Abstract
Alcohol use disorder (AUD) is a chronic brain disease with limited therapeutic options. Increasing evidence suggests that the gut microbiome contributes to AUD via the microbiome-gut-brain axis. Here, we conducted a cross-species investigation of gut microbiota alterations in patients with clinically diagnosed AUD and in non-human primates (NHPs) subjected to long-term alcohol (ethanol) self-administration, using metagenomic sequencing. Both cohorts showed reduced microbial diversity and conserved dysbiosis, with consistent depletion of Verrucomicrobia, Actinobacteria, Faecalibacterium, Akkermansia, Intestinibacter, Phascolarctobacterium, and Ruminococcus, alongside increased Blautia and Coprococcus. These microbial shifts correlated with liver function indices, notably positive associations between Ruminococcus and bilirubin levels in both species, suggesting a potential role in liver injury. Functional analyses revealed conserved microbial adaptations, including upregulated DNA repair pathways, fermentative energy metabolism, and downregulated glutamate/glutamine biosynthesis. Together, these results identify evolutionarily conserved microbial and metabolic alterations linking alcohol consumption, gut dysbiosis, and hepatic dysfunction. Our cross-species evidence highlights the gut microbiome as a potential biomarker and therapeutic target for AUD.