Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal disorders, which is defined as the movement of stomach contents into the esophagus or mouth, causing troublesome symptoms or complications with heartburn and reflux as the most typical symptoms (1, 2). According to estimates from a global epidemiological study, approximately 13.3% of the population worldwide suffered from heartburn or reflux symptoms at least once a week, with prevalence varying from 2.5 to 51.2% across different countries (3). Worse still, the number continues to rise (4). Due to its high prevalence and chronicity, GERD impairs the patient’s quality of life seriously and contributes to substantial economic and medical burdens. GERD has been identified to increase the risk of esophageal strictures and esophageal carcinoma (5), which can be life-threatening. Reflux exposure, epithelial resistance, inflammation, motility disorder, and visceral hypersensitivity were all involved in the complicated pathogenesis of GERD (6, 7).

Ambient air pollution is a prominent environmental risk factor for various diseases. Particulate matter has been the leading contributor to the Global Burden of Disease Study 2021 (GBD 2021) (8). Inhalable particulate matter (PM₁₀) could be mainly classified into coarse particulate matter (PM_2.5–10) and fine particulate matter (PM_2.5) (9). According to the Integrated Science Assessment (ISA), approximately 71% of the particulate matter deposited in the nose is subsequently transported to the gastrointestinal tract (9), underlining the significance of the gastrointestinal exposure pathway for air pollutants. Nitrogen oxides (NO_X) are one of the typical types of gaseous pollutants, consisting of nitrogen dioxide (NO₂) and nitric oxide (NO). NO_X is mainly sourced from vehicle emissions, industrial processes, and fuel combustion, and has specific adverse health effects (10, 11). It is predicted that NO_X is emitted into the atmosphere predominantly as NO (more than 90%) (10), which is a highly reactive free radical as a noxious air pollutant (12). While previous research has largely focused on respiratory and cardiovascular diseases, only limited studies have examined its role in gastrointestinal disorders (13–15). In particular, the potential association between long-term exposure to air pollutants and the risk of GERD incidence has not been investigated.

To address existing knowledge gaps, our study aimed to evaluate the impact of long-term particulate matter (PM₁₀, PM_2.5–10, and PM_2.5) and gaseous pollutants (NO_X, NO₂, and NO) exposures on incident GERD as well as its subtypes (GERD without esophagitis and GERD with esophagitis). Furthermore, we sought to identify populations that may be more susceptible to the association between air pollution and incident GERD.

In this large-scale and long-term prospective cohort study, we estimated a robust association between several air pollutants and the risk of GERD. Our findings indicated that long-term exposure to both particulate matter (PM₁₀, PM_2.5–10, and PM_2.5) and gaseous pollutants (NO_X, NO₂, and NO) is associated with an increased risk of GERD incidence, particularly for GERD without esophagitis (K21.9). We observed almost linear exposure-response curves for the association between long-term exposure to air pollutants and the risk of GERD. Subgroup analyses revealed a stronger association with particulate matter among individuals under 60 years old, while females, individuals under 60 years old, and the overweight individuals (BMI ≥ 25 kg/m²) were more sensitive to gaseous pollutants.

Most previous research has concentrated on the effects of air pollution on respiratory and cardiovascular diseases (23–25), with relatively limited attention to the associations between air pollution and gastrointestinal diseases. Several previous epidemiological studies have revealed associations between air pollutant exposure and gastrointestinal diseases. In accordance with previous research examining the relationship between long-term PM_2.5 exposure and the risk of esophageal cancer incidence (13), our study also observed nearly linear exposure-response curves for the association between long-term PM_2.5 and PM₁₀ exposure and GERD. Although it is well established that GERD is a major risk factor for esophageal cancer (5), current evidence is insufficient to confirm whether air pollution indirectly increases the risk of esophageal cancer by promoting GERD progression. Further studies are needed to confirm this potential linkage. Only a few studies have investigated the potential association between air pollution and GERD. One study from Korea found that GERD-related medical utilization increased with the levels of PM_2.5 and carbon monoxide (26), which only reflected healthcare utilization patterns rather than the incidence risk of GERD. Furthermore, the study did not differentiate GERD subtypes. Another cohort study examined the relationships of air pollutants and the risk of multiple gastrointestinal diseases (27), which included GERD in their investigation, and found an association between PM_2.5 exposure and GERD. In contrast to these two studies, our study offers a more comprehensive and disease-specific perspective by analyzing the associations between multiple air pollutants and GERD incidence, including distinct analyses by GERD subtypes. Moreover, we conducted comprehensive subgroup analyses to identify vulnerable populations and estimated exposure-response relationships, which provide novel insights into pollutant-specific and subtype-specific risks of GERD.

Additionally, we observed a stronger association between air pollution and GERD without esophagitis (K21.9) compared to GERD with esophagitis (K21.0). This difference is more likely attributable to the different pathophysiological mechanisms underlying these two subtypes. GERD with esophagitis is characterized by visible mucosal injury on endoscopy and is primarily associated with prolonged acid exposure and overt epithelial damage (28), which may be less directly influenced by pollutant-induced pathways. In contrast, GERD without esophagitis lacks macroscopic mucosal erosion and involves impaired mucosal resistance, increased epithelial permeability, and enhanced visceral hypersensitivity (29, 30), which could be more susceptible to pollution-induced oxidative stress and inflammatory responses.

The associations between air pollutant exposures and GERD present a biological mechanism of rationality. In addition to the respiratory tract, the gastrointestinal tract is another important exposure route for air pollutants (9). Particulate matter can enter the gastrointestinal tract through multiple pathways, including ingestion of contaminated food and water, mucociliary clearance from the respiratory tract, and the systemic blood circulation (31–33). Besides, gaseous pollutants might also affect the digestive tract through swallowed air. Although NO_X itself is unlikely to enter the bloodstream directly, its various reaction products may migrate into the blood and spread to other tissues or organs (10). All the above indicate that the gastrointestinal tract serves as an important pathway for exposure to air pollutants.

Although direct evidence linking air pollution to GERD remains limited, existing studies have demonstrated that air pollutants can induce oxidative stress, systemic inflammation, and epithelial barrier dysfunction in the gastrointestinal tract (34–37), which provides important biological plausibility for the observed associations in our study. Experimental studies indicated that exposure to particulate matter may enhance the generation of reactive oxygen species (ROS), cause damage to epithelial cells, and lead to the disruption and increased permeability of the gastrointestinal barrier (35). Furthermore, particulate matter exposure could activate immune and inflammatory responses in the gastrointestinal tract. It has been reported that exposure to particulate matter is associated with increased infiltration of inflammatory cells, heightened expression of inflammation-related genes (such as IL-1β, IL-6, and TNF-α), and exacerbation of mucosal inflammation in the colon (36, 37). Barrier disruption, immune and inflammation activation contributed to the pathogenesis of GERD, highlighting potential mechanisms that may underlie the association between particulate matter exposure and GERD. Regarding gaseous pollutants, this is the first cohort study to evaluate the association between ambient NO_X exposure and the risk of GERD, which revealed that both NO₂ and NO exposures increase the risk of GERD without esophagitis (K21.9). The association between NO_X exposure and GERD is biologically plausible. NO_X can convert into various reactive nitrogen oxide species (RNOS) in the human body. RNOS at the human gastro-esophageal junction can damage the barrier function of the adjacent tissue by disrupting the tight junction (38). Studies suggested that the products of NO₂, such as nitrite, may migrate into the blood and induce systemic inflammation and oxidative stress, providing a potential mechanism by which NO₂ exposure could lead to health effects beyond the respiratory system (10). Additionally, swallowed NO₂ might cause nitration of different compounds, including nitrate and nitrite in the stomach, which could induce the redox interplay and inflammatory response (14, 39). Previous studies have provided evidence that NO can inhibit esophageal motility, disrupt epithelial barrier function, exacerbate inflammation, and accelerate columnar transformation in the esophagus (39, 40), suggesting that NO could also contribute to GERD pathogenesis in addition to conventional causative factors. This evidence provided biological plausibility and enhances the reliability of our findings. While direct evidence remains limited, these mechanisms may provide important biological plausibility for the associations observed in our study. Further experimental and longitudinal studies are needed to confirm the causal relationships and to elucidate the exact role of air pollutants in the pathogenesis of GERD.

Our subgroup analyses indicated that the associations between air pollutants and GERD varied in different groups. Specifically, we observed that females displayed greater sensitivity, especially for gaseous pollutants. Several previous studies have reported increased risks among females (41, 42), which may partly be attributed to sex-related differences in susceptibility and the greater exposure to indoor air pollution, particularly from sources such as cooking (41). We also observed that the risk of GERD tended to be higher in middle-aged individuals (<60 years) when exposed to air pollutants. Younger populations tend to experience greater exposure to air pollution due to their increased frequency of outdoor activities compared to older individuals, which may be one of the reasons why the younger population is more vulnerable. Besides, we discovered stronger associations between air pollutants (especially NO_X, NO₂, and NO) and GERD in overweight individuals (BMI ≥ 25 kg/m²) than those with BMI < 25 kg/m², which is consistent with other studies that air pollution exposure associated with overweight and obesity (43, 44). Additionally, we observed stronger associations in White ethnicity and those with higher SES. A previous study also found that GERD was more prevalent among individuals with higher SES (45). The differential vulnerability may be partially explained by SES-related lifestyle factors, such as dietary patterns and obesity. Moreover, individuals with higher SES are more likely to seek medical attention for GERD symptoms and undergo diagnostic testing, which may contribute to increased case detection.

Our study exhibits several significant advantages. First, it represents the first large-scale, population-based, and long-term cohort study revealing the impact of both particulate matter (PM₁₀, PM_2.5–10, and PM_2.5) and gaseous pollutants (NO_X, NO₂, and NO) on different subtypes of GERD (including K21.9 and K21.0). The large sample size and long follow-up period greatly enhanced the statistical power. Second, we introduced a DAG to provide a comprehensive and transparent process for more appropriately selecting confounders, which boosts the scientificity of our study. Finally, we conducted several sensitivity analyses to verify the robustness of the main model, further improving the credibility of the results.

It is also important to acknowledge several limitations in our study. First, because of the limited time scale of exposure data available in the UK Biobank, we used the annual average concentration of air pollutants for the year 2010 to represent long-term exposure, which is in accordance with methodologies employed in prior research within the UK Biobank cohort. Second, the annual concentrations of air pollutants in the UK were relatively low, preventing us from exploring the impact of higher concentrations of air pollutant exposures on GERD. Additional research is warranted in developing countries with higher ambient air pollution levels. Third, as the UK Biobank only includes participants aged 40–69 years at baseline, our results primarily reflect associations in middle-aged and older adults and may not be fully generalizable to younger populations.

In conclusion, this study demonstrated that air pollution may serve as an ‌unignorable environmental risk factor for GERD. Our findings indicated that long-term exposure to both particulate matter (PM₁₀, PM_2.5–10, and PM_2.5) and gaseous pollutants (NO_X, NO₂, and NO) may increase the incidence risk of GERD, particularly GERD without esophagitis rather than GERD with esophagitis. Considering the hazardous impact of air pollution, our research suggested the necessity of reducing emissions and restricting the air pollutants standards to alleviate the disease burden of GERD.