Abstract Background Crohn’s disease (CD), a major type of inflammatory bowel disease (IBD), is a chronic relapsing inflammatory disorder of the gastrointestinal tract. Emerging evidence suggests that exposure to environmental pollutants such as per- and polyfluoroalkyl substances (PFASs) contributes to IBD pathogenesis. However, the relationship between PFAS, particularly short-chain PFAS, and CD remains poorly defined. This case-control study aimed to investigate the association between serum PFAS concentrations and CD risk, with a focus on differences between short- and long-chain PFAS. Methods Serum samples from 131 CD cases and 99 healthy controls (HC) were obtained from the Inflammatory Bowel Disease Biobank in Nanjing Drum Tower Hospital. Concentrations of 18 PFAS and untargeted metabolomic profiles were quantified using liquid chromatography-high resolution mass spectrometry. Variable selection was performed using Elastic Net (ENET) and Support Vector Machine (SVM) Kernel models. Associations between PFAS mixtures and CD risk were evaluated using Bayesian kernel machine regression (BKMR), quantile g-computation (Qgcomp), and weighted quantile sum (WQS) regression. Individual PFAS associations were assessed using restricted cubic spline and logistic regression models, correlations with CD-related biomarkers were explored to infer potential mechanisms. Results All 18 PFAS were detected in over 80% of participants. Serum concentrations of short-chain PFAS, particularly perfluorobutanesulfonic acid (PFBS) and perfluoropropanoic acid (PFPrA), were significantly higher in CD patients than in HC (P 0.05), wheras most long-chain PFAS levels were lower (Table 1). PFBS was consistently identified as the key contributor across all mixture models (WQS OR = 1.898; Qgcomp OR = 1.174; BKMR, consistent positive association). Higher PFBS (75th percentile) was strongly associated increased CD risk (OR = 42.791, P 0.05), accounting for 56.6% of the WQS model’s positive weight (Fig 1A-B). Moreover, PFBS levels were positively correlated with C-reactive protein (CRP) levels (R = 0.23, P 0.05), suggesting an inflammation-related mechanism (Fig 1C). Conclusion This study demonstrates a significant positive association between short-chain PFAS exposure, especially PFBS, and CD risk. The correlation between PFBS and CRP supports a potential pro-inflammatory pathway underlying PFBS-related disease susceptibility. These findings underscore the emerging health risks of short-chain PFAS and highlight the need for validation through larger prospective studies. Conflict of interest: Dr. Zhou, Fan: No conflict of interest Xu, Shengxuan: No conflict of interest Zhang, Zhan: No conflict of interest
Zhou et al. (Thu,) studied this question.