Chronic hepatitis B (CHB) remains a major global challenge. Current therapies suppress HBV but rarely achieve functional cure (sustained HBsAg loss). Emerging gut\u2011liver axis evidence shows that microbial metabolites-short\u2011chain fatty acids (SCFAs) and bile acids (BAs)-modulate HBV replication and immunity. Butyrate suppresses HBV via HDAC inhibition and cccDNA epigenetic remodelling. SCFAs may enhance antiviral immunity but can also reinforce tolerance. BAs signal through FXR, TGR5, and the HBV entry receptor NTCP, forming a dual\u2011effect hub. Early studies suggest FXR agonists combined with PegIFN\u2011\u03b1 may reduce HBsAg. This review proposes biomarker\u2011guided stratification and multi\u2011target strategies to improve functional cure rates.<\/p>\n
Introduction<\/p>\n
CHB affects ~254 million people, causing ~1.1 million annual deaths. Functional cure (HBsAg loss with undetectable HBV DNA) is rarely achieved with current NAs or PegIFN\u2011\u03b1 (HBsAg clearance rates: 1.4\u20135.1% for NAs, 2.1\u201320% for PegIFN\u2011\u03b1). Most patients need lifelong therapy. The gut\u2011liver axis offers new targets via SCFAs and BAs, which regulate viral replication and hepatic immunity.<\/p>\n
SCFAs in HBV infection<\/p>\n
SCFAs (acetate, propionate, butyrate) are produced by colonic fermentation. Butyrate directly suppresses HBV in cell lines via HDAC inhibition, remodelling cccDNA chromatin, and may enhance p53 activity. However, effective in vitro concentrations are millimolar, far exceeding physiological micromolar levels-a key translational gap.<\/p>\n
Immunologically, SCFAs act through GPR41\/43 and GPR109A: they can promote antiviral responses (T cells<\/a>, NK cells, macrophages) and reduce hepatic stellate cell inflammation<\/a>. Conversely, they may promote Treg differentiation and IL\u201110\/TGF\u2011\u03b2, reinforcing immune tolerance-particularly concerning in the immune\u2011tolerant phase. The net effect depends on disease stage and immune context.<\/p>\n Bile acids in HBV infection<\/p>\n Primary BAs are synthesised from cholesterol and converted to secondary BAs by gut microbiota. They signal through FXR (nuclear) and TGR5 (membrane). FXR has dual effects: physiological activation enhances HBV transcription (proviral), but sustained high\u2011dose FXR agonists may downregulate FXR and suppress HBV via negative feedback. FXR activation also downregulates NTCP, the HBV entry receptor, potentially reducing de novo infection. TGR5 activation reduces inflammation via cAMP\/NF\u2011\u03baB but has no direct antiviral effect; dual FXR\/TGR5 agonists like INT\u2011767 may block viral entry by binding preS1. NTCP is both the BA uptake transporter and essential HBV receptor; its inhibition (e.g., bulevirtide) blocks entry but risks BA homeostasis disruption.<\/p>\n SCFA\u2011BA synergies and therapeutic strategies<\/p>\n BAs can suppress butyrate\u2011producing bacteria, further reducing SCFAs in advanced fibrosis; SCFAs regulate BA synthesis via the FXR\u2011FGF19 axis and strengthen gut barrier. Thus, a self\u2011reinforcing cycle of dysbiosis, BA dysregulation, and SCFA depletion is a key therapeutic target.<\/p>\n Therapeutic approaches include direct SCFA supplementation, prebiotics\/probiotics\/FMT, and FXR agonists (vonafexor, ASC42) in early trials. Combinations with PegIFN\u2011\u03b1 may improve HBsAg decline. Future strategies include intestinal\u2011targeted FXR modulators and dual FXR\/TGR5 agents. Metabolic\u2011immune combinations (e.g., SCFA prodrug + NA + immunotherapy<\/a>) may target multiple mechanisms. Patient stratification by disease phase and gut microbiota\/metabolic profiles is essential.<\/p>\n Limitations and risks<\/p>\n Evidence is predominantly preclinical; clinical data are scarce and small\u2011scale. Dosing gaps exist (in vitro vs. physiological concentrations). FXR agonists may cause pruritus, dyslipidaemia, and cholestasis; SCFAs may cause GI effects or promote tolerance; probiotics\/FMT carry infection risks. Long\u2011term viral adaptation and durability of HBsAg loss are unknown.<\/p>\n Conclusion and outlook<\/p>\n Targeting SCFA and BA pathways offers a promising frontier for CHB. SCFAs suppress HBV epigenetically and modulate immunity; BAs influence viral transcription (FXR), entry (NTCP), and inflammation (TGR5). These axes are complementary, supporting multi\u2011target combination strategies. Future work should focus on multi\u2011omics profiling for stratification, humanised models, rigorous RCTs, and next\u2011generation delivery platforms. With careful development, metabolic\u2011immune combinations may improve functional cure rates and patient outcomes.<\/p>\n Source:<\/p>\n Journal reference:<\/p>\n