Gut Microbiota in Hepatocellular Carcinoma: Etiology-Specific Evidence, Mechanisms, and Translational Challenges

Hepatocellular carcinoma (HCC) usually develops in patients with chronic liver disease and remains a major cause of cancer-related death worldwide. Increasing evidence suggests that dysbiosis of the gut microbiota is related to hepatocarcinogenesis through the gut-liver axis. Patients with HCC often show enrichment of pro-inflammatory or endotoxin-producing bacteria and loss of short-chain fatty acid-producing and barrier-protective taxa. These changes may increase intestinal permeability and microbial translocation and may contribute to chronic hepatic inflammation, immune disturbance, and metabolic changes. Lipopolysaccharide, secondary bile acids, and trimethylamine-N-oxide are among the microbial products that may connect intestinal dysbiosis with liver fibrosis and tumor progression. Clinical studies have also examined microbial signatures for early HCC detection, risk stratification, recurrence, and response to immune checkpoint inhibitors. However, most cohorts are small and differ in etiology, region, medication exposure, and sequencing method. Animal studies indicate that antibiotics, probiotics, fecal microbiota transplantation, and diet can change tumor development or treatment response, but direct clinical evidence in HCC remains limited. This review summarizes the compositional, mechanistic, and clinical evidence and discusses the present status of microbiota-targeted strategies in HCC.