Editorial Note: Hepatitis B virus (HBV) infection is a global public health challenge, causing nearly a million deaths annually due to complications such as liver failure, cirrhosis, and hepatocellular carcinoma. Achieving a functional cure (FC) has become a major goal in the treatment of chronic hepatitis B (CHB). In recent years, increasing attention has been given to the role of gut microbiota in chronic liver disease, making it a new research hotspot. A recent study published in Hepatology International explores the relationship between gut microbiota and FC in CHB by comparing the gut microbiome composition of FC patients and those with different HBV DNA levels. The study also evaluates the antiviral effects of short-chain fatty acids (SCFAs) using an HBVcc (cell culture-derived HBV) model, offering new insights into CHB treatment.Study Overview
The study included 70 HBeAg-negative CHB patients, who were categorized into three groups based on HBV DNA levels. The FC group (n=18) had undetectable HBV DNA and HBsAg. The low-titer group (LT, n=40) had HBV DNA levels below 3.3 log IU/mL, regardless of HBsAg levels, while the high-titer group (HT, n=12) had HBV DNA levels of 3.3 log IU/mL or higher. Additionally, eight healthy volunteers were recruited as a control group (CT).
Patients in the FC group had undetectable HBsAg and HBV DNA. Median HBsAg and HBV DNA levels in the LT group were significantly lower than those in the HT group. The median age of FC patients was significantly higher than that of HT patients (P < 0.05). ALT and albumin levels were also significantly lower in the FC group compared to the HT group (ALT, P < 0.001; Alb, P < 0.05). Both the FC and LT groups had undetectable hepatitis B core-related antigen (HBcrAg) levels. There were no significant differences between groups in terms of diabetes, probiotic use, or proton pump inhibitor (PPI) use—factors that could potentially influence gut microbiota composition.
Gut Microbiota Composition in FC, LT, and HT Groups
The study first analyzed the alpha and beta diversity of gut microbiota in the FC, LT, and HT groups. No significant differences were found among the three groups in overall microbial diversity.
Using linear discriminant analysis effect size (LEfSe), researchers identified differences in microbial abundance between the FC and LT groups, as well as between the FC and HT groups. In the comparison between the FC and LT groups, seven bacterial species were significantly enriched in the LT group, while nine were enriched in the FC group. When comparing the FC and HT groups, five bacterial species were more abundant in the HT group, whereas 11 were enriched in the FC group.
The study further focused on bacterial species that increased in abundance as the disease state improved. The researchers identified Clostridium bartlettii, Genus Butyricimonas, Coprococcus catus, Bifidobacterium breve, and Genus Campylobacter as key bacteria associated with FC.
Gut Microbes Associated with FC
The abundance of these five bacterial species was compared across the FC, LT, HT, and CT groups. The FC group had a higher abundance of these bacteria compared to the HT group, and their levels remained relatively high in the CT group as well. Among these bacteria, three species—Genus Butyricimonas, Coprococcus catus, and Bifidobacterium breve—are known to produce SCFAs, particularly butyrate. This finding led researchers to hypothesize that butyrate production could be linked to FC and prompted further investigation into the impact of SCFAs on the HBV life cycle.
Impact of SCFAs on the HBV Life Cycle
In vitro experiments assessed the effect of SCFAs on HBsAg production in HBVcc-infected cells. The results showed that 1.0 mM sodium butyrate reduced HBsAg production to approximately 60% of control levels. Sodium propionate also demonstrated some antiviral activity, though its effect was weaker than that of sodium butyrate. Additionally, SCFAs exhibited the strongest antiviral effects when administered after HBV infection, suggesting that their mechanism of action is more likely to inhibit HBV replication rather than the initial infection process.
Further analysis indicated that sodium butyrate might exert its antiviral effect by inhibiting the expression of SIRT-1, a class III histone deacetylase. Previous studies have shown that reduced SIRT-1 expression can suppress HBV replication. In addition, sodium butyrate may promote regulatory T cell (Treg) differentiation, thereby reducing gut inflammation and indirectly influencing HBV infection.
Expert Commentary
According to the researchers, the gut microbiome of FC patients is enriched with bacteria capable of producing SCFAs, which may help suppress HBV replication and facilitate FC. This discovery introduces a novel approach to CHB treatment—modulating gut microbiota to enhance the host’s antiviral capacity.
However, the study has some limitations. The sample size was relatively small, and larger-scale studies are needed to validate these findings. Moreover, while the study establishes a correlation between gut microbiota and FC, the precise mechanisms by which gut bacteria influence HBV infection remain to be fully elucidated. Although SCFAs demonstrated significant antiviral effects in vitro, their efficacy in vivo must be confirmed through clinical trials.
Despite these challenges, the study provides promising new directions for CHB treatment. Modulating gut microbiota to enhance antiviral immunity could be a novel therapeutic strategy, particularly for patients who do not respond well to conventional treatments. Future research should explore how dietary interventions, probiotics, and other microbiota-targeted therapies influence gut microbiota composition and their potential therapeutic benefits in CHB management.
