Microbiota in liver carcinogenesis: Illuminating the complex relationship

Hepatocellular carcinoma (HCC) develops predominantly in patients with cirrhosis, yet the biological mechanisms underlying the transition from cirrhosis to malignancy remain incompletely understood. Increasing evidence suggests that the oral-gut-liver axis contributes to this process through coordinated interactions among oral and intestinal microbiota, the epithelial barrier, the immune system, and the liver. While previous reviews have primarily focused on gut dysbiosis in cirrhosis and its complications, emerging evidence indicates that microbiome-associated alterations actively contribute to hepatocarcinogenesis. In this review, we propose a transition-state model in which disruption of the oral-gut-liver axis promotes progression from cirrhosis to HCC through functional microbiome insufficiency, epithelial barrier dysfunction, microbial translocation, inflammatory remodeling, and immune dysregulation. We emphasize that disruption of microbial metabolic functions, including reduced butyrate biosynthesis, bile acid remodeling, altered tryptophan metabolism, and enrichment of virulence-associated pathways may be more biologically relevant than taxonomic changes alone. We further discuss emerging biomarkers representing distinct domains of the gut-liver axis, including butyryl-CoA:acetate CoA-transferase (BCoAT) as a marker of microbial function, intestinal fatty acid-binding protein (I-FABP) as a marker of epithelial injury, and lipopolysaccharide-binding protein (LBP) as a marker of microbial translocation and endotoxemia. Finally, we discuss the translational implications of integrating microbiome-derived functional biomarkers with immune and clinical profiling for biological risk stratification, early detection, and precision hepatology as well as therapeutic strategies based on microbiome modulation. This framework shifts the focus from descriptive dysbiosis toward mechanistic host-microbiome interactions, highlights the oral-gut-liver axis as an active contributor to hepatocarcinogenesis, and provides a conceptual foundation for future microbiome-informed surveillance, risk stratification, and therapeutic strategies.