Gender-Stratified Gut Dysbiosis Patterns in HCC Patients: A Cross-Sectional Microbiome Study

Background: Hepatocellular carcinoma (HCC) exhibits significant sex disparities, with males demonstrating a higher incidence. While hepatitis C virus (HCV) drives hepatocarcinogenesis and the gut microbiome influences liver disease progression, Sex-specific microbiome signatures in HCC remain underexplored.Methods: This cross-sectional study analyzed 36 participants stratified by sex and disease status: male controls (MC, n=9), male with HCC (MHCC, n=9), female controls (FC, n=9), and female with HCC (FHCC, n=9). Stool samples underwent 16S rRNA sequencing (V3-V4 regions). Results: Profound sex-specific dysbiosis emerged: MHCC patients showed significant enrichment of pro-inflammatory Proteobacteria (Succinivibrio), correlating with coagulopathy (INR: r= 0.62) and thrombocytopenia (r= –0.61), while FHCC exhibited depletion of commensal Prevotella_9 and enrichment of estrogen-associated Eggerthella, linked to hyperbilirubinemia (r= 0.54) and extreme AFP elevation (r= 0.49). Alpha diversity loss was universal but more severe in males (Shannon index, padj= 0.008). Machine learning identified Lachnospiraceae_ND3007_group (male AUC = 0.81) and Eggerthella (female) as top discriminators.Conclusion: Sex-stratified dysbiosis patterns reveal distinct HCC pathogenesis, inflammatory (Proteobacteria-driven) in males and metabolic (Eggerthella-mediated) in females. These signatures provide novel biomarkers for personalized risk stratification in HCV-associated HCC.