Understanding the interconnected roles of gut microbiota and metabolomic profiles in alcoholic liver disease pathophysiology and their potential for innovative treatment strategies
Jeyakumar Balakrishnan, Suganya Kannan, Ganeshbala Arivazhagan, Niranjjan Ramachandran, Vanitha Gnanasoundran Sundarasamy
Abstract
Alcoholic liver disease (ALD) remains a major global health burden driven by chronic alcohol consumption and characterized by progressive liver injury, inflammation, and fibrosis. A growing body of evidence highlights the central role of the gut-liver axis in ALD pathogenesis, where alcohol-induced dysbiosis and intestinal barrier disruption facilitate the translocation of bacterial endotoxins such as lipopolysaccharides (LPS) into the liver. These microbial products activate Kupffer cells via Toll-like receptor 4 (TLR4) signaling, triggering inflammatory cascades, oxidative stress, and hepatic stellate cell activation, thereby promoting fibrogenesis. Dysregulated bile acid metabolism, impaired FXR and TGR5 signaling, and depletion of beneficial microbial metabolites such as short-chain fatty acids (SCFAs) further contribute to liver damage. Advances in metabolomics have uncovered distinct microbial and host-derived metabolic signatures linked to disease severity, including SCFA depletion, elevated trimethylamine-N-oxide (TMAO), and bile acid imbalances. Precision interventions targeting the gut microbiota—such as probiotics, prebiotics, synbiotics, and microbial metabolite supplementation—are showing promise in modulating gut-liver interactions and mitigating ALD progression. Furthermore, the integration of multi-omics datasets with artificial intelligence (AI)-driven models is paving the way for personalized treatment strategies based on individual microbiome-metabolome profiles. This review consolidates current insights into ALD pathogenesis, the gut-liver axis, and emerging microbiota-centered precision therapies that are reshaping the future of ALD management. • Alcohol disrupts gut-liver axis causing microbial dysbiosis and liver injury. • Microbial metabolites serve as biomarkers and therapy targets in ALD treatment. • AI-driven multi-omics integration enables precision medicine in ALD therapy. • Precision probiotics and prebiotics restore gut homeostasis in ALD patients. • ALD significantly contributes to global liver morbidity, necessitating action.