OP14Risk of Inflammatory Bowel Disease Following Hospital-Treated Infections and Modulatory Role of Host Genetics to support a multi-hit pathogenesis model

Abstract Background As pervasive immune stressors, infectious diseases can disrupt immune homeostasis and predispose to chronic immune-mediated disorders1. However, the relationship between infections and inflammatory bowel disease (IBD) remains unclear2. To elucidate the contribution of infections to IBD pathogenesis, we evaluated their association with subsequent IBD risk and examined the modifying effects of immune-related genetic variants. Methods In this prospective cohort of 359,636 UK Biobank participants, Cox proportional hazards models estimated hazard ratios (HRs) for IBD, Crohn’s disease (CD), and ulcerative colitis (UC). The modifying effects of 51 immune-related genes (lead SNPs from whole-genome sequencing) were evaluated with functional and KEGG pathway analyses to characterize underlying processes3. Genes with significant pathogen-related interactions were integrated into an Infection IBD Score (IIS) to stratify post-infection susceptibility (Figure 1A). Results During a mean follow-up of 12.1 years after the first hospital-treated infection, such infections were associated with a markedly increased risk of IBD (aHR = 3.44; 95% CI: 3.14-3.77) (Figure 1B). Elevated risks were observed across all major pathogen characteristics (bacterial, viral, fungal, parasitic) and 7 anatomical sites. Analyses of 51 immune-related genes represented by lead SNPs identified 44 with significant modifying effects, including 11 for IBD (e.g., IL12B, IRGM), 9 for CD (e.g., IRGM, MAP3K8), and 7 for UC (e.g., CCL20, IL12B), showing strong and consistent modification across multiple pathogen categories (Figure 1C). Clustering based on these immune-related genes further identified genetically distinct subgroups, with Cluster 1 showing a significantly higher risk of IBD and UC. Pathway enrichment analysis revealed shared yet distinct immune mechanisms, with CD enriched in innate immune and autophagy pathways and UC in JAK–STAT signaling and T-cell differentiation (Figure 2A). The IIS, constructed from these 44 SNPs, showed strong infection-IBD risk gradients, with aHRs of 3.15 (95% CI: 2.86–3.48) and 6.35 (95% CI: 4.83–8.35) in the low- and high-score groups (Figure 2B-C). Proteomic analyses further validated the IIS and demonstrated biologically coherent molecular signatures differentiating CD and UC (Figure 2D). Conclusion Hospital-treated infections were strongly associated with incident IBD and were modulated by immune-related genetic variation, with 44 SNPs showing significant modifying effects. The IIS provided consistent risk stratification for infection-related IBD. These findings support a multi-hit model of IBD, linking infections with immune-genetic susceptibility, and highlight the potential of IIS for infection-based risk prediction. References: 1Baker RE, Mahmud AS, Miller IF, et al. Infectious disease in an era of global change. Nat Rev Microbiol. 2022;20(4):193-205. doi:10.1038/s41579-021-00639-z. 2Chhibba T, Gros B, King JA, et al. Environmental risk factors of inflammatory bowel disease: toward a strategy of preventative health. J Crohns Colitis. 2025;19(4):jjaf042. doi:10.1093/ecco-jcc/jjaf042. 3Liu Z, Liu R, Gao H, et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet. 2023;55(5):796-806. doi:10.1038/s41588-023-01384-0 Conflict of interest: Zhuang, Haiming: No conflict of interest Dan, Lintao: I have no COI related to submitted program Xiang, Xin: No conflict of interest Ruan, Xixian: I disclose no relevant conflict of interest. Yuan, Shuai: No conflict of interest Yao, Jialu: No conflict of interest Geng, Jiawei: No conflict of interest Jonas, Ludvigsson: No conflict of interest Fu, Tian: Have no conflict of interest. Ferreira de Abreu, Cândida Manuela: no Peyrin-Biroulet, Laurent: CONSULTING Abbvie, Abivax, Adacyte, Alimentiv, Alfasigma, Amgen, Apini, Banook, BMS, Celltrion, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Iterative Health, Janssen, Lilly, LifeMine, Medac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Par’ Immune, Pfizer, Prometheus, Roche, Roivant, Samsung, Sandoz, Sanofi, Sorriso, Spyre, Takeda, Teva, ThirtyfiveBio, Tillots, Vectivbio, Vedanta, Ventyx. LECTURE Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Iterative Health, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots Li, Xue: No conflict of interest Magro, Fernando: Fernando Magro served as speaker and received honoraria from Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor. Wang, Xiaoyan: No conflict of interest Sun, Jing: I have not COI related to submitted project. Chen, Jie: No conflict of interest