Illustration of the gut-immune-liver axis in early-stage alcohol-related liver disease: role and non-invasive potentiation of biomarkers and peptidomic signatures

Abstract Alcohol use disorder (AUD) can progress to alcohol-associated liver disease (ALD), yet early-stage ALD (eALD) remains poorly defined at the molecular level. We performed plasma proteomic and peptidomic analysis in 42 adults (AUD n = 10, eALD n = 26, healthy volunteers n = 6) using LC-MS/MS and pathway enrichment. Individuals with eALD exhibited greater alcohol burden, elevated liver injury markers (AST and ALT), and increased gut–immune dysfunction markers, including lipopolysaccharide, TNF-α, and K18M65, compared with AUD. Proteomic profiling identified 23 dysregulated peptides, with fibrinogen alpha (FIBA), fibrinogen beta (FIBB), COL1A1, and ITIH4 as key candidates. FIBB and COL1A1 were associated with AST, while FIBA and COL1A1 distinguished eALD from AUD. These findings identify circulating peptide biomarkers reflecting gut–immune–liver axis dysfunction and support their potential utility for non-invasive detection of early alcohol-associated liver disease.