Gut Microbiome Dysbiosis in Hepatocellular Carcinoma Patients with Persistent HCV Viremia versus Viral Clearance: A Cross-Sectional Study

Background Hepatocellular carcinoma (HCC) remains a lethal complication of chronic hepatitis C virus (HCV) infection, even after successful direct-acting antiviral (DAA) therapy. The gut microbiome influences hepatocarcinogenesis through the gut‒liver axis; however, microbial signatures predictive of HCC in DAA-treated patients are poorly defined. This study aimed to elucidate the patterns of microbiomes in HCV-treated patients who developed HCC, with a focus on bacterial diversity, differentially represented taxa, and their associations with clinical markers (FIB-4) and potential metabolic profiles as predictive biomarkers. Results A total of 138 participants were enrolled: 46 HCC patients with persistent HCV viremia (RHCC), 46 HCC patients with HCV eradication (THCC), and 46 healthy controls. RHCC patients exhibited pronounced dysbiosis, characterized by reduced alpha diversity (Kruskal-Wallis; H = 14.37, p =  0.00076) and an elevated Firmicutes/Bacteroidetes (F/B) ratio (1.55 vs. 1.05 in controls; Mann-Whitney U test, U = 87.32, p =  0.00079). At the genus level, Asteroleplasma was significantly enriched in RHCC (log₂FC = + 2.8, padj  = 0.008), while the butyrate-producing genus Faecalibacterium was depleted (log₂FC = − 2.1, padj  = 0.006). Machine learning identified Asteroleplasma, Moryella, Lachnoclostridium, Fournierella, Eubacterium xylanophilum, Succinivibrio , and Faecalibacterium as the top predictors of RHCC (AUC = 0.81). Functional profiling revealed a 58% reduction in butyrate synthesis ( p <  0.001) and increased lipopolysaccharide (LPS) biosynthesis (log₂FC = + 3.2, padj  = 0.002) in RHCC, both of which correlated with clinical deterioration (FIB-4 scores, r =  0.62). Conclusions Distinct gut microbial signatures distinguish HCC patients with persistent HCV viremia from those who achieve viral clearance, with implications for risk stratification and therapeutic targeting. The F/B ratio, Asteroleplasma abundance, and functional pathway disruption (butyrate depletion) could serve as potential biomarkers for HCC progression. These findings underscore the influential role of the gut microbiome in hepatocarcinogenesis and its potential utility in personalized HCC management.