Gut microbiota in hepatocellular carcinoma: pathogenic mechanisms and clinical translation

Abstract

The gut microbiota is an important modulator of host metabolism and immunity. In hepatocellular carcinoma (HCC), the most common form of primary liver cancer, dysbiosis, impaired intestinal barrier integrity, and dysregulated host-microbial immune signaling are considered contributing factors to disease progression. These perturbations may contribute to hepatocarcinogenesis across disease trajectories arising from metabolic dysfunction-associated steatohepatitis, alcohol-associated liver disease, and chronic viral hepatitis, many but not all of which involve progression through advanced fibrosis and cirrhosis. This narrative review synthesizes evidence indicating that microbiota-derived metabolites and microbial products, including short-chain fatty acids, bile acids, lipopolysaccharide and the host-microbial co-metabolite trimethylamine N-oxide, interact with host receptors and inflammatory pathways implicated in hepatocarcinogenesis. Preclinical studies have provided strong mechanistic support for microbiota modulation; however, clinical evidence in HCC remains preliminary, heterogeneous, and largely exploratory. This disparity underscores the need to elucidate the contributions of bacterial, fungal, viral, host genetic, sex-specific, and intratumoral microbial factors before their efficacy, safety and clinical utility in HCC can be rigorously assessed. Accordingly, microbiota-targeted strategies, such as probiotics, prebiotics, fecal microbiota transplantation, dietary modulation, and bacteriophage-based approaches, should be viewed as potential adjunctive or preventive interventions rather than as established HCC therapies.