Abstract Background Environmental contaminants are significant risk factors driving the development of inflammatory bowel disease (IBD). Heavy metals, as widely distributed environmental pollutants, contribute to the general population’s exposure. Although previous studies have revealed correlations between specific heavy metals (e.g., cadmium, lead) and the IBD risk, there is still a substantial gap in understanding the intestinal toxicity of other heavy metals and their impact on IBD onset1, 2. Methods We established a clinical cohort consisting of healthy controls, newly diagnosed Crohn’s disease (CD), and ulcerative colitis (UC) patients (n = 200 per group). Using mass spectrometry-based metallomics, a total of 35 heavy metal elements in blood samples were quantified. After adjusting for confounding factors including age, gender, BMI, smoking, and alcohol consumption, logistic regression analysis was performed to assess the association between blood metal levels and the risk of CD and UC. Weighted quantile sum (WQS) regression and partial least squares discriminant analysis (PLS-DA) were applied to identify the most influential heavy metal components contributing to IBD risk. Furthermore, using the adverse outcome pathway (AOP) strategy, we integrated the comparative toxicogenomics database with single-cell transcriptomic data from IBD patients, employing benchmark dose analysis, ingenuity pathway analysis, and molecular docking to further explore the toxicological pathways of core heavy metals. Results Logistic regression analysis revealed that elevated blood levels of antimony (Sb), arsenic, cadmium, lead, and copper were significantly associated with an increased risk of CD and UC (all p 0.05), whereas higher levels of zinc, silver, and selenium were significantly negatively associated with the risk of CD and UC (all p 0.05). WQS and PLS-DA analyses further indicated that elevated blood Sb levels were the most significant contributor to the increased risk of IBD (WQS weight = 0.819, VIP = 1.97, p 0.05). Using the AOP strategy and in silico toxicology approaches, we identified that under environmental exposure scenarios, Sb may promote the onset of CD and UC by antagonizing estrogen receptor α (ESRα) in colonic macrophages and inhibiting the interleukin-10 signaling pathway. Conclusion By integrating cross-sectional population studies, metallomics, and in silico toxicology analysis, this study identifies the previously overlooked role of Sb exposure in IBD pathogenesis and its potential mechanisms. This finding provides novel insights into environmental risk factors for IBD and highlights potential therapeutic targets for its prevention and treatment strategies. References: 1. Estevinho MM, Midya V, Cohen-Mekelburg S, Allin KH, Fumery M, Pinho SS, Colombel JF, Agrawal M. Emerging role of environmental pollutants in inflammatory bowel disease risk, outcomes and underlying mechanisms. Gut. 2025 Feb 6;74(3):477-486. 2. Ananthakrishnan AN, Bernstein CN, Iliopoulos D, Macpherson A, Neurath MF, Ali RAR, Vavricka SR, Fiocchi C. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):39-49. Conflict of interest: Dr. Yang, Wang: No conflict of interest Song, Xiaomei: No conflict of interest Liu, Yan: No conflict of interest Hu, Chaoqun: No conflict of interest Wang, Xinyue: No conflict of interest Shi, Ping: No conflict of interest Yang, Zeyu: No conflict of interest Teng, Yongsheng: No conflict of interest Guo, Hong: No conflict of interest
Yang et al. (Thu,) studied this question.