Pattern-specific plasma proteomic responses to alcohol drinking and gastrointestinal disease risk

Alcohol-related gastrointestinal risks vary by intake level, beverage type, and sex, but reported alcohol intake may not fully reflect biological responses to drinking. We aimed to characterize plasma proteomic responses to distinct drinking patterns, assess their associations with gastrointestinal risk states, and identify shared proteins of alcohol exposure. We analyzed plasma proteomic data from 47,514 UK Biobank participants. Drinking patterns were defined by intake level, dominant beverage type, and sex, yielding 12 pattern-specific proteomic signatures. Linear and nonlinear associations with gastrointestinal disease risks were evaluated. Shared alcohol-responsive proteins were examined and validated in an independent cohort and a graded ethanol-exposure mouse model. Alcohol drinking was associated with 475 plasma proteins enriched in immune, inflammatory, adhesion, and lipid-related pathways. Alcohol-related proteomic responses were highly pattern-specific, differing by intake level, beverage type, and sex in the composition, pathway enrichment, and overlap of signature proteins. Pattern-specific proteomic signatures showed heterogeneous and nonlinear associations with gastrointestinal outcomes. Even among drinkers with similar alcohol intake levels, beverage- and sex-specific signatures displayed distinct risk curves for the same outcomes, suggesting that alcohol-related proteomic responses capture information beyond alcohol volume alone. Despite this heterogeneity, APOM, MAMDC4, and SERPINA7 were consistently retained across drinking patterns, correlated with alcohol intake, discriminated regular drinkers from occasional drinkers better than conventional liver enzymes, and were validated in the Chinese cohort and ethanol-exposed mice. Distinct alcohol drinking patterns were characterized by different plasma proteomic response states, which provided biological context for heterogeneous gastrointestinal disease risks beyond reported alcohol volume alone. APOM, MAMDC4, and SERPINA7 represent shared exposure-responsive proteins that may complement questionnaire-based alcohol assessment.