Characterizing the mediating role of metabolic signatures in the associations between air pollution exposure and inflammatory bowel disease

The association between long-term air pollution exposure and inflammatory bowel disease (IBD) remains inconclusive. A total of 133,261 participants from the UK Biobank, a prospective cohort were included. Incident IBD cases were ascertained from the administrative database of the National Health Services. Air pollution exposure (PM_2.5, PM₁₀, NO₂ and NO_x) at participants’ residential addresses was estimated by spatio-temporal models. Cox regression models were used to assess the associations between air pollution and IBD. Metabolic signatures were constructed by summing selected plasma metabolites associated with air pollution through elastic net regression. Afterwards, mediation analyses were conducted to investigate the potential mediation of metabolic signatures on the air pollution-IBD associations. During a mean follow-up of 11.61 years (SD: 1.78), 824 incident IBD cases were identified. Long-term exposure to PM_2.5, PM₁₀, NO₂, and NO_x was positively associated with IBD risk: hazard ratios were 1.019 (95 % CI: 0.933, 1.112), 1.033 (95 % CI: 0.942, 1.132), 1.112 (95 % CI: 1.026, 1.227), and 1.121 (95 % CI: 1.028, 1.223), respectively. As PM_2.5 and PM₁₀ were not significantly associated with incident IBD, subsequent metabolic analysis was only conducted for NO₂ and NO_x. The metabolic signatures for NO₂ and NO_x included 26 and 18 metabolites (mostly related to amino acids, glucose metabolism, and lipid metabolism), respectively. The significant associations of NO₂ and NO_x with incident IBD were explained by their metabolic signatures (mediation: 10.13 % (95 % CI: 4.56 %, 42.87 %) and 9.17 % (95 % CI: 3.87 %, 38.64 %), respectively). Our findings suggest that long-term air pollution exposure could increase IBD risk, potentially through mediation by metabolic changes.