Understanding crosstalk between the gut and liver microbiome: pathogenesis to therapeutic approaches in liver cancer

HCC is the most common primary liver cancer, ranking as the sixth most prevalent cancer globally and the third leading cause of cancer-related deaths. Etiological factors include:chronic liver diseases driven by alcohol abuse, viral hepatitis, obesity, and metabolic disorders. Emerging evidence also suggests that gut microbiome alterations and subsequent immune and metabolic dysregulation contribute to the pathogenesis and progression of HCC. The gut-liver axis represents a dynamic interplay between the gastrointestinal tract and the liver, modulated by the gut microbiome, microbial metabolites, and immune responses. This bidirectional communication plays a pivotal role in maintaining metabolic homeostasis and immune surveillance, while its dysregulation is implicated in various pathologies, including hepatocellular carcinoma (HCC). The gut microbiome, through microbial dysbiosis and metabolite secretion, significantly influences the tumor microenvironment and immune evasion mechanisms in HCC. Perturbations in gut barrier function and Toll-like receptor 4 (TLR4) activation drive chronic inflammation, promoting tumor progression. Moreover, microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, modulate inflammatory and metabolic pathways, offering novel insights into disease pathogenesis and potential biomarkers. Therapeutic strategies, including probiotics, prebiotics, and immune checkpoint inhibitors demonstrate promise in reprogramming the gut microbiome and restoring immune balance in HCC management. This review explores the multifaceted roles of the gut-liver axis in pathogenesis, the contributions of the intra-tumoral microbiome, and the potential of microbial metabolites as therapeutic avenues. A deeper understanding of these interactions could pave the way for innovative, targeted interventions in liver cancer and other gut-liver axis-associated diseases.