IDDF2024-ABS-0110 Blood immune cell and metabolites mediating the causal associations between air pollution and inflammatory bowel disease: evidence from mendelian randomization study

<h3>Background</h3> Previous studies have reported a plausible association between air pollution and the onset and worsening of inflammatory bowel disease (IBD). However, the causal relationships and potential mediation pathways between air pollution and IBD remain uncertain. <h3>Methods</h3> We conducted cross-ancestry Mendelian Randomization (MR) analysis to evaluate the causal relationship between PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides, and the risk of IBD, ulcerative colitis (UC), and Crohn’s disease (CD) in European and Asian populations. We performed a comprehensive analysis of the immunome, metabolome, and gut microbiome to explore alterations in immune, metabolic, and gut microbiota profiles induced by air pollution. Additionally, we assessed the mediating effects of the immunome, metabolome, and gut microbiome on the causal links between air pollution and IBD. <h3>Results</h3> Our investigation revealed that PM2.5 exposure was linked to elevated risks of IBD and UC among European individuals (IBD: odds ratio (OR): 1.65, 95% confidence interval (CI): 1.03-2.63, P=0.04; UC: OR: 1.88, 95% CI: 1.12-3.17, P=0.02) (IDDF2024-ABS-0110 Figure 1A). Subsequent validation among the Asian population only confirmed a significant association between PM2.5 exposure and heightened risk of IBD (OR: 1.67, 95% CI: 1.02-2.75, P=0.04). Multiple sensitivity analyses supported the robustness of these findings. A total of 41 cytokines, 731 immune cells, 824 metabolites, and 212 gut microbiota were included in the multi-omics analysis. Exposure to PM2.5 induced changes in dozens of blood immune, metabolic features, and gut microbiota (IDDF2024-ABS-0110 Figure 1B). Furthermore, we identified that HLA-DR on CD33- HLA-DR+ cells in the immunome and glutamine in the metabolome mediated the interaction between PM2.5 and IBD, with mediation proportions of 21.1% and 11.9%, respectively, whereas gut microbiota did not exhibit mediating effects on this interaction (IDDF2024-ABS-0110 Figure 1C). <h3>Conclusions</h3> Long-term exposure to PM_2.5 was found to increase the risk of IBD, while HLA DR on CD33- HLA DR+ cell and glutamine partially mediated these causal effects. While this study enhances our understanding of the relationship between air pollution and IBD, further research is necessary to validate these associations.