Chronic hepatitis B remains a significant global health challenge, with current therapies rarely achieving a functional cure, according to a Jul. 30 review. While antiviral treatments can suppress the hepatitis B virus (HBV), sustained loss of surface antigen is uncommon, and most patients require lifelong therapy.
Recent research highlights the role of the gut-liver axis in HBV management. Microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids (BAs) have been shown to modulate HBV replication and immunity. Butyrate, an SCFA produced by colonic fermentation, can suppress HBV through histone deacetylase inhibition and epigenetic remodeling of viral DNA in cell lines. However, effective concentrations in laboratory studies are much higher than those found physiologically.
SCFAs interact with immune cells via receptors like GPR41/43 and GPR109A, potentially promoting antiviral responses from T cells, natural killer cells, and macrophages while also reducing inflammation in hepatic stellate cells. Conversely, SCFAs may encourage regulatory T cell differentiation and anti-inflammatory cytokine production—factors that could reinforce immune tolerance depending on disease stage.
Bile acids act through nuclear receptor FXR and membrane receptor TGR5 as well as NTCP—the HBV entry receptor—forming what researchers describe as a dual-effect hub. FXR activation has complex effects: it can enhance viral transcription at physiological levels but may suppress it when activated by high-dose agonists due to negative feedback mechanisms. Early studies suggest that combining FXR agonists with pegylated interferon-alpha might help reduce surface antigen levels.
Therapeutic approaches under investigation include direct supplementation with SCFAs, use of prebiotics or probiotics including fecal microbiota transplantation (FMT), and trials of FXR agonists such as vonafexor or ASC42. The review proposes biomarker-guided patient stratification alongside multi-target strategies that combine metabolic interventions with existing antivirals or immunotherapies to improve outcomes for chronic hepatitis B patients.
The evidence base remains predominantly preclinical; clinical data are limited by small sample sizes and translational gaps between laboratory dosing and physiological conditions. Potential risks include gastrointestinal side effects from SCFAs or probiotics/FMT-related infections; FXR agonists may cause pruritus or disrupt lipid metabolism, and the long-term durability of any virologic response is not yet known.
