Short-chain Fatty Acids and Bile Acids Signaling in Chronic Hepatitis B

Chronic hepatitis B (CHB) remains a major global public health challenge. Current therapies based on nucleos(t)ide analogues and interferon mainly achieve long-term viral suppression, whereas only a small proportion of patients attain a functional cure, defined as sustained hepatitis B surface antigen loss with hepatitis B virus (HBV) DNA below the limit of quantification for at least 24 weeks after treatment discontinuation, with or without anti-HBs seroconversion. Emerging evidence from the gut-liver axis indicates that gut microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs) and bile acids (BAs), modulate the HBV life cycle and immune regulation in CHB, thereby offering therapeutic targets to overcome immune tolerance. This review summarizes the biological characteristics of SCFAs and BAs and their mechanistic roles across different stages of HBV infection, with emphasis on translational relevance. In vitro and animal studies suggest that butyrate and related SCFAs suppress HBV gene expression by inhibiting histone deacetylases and remodeling covalently closed circular DNA minichromatin. SCFAs may also enhance antiviral immunity, although they may reinforce immune tolerance in certain contexts. For BAs, the farnesoid X receptor, Takeda G protein-coupled receptor 5, and the HBV entry receptor sodium taurocholate cotransporting polypeptide form a key signaling hub with dual effects on viral replication and host responses. Early-phase studies suggest that farnesoid X receptor agonists, pegylated interferon-α, or nucleos(t)ide analogues are associated with hepatitis B surface antigen reductions, though larger trials are needed. This review proposes biomarker-guided stratification and multi-target combination strategies to improve functional cure rates in CHB.