P1234The role of alcohol consumption in the incidence of inflammatory bowel disease depends on acetaldehyde metabolism burden

Abstract Background Clinical guidelines lack clear recommendations on alcohol’s impact on inflammatory bowel disease (IBD) incidence, largely due to heterogeneity in cohort studies linking alcohol consumption and IBD risk. While genetic variations in alcohol-metabolizing enzymes influence alcohol-related health effects, such evidence has not resolved the heterogeneity observed for IBD. Methods We hypothesised that this heterogeneity requires simultaneous consideration of alcohol’s conversion to acetaldehyde and subsequent conversion to acetate. We conducted multidimensional validation, including a prospective cohort study of 455,417 IBD-free participants from the UK Biobank, metabolomics analyses, and summary-data-based Mendelian randomisation (SMR). To assess the two-step metabolic process of alcohol, we developed a novel genetically validated acetaldehyde burden score (using eQTL and proteomic data) within the cohort (Figure 1). The Cox proportional hazards model was used to estimate the association between alcohol consumption and incident IBD. Results In the cohort study, the effect of alcohol varied by type, and red wine consumption was significantly associated with a lower risk of IBD (HR per SD = 0.93, 95% CI: 0.90-0.97) (Figure 2A). The association between red wine consumption and Crohn’s disease (CD) incidence was significantly modified by overall acetaldehyde metabolism burden (P-interaction = 0.001) (Figure 2B). High burden individuals had a 38% increased CD risk (95% CI: 13%-70%, P = 0.002) in red wine, while low burden individuals had a 20% decreased risk (95% CI: 7%-31%, P = 0.004). Across multiple categories based on acetaldehyde metabolism burden, a higher burden was associated with elevated risk of CD, with the HR per SD ranging from 0.79 (95% CI: 0.61-1.02) in the lowest group to 2.17 (95% CI: 1.46-3.22) in the highest group (Figure 2C). SMR and metabolomics analyses indicated that lower ALDH2 expression (higher acetaldehyde level) was associated with increased IBD risk, while higher acetate levels were inversely associated with IBD and systemic inflammation (Figure 2D-G). Conclusion The association between alcohol consumption and IBD risk appeared heterogeneous and was potentially influenced by genetically determined acetaldehyde metabolism burden. These findings emphasised the importance of integrating metabolic and genetic profiling to elucidate how lifestyle factors such as alcohol consumption contribute to chronic inflammatory diseases. Conflict of interest: Dr. Chen, Jie: None to Declare Guo, Yang: No conflict of interest Hu, Jia: No conflict of interest Ye, Shuyu: No conflict of interest Yao, Jialu: No conflict of interest Yanai, Henit: No conflict of interest Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Peyrin-Biroulet, Laurent: Consulting for 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. Giving lectures for Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Iterative Health, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots. Dan, Lintao: I have no COI related to submitted program Li, Xue: No conflict of interest Wang, Xiaoyan: I have no conflict of interest to disclosure. 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 &amp Dohme, Sandoz, Takeda, UCB, Vifor.