Background and aimsGiven hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV-HCC) exhibits unique gut microbiota characteristics and a significant immunosuppressive tumor microenvironment. Thus, a better understanding of the correlation between gut microbiota and the immunosuppressive response may help predict occurrence and prognosis of HBV-HCC.MethodsHere, in a cohort of ninety adults (healthy control n=30, HBV-cirrhosis n=30, HBV-HCC n=30) with clinical data, fecal 16S rRNA gene sequencing, matched peripheral blood immune response with flow cytometry analysis. Correlation between the gut microbiome of significantly different in HBV-HCC patients and clinical parameters as well as the peripheral immune response was assessed.ResultsWe found that community structures and diversity of the gut microbiota in HBV-CLD patients become more unbalanced. Differential microbiota analysis thatp:Acidobacteriota, p:Proteobacteria, p:Campilobacterota, f:Streptococcaceae, g:Klebsiellaassociated with inflammation were enriched. The beneficial bacteria off:Clostridia UCG−014, f:Oscillospiraceae, f:_Rikenellaceae, g:_Barnesiella, g:Prevotella, g:Agathobacterwere decreased. Functional analysis of gut microbiota revealed that lipopolysaccharide biosynthesis, lipid metabolism, butanoate metabolism were significantly elevated in HBV-CLD patients. Spearman’s correlation analysis showed thatMuribaculaceae, Akkermaniacaeae, [Eubacterium]_coprostanoligenes_group, RF39, Tannerellaceaehave positive correlation with CD3+T, CD4+T and CD8+T cell counts while negatively correlated with liver dysfunction. Furthermore, paired peripheral blood showed a decreased proportion of CD3+T, CD4+T and CD8+T cells, while an increased T (Treg) cells. The immunosuppressive response of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), immune receptor tyrosine based inhibitor motor (ITIM) domain (TIGIT), T-cell immune domain, and multiple domain 3 (TIM-3) of CD8+T cells were higher in HBV-HCC patients. They were positively correlated with harmful bacteria, such asActinobaciota, Myxococota, StreptococcaceaeandEubacterium coprostanoligenes.ConclusionsOur study indicated that gut beneficial bacteria, mainlyFirmicutesandBacteroidesappeared dysbiosis in HBV-CLD patients. They have negative regulation of liver dysfunction and T cell immune response. It provides potential avenues for microbiome-based prevention and intervention for anti-tumor immune effects of HBV-CLD.