Gut microbiota dysbiosis with hepatitis B virus liver disease and association with immune response.
Given 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.
Here, 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.
We found that community structures and diversity of the gut microbiota in HBV-CLD patients become more unbalanced. Differential microbiota analysis that p:Acidobacteriota, p:Proteobacteria, p:Campilobacterota, f:Streptococcaceae, g:Klebsiella associated with inflammation were enriched. The beneficial bacteria of f:Clostridia UCG-014, f:Oscillospiraceae, f:_Rikenellaceae, g:_Barnesiella, g:Prevotella, g:Agathobacter were 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 that Muribaculaceae, Akkermaniacaeae, [Eubacterium]_coprostanoligenes_group, RF39, Tannerellaceae have 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 as Actinobaciota, Myxococota, Streptococcaceae and Eubacterium coprostanoligenes.
Our study indicated that gut beneficial bacteria, mainly Firmicutes and Bacteroides appeared 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.
Yan F
，Zhang Q
，Shi K
，Zhang Y
，Zhu B
，Bi Y
，Wang X
... -
《Frontiers in Cellular and Infection Microbiology》
Entecavir therapy reverses gut microbiota dysbiosis induced by hepatitis B virus infection in a mouse model.
Chronic hepatitis B virus (HBV) infection is a global public health problem. The gut microbiota has been linked to pathogenesis of liver diseases induced by chronic HBV infection.
This study established a recombinant adeno-associated virus serotype 8 (rAAV8)-mediated persistent HBV infection mouse model. Entecavir (ETV) treatment significantly decreased the HBV DNA load both in serum and the liver. The comparison of gut microbiota composition of rAAV8-HBV-infected mice and ETV-treated mice with healthy controls was carried out using 16S rDNA sequencing analysis of caecal content samples. The intestinal microbiota alpha diversity of rAAV8-HBV-infected mice decreased, and significantly restored after 4 weeks of ETV therapy. Blautia and Clostridium sensu stricto significantly decreased in rAAV8-HBV-infected mice and was negatively correlated with both HBsAg and HBeAg levels. On the contrary, the Butyricicoccus and Prevotellaceae NK3B31 groups exhibited positive correlation with HBsAg and HBeAg. Furthermore, it was observed that Akkermansia, a known gut barrier-protecting bacterium, significantly decreased in rAAV8-HBV-infected mice and was restored to the level of that in healthy controls after ETV therapy, while the abundance of Akkermansia was negatively correlated with HBV DNA load both in serum and the liver.
Taken together, the results showed that dysbiosis of gut microbiota developed in the persistent HBV-infected mice and was effectively reversed by ETV treatment, shedding light on the mechanisms of gut microbiota on HBV-persistent infection and antiviral therapy.
Li X
，Wu S
，Du Y
，Yang L
，Li Y
，Hong B
... -
《-》
The diagnostic potential of gut microbiome for early hepatitis B virus-related hepatocellular carcinoma.
Gut microbiota is related with hepatocellular carcinoma (HCC). However, the relationship between the gut microbiota and the hepatitis B virus (HBV)-related HCC remains unclear. We aimed to characterize gut microbiome in HBV-related HCC patients and estimate the clinical potential of gut microbiome as biomarkers for HBV-related HCC.
We collected fecal and plasma samples from 20 health controls, 20 HBV-related cirrhosis and 20 HBV-related HCC in the First Affiliated Hospital of Chongqing Medical University. The fecal samples were subjected to the V3-V4 region of 16S rRNA Miseq sequencing. Plasma samples were calculated for interleukin-6 (IL-6), IL-2, IL-8, IL-10, tumor necrosis factor α (TNF-α), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Then, we analyzed the correlation between the index and the gut microbiota.
We have found that the bacterial richness of the liver cirrhosis group was lower than the HCC group. The bacterial diversities were in consistent with IL-2. The pro-inflammatory bacteria (Veillonella, Escherichia-shigella) have increased in the liver cirrhosis group. The random forest model has achieved an area under the curve value was 94% with 95% CI, 88-100% between the HCC group and the non-HCC group. The results revealed that IL-2 was highly associated with the whole gut bacterial communities of HCC and liver cirrhosis groups. ALT, AST and glutamyl transpeptidase have strongly elevated in liver cirrhosis and HCC groups, which were associated with gut microbiome.
It could be helpful to define the potential bacteria linking to pathological mechanisms of HBV-related HCC. The diagnosis potential of gut microbiome for early HBV-related HCC has been estimated.
Tang Y
，Zhou H
，Xiang Y
，Cui F
... -
《-》
Gut microbiota dysbiosis in patients with hepatitis B virus-induced chronic liver disease covering chronic hepatitis, liver cirrhosis and hepatocellular carcinoma.
The information regarding the effect of hepatitis B virus (HBV) infection on gut microbiota and the relationship between gut microbiota dysbiosis and hepatitis B virus-induced chronic liver disease (HBVCLD) is limited. In this study, we aimed at characterizing the gut microbiota composition in the three different stages of hepatitis B virus-induced chronic liver disease patients and healthy individuals. Faecal samples and clinical data were collected from HBVCLD patients and healthy individuals. The 16S rDNA gene amplification products were sequenced. Bioinformatic analysis including alpha diversity and PICRUSt was performed. A total of 19 phyla, 43 classes, 72 orders, 126 families and 225 genera were detected. The beta-diversity showed a separate clustering of healthy controls and HBVCLD patients covering chronic hepatitis (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC); and gut microbiota of healthy controls was more consistent, whereas those of CHB, LC and HCC varied substantially. The abundance of Firmicutes was lower, and Bacteroidetes was higher in patients with CHB, LC and HCC than in healthy controls. Predicted metagenomics of microbial communities showed an increase in glycan biosynthesis and metabolism-related genes and lipid metabolism-related genes in HBVCLD than in healthy individuals. Our study suggested that HBVCLD is associated with gut dysbiosis, with characteristics including, a gain in potential bacteria and a loss in potential beneficial bacteria or genes. Further study of CHB, LC and HCC based on microbiota may provide a novel insight into the pathogenesis of HBVCLD as well as a novel treatment strategy.
Zeng Y
，Chen S
，Fu Y
，Wu W
，Chen T
，Chen J
，Yang B
，Ou Q
... -
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ResearchGate
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钛学术
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