The Dual Role of Gut Microbiota and Their Metabolites in Hepatocellular Carcinoma: A Context-Dependent Framework

Hepatocellular carcinoma (HCC) is a global health threat, and gut microbiota play a pivotal role in its pathogenesis through the gut-liver axis. However, the literature contains divergent or opposing findings: key microbial metabolites, such as secondary bile acids and indole derivatives, exhibit potent pro- and anti-tumorigenic activities across different studies, hindering a unified understanding of their veritable roles. To resolve this ambiguity, this review proposes a unifying "context dependency" framework. We posit that the functions of gut microbiota and their metabolites are not fixed but are dynamically determined by the host's physiological and pathological "context," defined here as the integrated dynamic background shaped by local metabolite concentrations, host immune status, specific receptor expression, and tumor microenvironment (TME) features. This framework is systematically substantiated through an analysis of the dichotomous effects of major microbial metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and indole derivatives. We further elucidate that the key "contextual factors" governing these functional outcomes include the TME, host immune status, metabolite concentration gradients, and the activation patterns of specific signaling pathways (e.g., farnesoid X receptor/takeda G protein-coupled receptor 5, aryl hydrocarbon receptor). This novel framework not only provides a theoretical foundation for integrating existing paradoxical findings but also paves the way for the future development of context-specific precision diagnostic biomarkers and targeted microbial intervention therapies for HCC.