index, an increase in residential greenspace during childhood was associated with a decreased risk of developing pediatric-onset IBD (232).
When addressing the relationship between air pollution exposure and pediatric IBD, it is important to consider the dynamic developmental physiology of a child. In general, exposure to air pollutants during fetal development and early postnatal life is associated with a number of negative health effects including abnormal development, decreased lung growth, increasing rates of respiratory tract infections, childhood asthma, behavioral problems, and neurocognitive decrements (233). Among the epidemiological studies included in this literature review, presented in Table 1, three studies have focused on pediatric IBD. In the retrospective cohort study by Elten et al. (88), analyzing the incidence of pediatric-onset IBD associated with maternal and early-life exposure to NO2, PM2.5, O3 and Ox (oxidant capacity), statistically significant associations were found only for Ox, indicating that oxidative stress plays an important role in the disease onset. Ozone constitutes a powerful oxidizing agent where the effects resulting from exposure may differ between children and adults due to differences in antioxidant defense responses and vulnerabilities to cellular injury. It is also possible that exposure to O3 during the postnatal period may constitute a priming event that increases the toxicity of other pollutants or allergens, as proposed by a study focusing on O3 and the development of asthma during the postnatal period (234).
When considering air pollution in rural and urban environments, and the potential differences in terms of being a risk factor for IBD, it is important to take into account differences in the composition of air pollutants in rural and urban environments. A higher incidence of IBD in urban environments compared to rural environments has been shown for both children and the general population (124, 126, 225). Apart from the hygiene hypothesis previously described, differences in the composition of air pollutants could also be a contributing factor. Air pollutants in the urban environment are in general dominated by emissions originating from traffic, while agriculture, and in some cases industries, are in general more significant sources in the rural environment (235). Additionally, airborne particles can contain a variety of bacterial strains depending on its source (236), and certain bacterial strains including phylum Firmitus and Proteobacteria phylum have been shown to be decreased and increased, respectively, among IBD patients (237). Both phylum Firmitus and Proteobacteria phylum are present in aerosols near cows at dairy farms (238), and similar to the hygiene hypothesis, exposure to different bacterial contents in particles, with respect to urban and rural conditions, could also have some impact on the development of IBD.
To sum up, air pollution probably acts synergistically together with a number of other environmental factors mentioned above when it comes to the onset and exacerbation of pediatric IBD. According to Elten et al. (88), the oxidant capacity (the redox-weighted oxidant capacity based on both O3 and NO2) has been shown to be important when it comes to the onset of pediatric IBD. That is in line with the study suggesting O3 as especially important regarding asthma during the postnatal development (234). Besides oxidant capacity as a potentially important factor regarding pediatric-onset IBD, the dynamic developmental physiology of a child needs to be considered when air pollution and IBD is addressed in terms of prevention measures.
4.2 Opportunities to alleviate IBD associated with air pollutants
This review underscores the imperative for further research employing robust study designs and standardized exposure assessment methods to deepen our understanding of the impact of air pollution on IBD. By elucidating these associations, policymakers and healthcare professionals can develop effective strategies to mitigate the adverse effects of air pollution on the digestive health. However, the multifactorial nature of IBD, with several environmental factors acting together in its development, necessitates exploring various approaches to mitigate and limit the disease.
On an individual level, mitigating the effects of air pollution exposure on IBD and digestive health can be challenging. However, strengthening mucosal and epithelial barriers can help mitigate air pollution-induced systemic inflammation and oxidative stress. Probiotics and prebiotics, collectively known as synbiotics, are well-known gut health stimulators that optimize the composition of the gut microbiome and microbial metabolites (51). Additionally, natural antioxidants have shown effectiveness in relieving IBD by combating oxidative stress, as indicated by research conducted by Sahoo et al. (170). Furthermore, maintaining adequate plasma concentrations of vitamin D has been demonstrated to have a protective effect against the development of IBD (146).
These interventions offer promising avenues for both individual and population-level strategies to mitigate the impact of air pollution on IBD and promote digestive health.
4.3 Policy implications and future research needs
The presence of IBD entails both great costs for society and personal suffering for those affected. The societal costs attributed to IBD can be divided into several factors including healthcare, sick leave, disability pension, and medications (239). The costs related to IBD are also increasing in high-income settings (240), and based on the total costs related to gastrointestinal diseases in U.S., IBD is estimated to make up roughly five percent of this total cost (46). Therefore, identifying and mitigating environmental risk factors are of significant importance to reduce unnecessary suffering and alleviate the burden on healthcare systems. Reallocation of resources can enhance the care provided to individuals living with IBD.
Moreover, when considering air pollution as a risk factor for the onset or exacerbation of IBD, the societal costs attributed to air pollution would likely be underestimated, as IBD is not usually included in terms of costs associated with air pollution. Thus, there is an urgent need for expanded research efforts, employing robust study designs and standardized exposure assessment techniques, to deepen our understanding of the intricate relationship between air pollution and IBD. By uncovering these associations, policymakers and healthcare practitioners can develop targeted interventions to reduce exposure to specific pollutants, raise public awareness about the risks associated with air pollution, and integrate pollution control measures into broader public health initiatives. Additionally, further research can inform the development of tailored interventions and treatments to mitigate the worsening of IBD symptoms in individuals exposed to air pollution. Ultimately, a multifaceted approach that integrates scientific findings with policy and practice is essential to safeguarding digestive health in the face of environmental challenges posed by air pollution.
5 Conclusions
An overall conclusion of this systematic literature review is that there is a link between air pollution exposure and the onset and exacerbation of IBD, and where air pollution exposure constitutes one of many environmental factors which probably act synergistically in the development of IBD. The mechanisms behind air pollution exposure and the onset or exacerbation of IBD are very complex, and all details are not fully understood. These mechanisms constitute a combination of several interrelated and interacting factors where microbial composition, oxidative stress, lipid metabolism, and gut permeability play significant roles. Due to the lack of multi-pollutant models in the epidemiological studies included in this literature review, the role of specific air pollutants is difficult to determine. Thus, there is an urgent need for expanded research efforts, employing robust study designs and standardized exposure assessment techniques, to deepen our understanding of the intricate relationship between air pollution exposure and IBD.
Author contributions
HO: Conceptualization, Data curation, Formal Analysis, Writing – original draft. HM: Conceptualization, Data curation, Writing – review & editing. JH: Writing – review & editing. JS: Writing – review & editing. TS: Writing – review & editing. BF: Writing – review & editing. AO: Conceptualization, Formal Analysis, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Funded by the European Union (Horizon Europe project MARCHES: Methodologies for Assessing the Real Costs to Health of Environmental Stressors, grant no. 101095430). Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them.
Acknowledgments
Great thanks to Joy Sandberg, librarian at the Medical Library at Umeå University, for the help in finding relevant literature through appropriate search paths.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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Appendix A
Table A1. The evaluation from very low to high, with a description of the assessment criteria (101).
Table A2. Factors that determine the quality of evidence graded on a scale from 1 to 4 (1 = very low; 2 = low; 3 = average; and 4 = high).
Keywords: air pollutants, IBD, Crohn's disease, ulcerative colitis, disease onset, disease exacerbation, toxicology
Citation: Olstrup H, Mohamed HAS, Honoré J, Schullehner J, Sigsgaard T, Forsberg B and Oudin A (2024) Air pollution exposure and inflammatory bowel disease: a systematic literature review of epidemiological and mechanistic studies. Front. Environ. Health 3:1463016. doi: 10.3389/fenvh.2024.1463016
Received: 11 July 2024; Accepted: 6 September 2024;
Published: 20 September 2024.
Edited by:
Godfred O. Boateng, York University, CanadaReviewed by:
Yuhan Yang, Georgia Institute of Technology, United StatesGiovanni Giurdanella, Kore University of Enna, Italy
Copyright: © 2024 Olstrup, Mohamed, Honoré, Schullehner, Sigsgaard, Forsberg and Oudin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Henrik Olstrup, henrik.olstrup@umu.se