Combined acetaldehyde metabolism burden modifies IBD susceptibility to alcohol consumption

BACKGROUND: The effect of alcohol consumption on IBD remains inconclusive, potentially due to the overlooked role of alcohol metabolism. OBJECTIVE: We aimed to investigate the potential modifying role of alcohol metabolic capacity in the associations. DESIGN: A prospective cohort study (n=455 417) was used for association analysis between alcohol consumption and IBD risk using Cox proportional hazards regression. An acetaldehyde burden score, using genetic variants of alcohol dehydrogenase and aldehyde dehydrogenase validated by expression quantitative trait loci and proteomic data, was constructed to test effect modification. Genetic and metabolomic analyses, along with mice and human-derived colonic organoid experiments, were conducted to strengthen causal inference. RESULTS: The inverse association between alcohol and IBD risk was mainly attributable to red wine. Among individuals with low burden, reflecting low acetaldehyde generation and high acetaldehyde metabolism, per SD increase in red wine consumption (equivalent to 59.4 g/week of pure alcohol intake) was associated with a 20% (95% CI 7% to 31%) reduced Crohn's disease risk, whereas a 38% (95% CI 13% to 70%) increased risk among those with high burden. Genetic and metabolomic analyses further revealed harmful effects of acetaldehyde and protective effects of acetate. In vivo and in vitro experiments further confirmed these effects and showed that modulation of aldehyde dehydrogenase activity significantly altered colitis outcomes. CONCLUSION: Acetaldehyde metabolism burden modifies susceptibility to alcohol-related IBD and emphasises the importance of considering individual differences in alcohol metabolism when developing precision prevention strategies for IBD.