The emerging role of environmental pollutants in inflammatory bowel disease risk, outcomes, and underlying mechanisms

Abstract

Epidemiological and translational data increasingly implicate environmental pollutants in inflammatory bowel disease (IBD). Indeed, the global incidence of IBD has been rising, particularly in developing countries, in parallel with the increased use of chemicals and synthetic materials in daily life and escalating pollution levels. Recent nationwide and ecologic studies have reported associations between agricultural pesticides and IBD, particularly Crohn’s disease (CD). Exposure to other chemical categories has also been linked with an increased risk of IBD. To synthesize available data and identify knowledge gaps, we conducted a systematic review of human studies that reported on the impact of environmental pollutants on IBD risk and outcomes. Further, we summarized in vitro data and animal studies investigating mechanisms underlying these associations. The 32 included human studies corroborate that heavy and transition metals, except zinc, air pollutants, per- and polyfluorinated substances (PFAS), and pesticides are associated with an increased risk of IBD, with exposure to air pollutants being associated with disease-related adverse outcomes as well. The narrative review of preclinical studies suggests several overlapping mechanisms underlying these associations, including increased intestinal permeability, systemic inflammation, and dysbiosis. A consolidated understanding of the impact of environmental exposures on IBD risk and outcomes is key to the identification of potentially modifiable risk factors and to inform strategies towards prediction, prevention and mitigation of IBD.

1. INTRODUCTION

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated disease, primarily involving the gastrointestinal tract. IBD was first reported in Western countries in the late 18^th to mid-19^th centuries, coinciding with the Industrial Revolution and a major ecologic shift towards the modern environment. A similar pattern has been observed in developing and recently developed countries in Asia and Africa, where IBD has increased in incidence following modernization and urbanization in the 1990s-2000s[1]. Globally, the estimated number of IBD cases increased from 3.3 million in 1990 to 4.9 million in 2019, a rise of 47.5%[2], accounting for over $25 billion in annual direct healthcare costs in the United States[3]. Therefore, IBD is a global public health concern [2]. While both genetic and nongenetic risk determinants are implicated, the etiology of IBD remains inadequately elucidated, a roadblock to IBD prediction and prevention efforts. Genome-wide association studies have identified over 200 loci associated with IBD, but less than a third of cases are attributed to genetics alone, further supporting the role of the environment in IBD onset and outcomes [4]. Uncovering how environmental factors influence IBD onset and disease course could ultimately inform strategies towards mitigation of risk and disease progression [5]. The imperative to delve into this topic is heightened considering the increasing levels of global pollution and environmental contaminants (e.g., air pollutants and industrial chemicals) over the last decades, resulting from unregulated modernization and industrialization[6]. It is also relevant to acknowledge that changes in exposure patterns are associated with climate change and widening health disparities, pertinent concerns in the current era. In this systematic review, we summarize the available human studies on the impact of environmental pollutants on IBD risk and outcomes. Additionally, we compile available in vitro and animal studies data on underlying mechanisms and identify knowledge gaps.

2. METHODS

2.1. Systematic review

We conducted this systematic review after registration in the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42024524629), following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidance for data extraction and reporting[7]. Our research question was formulated using the “Population, Intervention, Comparison and Outcome” (PICO)[8] methodology. The population of interest was healthy individuals at risk of developing IBD (prospective cohorts) or individuals with IBD (retrospective cohorts, genome-wide association studies, or studies evaluating the impact of exposure on disease outcomes); the intervention, or exposure of interest, was specific environmental pollutants; the comparator was individuals without IBD diagnosis/outcomes; and the outcomes were the development of IBD or IBD-related outcomes.

Literature search

Three online databases (MEDLINE, Web of Science, and Scopus) were searched for studies addressing the PICO. The query used for PubMed was: (pollutants or pesticides or particulate matter (PM) or heavy metals or PFAS or PM_2.5 or PM₁₀) AND (inflammatory bowel disease or Crohn’s disease or ulcerative colitis or intestinal inflammation). The search included studies published from databases inception dates up to April 29, 2024. In addition, the references of articles identified as being relevant were reviewed for further published data matching the PICO question. Studies screening and selection were done by two authors (MME and MA) using Rayyan and discrepancies were resolved by a third arbitrator (VM).

Inclusion and exclusion criteria

Original research studies were included if they evaluated the impact of specific environmental pollutants, either in utero or throughout life, on healthy individuals at risk of developing IBD or on patients diagnosed with IBD, across all ages, in both urban and rural areas of developed and developing regions. Studies not meeting the inclusion criteria, as well as those focusing solely on diet or other exposures, reviews, case reports, guidelines, or editorials were excluded. No restrictions were imposed based on language. We excluded studies on exposure to plastics in this review due to the unique physical and chemical properties of these pollutants, challenges associated with their measurement, and the limited available human data on plastic exposure and IBD at present.

Data extraction and quality assessment

The following information was extracted from the studies: citation details, characteristics of the study population, follow-up duration, details on the exposure, tools used to assess exposure (e.g. biomarkers, surveys), study outcomes (incidence/prevalence of IBD, disease characteristics or outcomes), studied confounders, assessment of exposure-response (if available). The reporting quality of the studies was evaluated independently by two reviewers (MME and MA) using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria[9], considering 22 parameters for cohort and case-control studies. For ecological studies and genome-wide association studies, only the criteria relevant to those specific designs were evaluated.

2.2. Narrative review

We summarized data on the impact of pollutants on intestinal inflammation, relevant to IBD, from in vitro and animal model studies using a narrative approach. The studies included in the narrative review were gathered through a non-systematic search on PubMed. The search query used was “pollutants or pesticides or particulate matter (PM) or heavy metals or PFAS or PM2.5 or PM10) AND ((in vitro) or (in vivo)) and (intestinal inflammation)”. References from clinical studies included in our systematic review and prior review papers on the subject were also considered.

3. RESULTS

3.1. Categories of pollutants - characteristics, sources, and distribution

A pollutant is any chemical substance that appears in an organism or the environment at levels exceeding permissible limits[10]. These compounds are typically known for their widespread distribution, and, along with their byproducts, they can persist in and interact with the environment for extended periods. Pollutants can be categorized based on different parameters, for example, sources, physical and chemical properties, and impact on the environmental and human health[10]. Considering the source, pollutants may be classified into: i) water pollutants (e.g., chemicals, microbial contaminants, algal toxins, pharmaceuticals, and personal care products); ii) air pollutants (e.g., industrial and agricultural emissions, vehicle exhaust, smoking); iii) soil pollutants (e.g., -cidal agents, heavy metals, and industrial byproducts); and iv) others (comprising light, noise, radioactive, thermal, and microbial pollutants)[11]. Pollutants can also be grouped based on chemical composition (inorganic vs. organic), boiling point (volatile or nonvolatile), and the ability to undergo biomagnification through the food chain based on their fat solubility[11]. Highly persistent organic pollutants include per- and poly-fluoroalkyl substances (PFAS), pesticides, and polycyclic aromatic hydrocarbons (PAH), the former representing a highly persistent group of thousands of fluorinated compounds, “forever chemicals”, that are used extensively in industries, in household and personal items, food and packaging[12]. In this review, based on a composite[13] of the above features as well as available data, chemical pollutants were classified into the following subtypes: i) heavy and transition metals; ii) air pollutants, including PM (fine inhalable particle[14]s subdivided according to their sizes in PM_2.5, PM_2.5–10, and PM₁₀[13]), gaseous molecules (nitrogen oxides - NOx, sulfur dioxide - SO₂, carbon monoxide - CO, and ozone - O₃), volatile organic compounds, and greenhouse gases (carbon dioxide - CO₂, methane -CH₄, nitrous oxide - N₂O, fluorinated gases); iii) industrial compounds and organic pollutants (including PFAS, PAH, solvents and flame retardants); iv) -cidal agents (pesticides, herbicides, insecticides).

3.2. Summary of literature search

The systematic search yielded 3,743 results. Of these, 583 duplicates were excluded, and 3,128 records were eliminated based on inclusion and exclusion criteria (Figure 1). We included 32 studies in the final qualitative systematic review. Study characteristics and main results are presented in Supplementary Table 1. Of these, twelve[12,14–24] were case-control studies, seven[25–31] were retrospective cohort analyses, four[32–35] were ecological analyses, four[36–39] were cross-sectional, three[40–42] were prospective cohort studies, and two were genome-wide association studies[43,44]. These studies pertained to the following categories of specific pollutants: heavy metals or transition metals (n=5[14–16,31,40]), air pollutants (n=16[17–21,25–27,32–34,36,39,41,43,44]), industrial compounds and organic pollutants (n=10[12,22–24,28–30,35,37,38]) or pesticides (n=1[42]). Twenty-five studies reported on CD and UC risk, while five[15,17,29,36,44] reported on UC alone and one[32] on CD alone; the pediatric population was the focus of one[27] study. Six studies analyzed the impact of pollutants on disease course [25,32,34,36,39,41]. Supplementary Table 2 summarizes the STROBE assessment for all studies.

Figure 1.

PRISMA flowchart of studies’ selection.

3.3. Impact of pollutants on IBD risk

In this section, we summarize the results of the human studies focusing on the impact (harmful, null, or protective) of specific pollutants on IBD risk (Figure 2).

Figure 2.

Summary of the main findings in each pollutant category. Abbreviations: arsenic (As), carbon monoxide (CO), copper (Cu), Crohn’s disease (CD), inflammatory bowel disease (IBD), iron (Fe), lead (Pb), mercury (Hg), nitrogen dioxide (NO2), nitrogen oxides (NOx), organochlorine (OC), organophosphate (OP), oxidants (Ox), ozone (O3), particulate matter (PM), per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAH), selenium (Se), sulfur dioxide (SO2), ulcerative colitis (UC), zinc (Zn).

Heavy metals or transition metals

It is important to acknowledge that while some metals are essential as nutrients (cobalt [Co], copper [Cu], chromium [Cr], iron [Fe], magnesium [Mg], manganese [Mn], molybdenum [Mo], nickel [Ni], selenium [Se], and zinc [Zn]), others (arsenic [As], cadmium [Cd], chromium [Cr], lead [Pb], and mercury [Hg]) are considered systemic toxicants and human carcinogens. Additionally, all metals can be toxic at some level, depending on several factors, including the dose, route of exposure, chemical species, and characteristics of the exposed individuals.

Five studies investigated the impact of metal exposure on IBD risk. The methods used to assess exposure were variable: two studies evaluated the quality of water consumed by the study population (at the region[40] and district level[31], at or shortly after diagnosis), while others measured metals in colon biopsies, deciduous teeth[16], and hair samples[14]. Notably, only the last two matrices allowed for measuring metals at a high temporal resolution, with the analysis of tooth dentine being the only one that generates temporal profiles of uptake during fetal growth[45]. The study on teeth[16] evaluated exposures from the second trimester of pregnancy until 6 months after birth, while the hair[14] analyses using 3–4 cm of hair proximal to the scalp allowed for the assessment of exposure in adulthood, reflecting exposure up to 4 months before sampling. In all studies, individuals who developed IBD had higher concentrations of metals than healthy controls. An association between measured heavy metals and IBD was reported in three studies [15,31,40]. The specific profile of heavy metals varied across studies; Pb, Cu[15,16], and Fe[15,31] were associated with IBD risk in more than one study. Conversely, three[14,15,40] studies reported higher levels of Zn in individuals without IBD, relative to those with IBD. The reporting quality of the studies was moderate-high for all studies apart from one[15] (Supplementary Table 2), which provided a less detailed description of the recruitment process and did not address bias or confounders. Also, most did not provide information regarding sample size calculation due to the exploratory nature of these studies.

Air pollutants

The impact of air pollution on the risk of IBD was estimated in ten[17–21,26,27,33,43,44] studies, of which two[17,44] focused on UC outcomes. The methodology for exposure assessment was variable: four[19,20,43,44] used land use regression modeling, two used surveys[18,32], and the remaining used geographic information systems (GIS) and satellite monitoring data. Four[17,19,43,44] studies reported that higher levels of PM_2.5 were associated with UC risk, and one study[26] reported an association with IBD overall. When limiting analysis to pediatric-onset IBD, there was no impact of PM_2.5 exposure [27]. Conversely, in a nested case-control study[20] with a smaller sample size, the opposite association was reported, with lower levels of PM_2.5 in individuals with IBD, compared to those without IBD (adjusted OR of 0.24 [95%CI 0.07–0.81] per 5 lg/m³). One[19] study reported a positive association between PM_2.5–10 and PM₁₀, and the risk of UC, in a dose dependent manner. On the other hand, another study reported null findings[44].

With respect to other air pollutants, based on GIS data, nitrogen oxides were reported to be significantly associated with the risk of UC in one[19] study, and CD in another[21]. In another GIS-based analysis of air pollutants, oxidant levels during pregnancy and childhood were recognized as risk factors for pediatric-onset IBD, but null associations were reported for exposure to other gases[27]. Regarding reporting quality, four[17,25,33,39] of the 15 studies did not provide detailed information on recruitment criteria, patients’ selection, data collection and analysis, or management of confounders and sources of bias.

Industrial compounds and organic pollutants

We identified ten relevant studies in this subgroup, of which seven studied the impact of exposure to perfluoroalkyl substances (PFAS) on IBD[12,22,23,28–30,38]. In a nested case-control analysis[12] of military recruits, higher concentrations of PFAS mixture (consisting of nine PFAS chemicals) up to 10 years before IBD diagnosis were associated with increased risk of both CD and UC in a dose-dependent manner. Other studies focusing on specific legacy PFAS identified associations between individual PFAS chemicals (perfluorooctanoic acid [PFOA][23,28–30] and perfluorooctane sulfonate [PFOS][23]) and the risk of UC, with a dose-response relationship reported in two[28,30] of them. Conversely, in another report from the Nurses’ Health Study, inverse associations were identified between the levels of three legacy PFAS (PFOA, PFOS, and perfluorodecanoic acid [PFDA]) and the risk of CD, while no association was found for UC[22]. Of note, the median PFAS level in this cohort was lower than the national average. Two[35,38] other analyses reported null associations between PFAS and IBD, based on zip-code level exposure data.

Regarding other industrial contaminants, one case-control study[24] identified a higher risk of UC in men exposed to silica dust in a time-dependent manner, whilst the risk of CD was higher in exposed women. Exposure to electronic waste (discarded electronic devices and equipment) enriched with polycyclic aromatic hydrocarbon compounds has been associated with systemic inflammatory changes in children (increased absolute lymphocyte and monocyte counts, lower serum levels of CD4⁺ T cells, increased B cells and sialyl Lewis A concentrations), although their impact on IBD as an outcome is not known[37]. The reporting quality of the studies addressing industrial and organic contaminants was adequate.

Pesticides

One study[42] prospectively determined exposure to specific pesticides among agricultural workers and families using questionnaires. Exposure to organochlorine (OC) and organophosphate (OP) insecticides was associated with elevated hazards of IBD, particularly dieldrin (adjusted hazard ratio [aHR] 1.59, 95%CI 1.03–2.44), toxaphene (aHR 1.56, 95%CI 1.05–2.32), and terbufos (aHR 1.53, 95%CI 1.19–1.96), without a clear exposure-response trend. The reporting quality was adequate.

3.4. Impact of pollutants on IBD-related outcomes

Data on the impact of specific pollutants on IBD-related outcomes is more limited. Six studies examined the impact of air pollutants on disease course (both CD and UC n=4[25,34,39,41], CD n=1[32], UC n=1[36]). The studies that assessed IBD exacerbations based on hospitalization[25,34,39] or outpatient visits[36] found a positive association with air pollutant emissions. A dose-response association was reported between total air pollutants and IBD-related hospitalizations [35], and between daily outpatient visits for UC and PM_2.5 concentrations [36]. Exposure to PM_2.5 and nitrogen oxides was associated with an increased risk of enterectomy or all-cause mortality in a prospective analysis of over 4,700 individuals with IBD[41]. In this study, a concentration-response relationship was observed; patients exposed to each interquartile range increase in pollutants such as PM_2.5, NO_x, NO₂, and PM₁₀ experienced a 10–16% higher risk of enterotomy and all-cause mortality. An ecological study[32] reported a higher CD-related mortality rate in zip codes with higher exposure to sulfur dioxide (SO₂); however, no association was found for PM_2.5. Carbon monoxide (CO) was also reported to increase the risk of hospitalizations, particularly due to UC[25,39]. On the other hand, the role of ozone (O₃) is not clear[25,39].

3.5. Association between pollutants and gut inflammation - data from in vitro and animal studies

Here, we summarize available data on mechanisms underlying the impact of different exposures on gut inflammation, based on in vitro data and animal studies (Figure 3).

Figure 3.

Proposed underlying mechanisms mediating IBD risk with exposure to environmental pollutants: a summary of in vitro data and in vivo animal studies. Abbreviations: aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), interleukin (IL), lead (Pb), myeloperoxidase (MPO), nickel (Ni), particulate matter (PM), per- and polyfluoroalkyl substances (PFAS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt), reactive oxygen species (ROS), short-chain fatty acids (SCFA), silver (Ag), tumor necrosis factor (TNF)

Heavy metals or transition metals

Exposure to different metals (Al[46], Cd[47], Ni[48], Ag[49], Hg[50], Pb[51], Cr[52], As[53]) was shown to induce a pro-inflammatory phenotype in intestinal epithelial cells (increased expression of interleukin [IL]-1β[53,54], IL-17α[53], IL-8[53], tumor necrosis factor[TNF]-α[47,54], IL-6[54], IL-4[54], IL-10[49], and IL-18[49]). Also, exposure to metals like Al and Cd has been shown to impact cell death and renewal, increase gut permeability, and exacerbate experimental colitis in mice[55,56]. Other mechanisms have also been proposed, including reduced gut microbiota diversity, altered composition (e.g. decreased abundance of Akkermansia with chronic exposure to Al, Cd, Cr, Cu and Pb[52]), and changed metabolic function that may, in turn, affect the host’s immune and metabolic responses[51]. In addition, exposure to Pb, Cu, and Fe, for instance, may also directly induce inflammatory responses and cause oxidative stress[51,57]. A recent exploratory pilot analysis examined the complex connection among metals, microbiome, and intestinal inflammation. This analysis revealed that exposure to certain metals during pregnancy, combined with specific bacterial types during childhood (termed metal-microbial cliques), correlated with elevated fecal calprotectin levels, a marker of subclinical inflammation[58]. Conversely, Zn seems to have a protective role, improving the antioxidant and immune capacities and reducing apoptosis of intestinal epithelial cells in animal models[59]. Recent reports suggest that exposure to Pb may secondarily induce changes in Cu, Fe, and Zn levels[60], broadening further the complexity and relevance of metal exposure.

Air pollutants

Particulate matter, specifically PM_2.5 which has the highest penetration ability, is the most studied air pollutant. In mouse models, exposure to PM_2.5 alters circulating cytokine levels (decrease in Th17[61], increase in TNF-α[61], IL-1β[62], and IL-6[62]). Also, PM_2.5 is reported to impact the gut microbiome in several animal models, decreasing bacterial diversity, changing the Firmicutes/Bacteroidetes ratio[63], and microbial metabolic pathways[62]. PM_2.5 also promotes oxidant-dependent activation of the NF-κB pathway, with downstream disruption of tight junctions, and increases the permeability of human Caco-2 cell monolayers[63]. However, two-dimensional models, like Caco-2 cells, may not accurately reflect the characteristics of native cells, particularly regarding the expression of receptors and transporters. Using a three-dimensional model that incorporates stromal cells and extracellular matrix, Woodby et al.[64] have shown that chronic exposure to PM affects gut redox homeostasis and decreases the levels of cell-cell adhesion proteins (zonula occludens protein-1 and claudin-1). Moreover, other reports have demonstrated that PM can accelerate chemically induced colonic tumor formation in murine models, a process that relies on the phosphoinositide 3-kinase (PI3K)/AKT pathway[65]. This finding may be relevant considering the increased risk of colorectal cancer in IBD patients with active inflammation. Finally, PM₁₀ was demonstrated to interfere with calcium signaling, absorption, and digestion pathways, exacerbating preexisting intestinal inflammation in an organoid model[66].

Industrial compounds, byproducts, and organic pollutants

In mice studies, exposure to PFAS was associated with a decrease in Firmicutes/Bacteroidetes ratio, a decrease in Clostridiales, Enterobacteriale, and Lactobacillales, and a loss of gut barrier integrity due to a reduction in short-chain fatty acids production and intestinal tight junction proteins (zonula occludens-1, occludin and claudin-1) [67]. Others have demonstrated increased expression of proinflammatory cytokines (particularly IL-6, TNF-α, and IL-1β) and expansion of systemic CD4⁺ T cells with PFOS[68]. This compound was also reported to increase the neutrophil recruitment to the intestine of zebrafish larvae, which was later validated in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice[68]. Studies conducted on bivalves using multi-omics analyses suggested that the Peroxisome proliferator-activated receptor (PPAR)-mediated lipid metabolism (TLR/MyD88/NF-kB and PI3K-Akt-mTOR), and the autophagy pathways likely mediate PFOA-associated immunotoxicity[69]. These pathways coordinate cellular responses to environmental stimuli, cell growth and proliferation, and immune regulation[69].

Furthermore, evidence from human metabolomics suggests that PFAS exposure impacts important cellular metabolic pathways, including lipid, amino acid, carbohydrate/glycans, nucleotide, energy metabolism, and glycan biosynthesis, which may suggest the effects of PFAS exposure in cellular energy and membrane disruption that can be potentially associated with pathological processes [70]. Also, levels of PFOS and PFOA in human serum samples are associated with altered IgG glycosylation, in both children and adults [71]. Several glycosylation abnormalities have been described in IBD as, for example, defects in N-glycan branching of mucosal T cells from UC, leading to T-cell hyperactivation and increased disease severity[72]. More recently, in a pilot analysis of PFAS mixture in dried blood spots from neonates, an estimate of prenatal exposure, PFAS levels were associated with fecal calprotectin at 3 years of age, particularly in offspring of women with IBD[73].

Data regarding the mechanistic effects of other contaminants such as benzo[a]pyrene[74], polychlorinated biphenyls, ammonia[75], and triclocarbanm[76] are few. However, in line with PFAS data, exposure to these chemicals increase expression of IL-6, TNF-α, and IL-1β, and lead to altered intestinal permeability.

Pesticides

Recent pre-clinical evidence supports the impact of diverse pesticides on the intestinal mucosa. Phosalone[77] and chlorpyrifos[78], organophosphate pesticides, were reported to increase oxidative stress, TNF-α, IL-1β, and IL-6 levels, and to decrease intestinal permeability in mice. Similarly, exposure to avermectin and pyrethroid pesticides (fenpropathrin and deltamethrin) was found to increase oxidative stress and inflammation and to compromise the integrity of the intestinal barrier in carp[79] and mice[80]. Recently, a study used an innovative approach combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to test for the effects of over 200 chemicals on intestinal inflammation[81]. Of the 20 top candidate chemicals to induce intestinal inflammation, 11 were - cidal agents; two herbicides (flumetralin and propyzamide) and two pesticides (azinphos-methyl and phorate) boosted TNBS-induced intestinal inflammation in zebrafish. Propyzamide was also found to induce colon shortening and intestinal inflammation (promoting T_H1 and T_H17 cell differentiation and increased expression of IL-17+ T cells) in mice[81].

4. DISCUSSION

We systematically summarized 32 human studies on environmental pollutants relevant to IBD risk and outcomes. Overall, these studies support an association between heavy and transition metals, air pollutants, industrial contaminants, insecticides and an increased risk of IBD. In contrast, Zn exposure may be protective against IBD. Limited data suggest that IBD outcomes, such as hospitalizations, are more prevalent with increased exposure to air contaminants. Studies with comparable study designs will be important to clarify, as well as quantify, the impact of pollutants on IBD. Based on animal models and in vitro data, most of these pollutants promote intestinal inflammation through changes in the gut microbiome, loss of intestinal barrier function, and systemic inflammation. Globally, the reporting quality of the studies was adequate.

Heavy and transition metals play vital roles in biological processes, including as enzyme cofactors and electron transporters. Thus, any dyshomeostasis in these metals can disrupt metabolic and physiological functions. Both case-control[14–16] and cohort[31,40] studies demonstrated associations between metals and IBD, with individuals exposed to elevated concentrations of Mn, Hg, As, Pb, and Fe at a greater risk of IBD. These findings are supported by evidence from a pilot study on deciduous teeth and an exploratory analysis of healthy children, the latter reporting an interaction between prenatal metal exposure and microbiome signatures, toward downstream intestinal inflammation[58]. In line with this, preclinical studies have shown both direct and microbiome-related effects of metals on microbial metabolic profile, intestinal permeability, cytokine milieu, and systemic immune dysregulation [82]. In contrast, Zn appears to decrease the risk of IBD[15]. This has biological plausibility considering Zn’s anti-inflammatory and antioxidant effects in animal studies[59]. Further, this is corroborated by two large prospective cohort studies in which an inverse relationship between dietary Zn intake and the risk of CD was detected. Yet, no such association was observed for UC[83].

With respect to air pollutants, which may be inhaled or ingested, five[19,37,41,42] of the seven reports that investigated the effect of PM_2.5 [19,37,41,42]reported a harmful association with IBD, particularly with UC[43,44]. This association is supported by the pro-inflammatory effects of PM_2.5 in the intestinal tract in in vitro and animal studies. The association of PM_2.5 with UC but not with CD, highlighted in some studies, may be related to perturbation of colonic microbiota composition by air pollutants and warrants further study. Other air pollutants such as total oxidant agents[27], NO[21] and SO₂[21] may be particularly relevant in early life [84]. Indirect data also support this framework. In a population-based cohort study, early life exposure to agricultural land use was associated with increased CD risk, while exposure to greenspace and biodiversity was protective[85]. These exposures may modulate NO and SO₂ levels, mainly from vegetable crops fertilizers or livestock. Certainly, exposures during the early life period, which extends from prenatal period to early childhood, are critical towards microbiome establishment, immune maturation and the risk of IBD later in life[85–88]. Exposures in adulthood may be relevant towards older onset IBD[89]. Studies exploring the effects of pollutants at different stages of life are likely to be relevant, particularly towards honing prediction and prevention strategies. The impact of air pollutants on adverse IBD outcomes such as hospitalization[25,34,39], surgery[41] and mortality[32] are consistent with those pertaining to other immune-mediated diseases, such as rheumatoid arthritis[90], and emphasize the importance of mitigation strategies.

The importance of industrial contaminants has increased, not only because their sources are proliferating but also because some have long-lasting persistence rising over time[12]. Among these, the most relevant are PFAS, a family of over 8,000 synthetic chemicals widespread in the environment. The adverse effects of PFOS and PFOA on gut homeostasis are consistently reported in animal and in vitro studies, as well as in recent analyses of human serum samples and neonatal dried blood spots. This knowledge and the PFAS association with a broad range of conditions[91], including cancer and immunotoxicity has been recognized by European and American agencies and authorities[91]. However, not all epidemiological studies reported an association between PFAS levels and IBD risk. This highlights the importance of studying PFAS (and other pollutants) in totality, such as a mixture, rather than measuring individual compounds, such as legacy PFAS[12]. Further, delineating the impact of PFAS on gut mucosal integrity and permeability by assessing its effects on mucosal glycocalyx composition and microbiota functions is relevant. This approach can provide insights into the underlying causes of the transition from health to inflammation associated with the onset of IBD.

With respect to pesticides, their detrimental impact on intestinal mucosa has been reported in numerous in vitro and animal studies. However, only one clinical study explored the role of pesticides in modulating the risk of IBD. Although this prospective study found a positive association with OC and OP insecticides, the exposure was measured using questionnaires, making it subjective and prone to recall bias[42]. While more objective exposure assessments are needed, two[85,92] recent population-based studies indirectly support the role of pesticides as risk factors. The first, from the Danish population, identified that early life exposure to agricultural land use was linked to a higher risk of CD[85]. The second, which evaluated French farmers, identified some agricultural activities in which pesticides are commonly applied, like fruit arboriculture and crop farming, to be more strongly associated with IBD risk[92].

While reporting important findings for specific pollutants, this review also highlights knowledge gaps (Figure 4). Regarding metals, these include the limited number of human studies with relatively small sample sizes and the absence of individual-level and long-term assessments of exposures in many cases. Further, there are few tools available to establish concentration-effect relationships. Future work is also needed to understand the interactive effects of multiple metals or metal mixtures and to unravel the dysregulation in fetal metal biodynamics (e.g., altered rhythmicity, a biomarker of metal homeostasis, a concept different from exposure)[93]. The complex relationship between metals and the gut microbiome is also just beginning to be understood. Even though the existing evidence for air pollutants is robust, there is a need for more comprehensive exposure assessments, accounting for the dynamics introduced by environmental policies and understanding how exogenous exposure to air pollutants exacerbates the effect of endogenous pollutants like pesticides and PFAS. Concerning industrial products, although several clinical studies address PFAS, using advanced laboratory techniques and statistical models is crucial to detect meaningful immunological effects and to conduct valid risk assessments. Pertaining to in vitro and in vivo animal studies, little evidence exists for other PFAS compounds other than PFOS and PFOA. The impact of relevant industrial contaminants like hydrogen sulfide, triclocarban, ammonia, and flame retardants on gut inflammation remains to be explored. Regarding -cidal agents, it remains difficult to evaluate past and time-varying exposures, dose-effect measures, and the role of unexplored vectors such as soil. There is a paucity of data for other agents, such as pharmaceutical products and endocrine disruptors.

Figure 4.

Main findings of the review

Overall, the measurement of exposure biomarkers with high temporal resolution, particularly in pre-clinical biological samples, and application of advanced measurement techniques and composite data analysis are needed to clearly delineate the impact of environmental pollutants on IBD. This approach may also provide insights into the role of different environmental insults in different stages of life and clarify whether the timing of exposure may be more critical than the duration. Mechanistic data using IBD models, rather than extrapolation from other models, will provide granular insights into IBD pathogenesis. Finally, it is important to note that variables beyond environmental pollutants, such as genetic, epigenetic, and dietary factors are likely to modulate IBD risk and outcomes via direct and interaction effects, highlighting the complexity of IBD pathogenesis. For example, the effect of smoking on health outcomes is modulated by genetic variants that influence its metabolism[94,95]. Future multi-omic analyses will uncover gene-pollutants interaction in the context of IBD.

Finally, it is key to advance and upscale the field of bioremediation, identifying microorganisms, enzymes, and inert compounds that may help eliminate or, at least, neutralize pollutants. These transdisciplinary approaches will provide evidence towards effective prevention strategies in regulatory and clinical contexts, as well as provide a framework towards understanding of environmental impacts on other immune-mediated diseases. In the meantime, based on current knowledge and in line with international recommendations, it is crucial to minimize harmful exposures through modification of production processes, use of less toxic materials, implementation of conservation techniques, reuse and upcycling. Such practices, at individual and societal levels, are likely to be relevant towards improving health outcomes overall.

Supplementary Material

Supp1

Supplementary Table 1. Summary of the evidence from human studies on the association between inflammatory bowel disease and the different categories of environmental pollutants.

Supplementary Table 2. Assessment of the reporting quality of the studies included in the systematic review (n=32).