Gut Microbiome Alterations, Microbial Metabolites and Hepatobiliary Cancer: A Descriptive Systematic Review of the Microbial–Metabolic Axis

Background: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are considered major causes of cancer-related mortality. Evidence suggests that gut microbiome dysbiosis and the microbial–metabolic axis and its metabolites in hepatic chronic inflammation might be implicated in carcinogenesis in the gut–liver axis. This descriptive systematic review examines the microbial–metabolic axis in hepatobiliary cancer, focusing on patterns of dysbiosis, microbiome-associated metabolites, and the diagnostic or prognostic potential in this field. Methods: This manuscript was developed according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420261455009). PubMed, Scopus, Cochrane Library, Web of Science, and Embase were searched. Eligible studies were published medical manuscripts reporting gut (oral/duodenal/fecal) microbiome alterations with links to HCC or CCA. Risk of bias was assessed with Rob 2.0 for the randomized clinical trial study included in this manuscript and ROBINS-I for the non-randomized studies. Ultimately, 13 studies met the inclusion criteria and were included in this qualitative study. Results: In the included studies, patients with HCC or CCA showed altered gut microbial diversity, a depletion of beneficial taxa such as Faecalibacterium and Bifidobacterium, and increased levels of potentially pro-inflammatory genera. Specific signatures such as Alloprevotella and the B.F.R. genera models in CCA were associated with diagnostic performance, with AUCs that frequently exceeded 0.90 in internal validation. Furthermore, circulating and host microbial metabolites, such as methionine, methionine sulfoxide, taurocholic acid, and microbial-derived TMA/TMAO pathway components, were associated with HCC risk. Conclusions: According to our analysis, gut microbiome alterations are associated with HCC and CCA and show promising diagnostic and prognostic potential. The findings are consistent with a possible microbial–metabolic contribution to hepatocarcinogenesis through chronic inflammatory and metabolic pathways. However, most included studies evaluated virus-related liver disease, and direct evidence linking obesity or MASLD-related dysbiosis to hepatobiliary cancer remains limited. Prospective and interventional investigations of metabolic liver disease populations are needed to clarify this axis.