Microbial metabolites could help improve functional cure rates for hepatitis B

Chronic hepatitis B (CHB) remains a major global challenge. Current therapies suppress HBV but rarely achieve functional cure (sustained HBsAg loss). Emerging gut‑liver axis evidence shows that microbial metabolites-short‑chain 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‑effect hub. Early studies suggest FXR agonists combined with PegIFN‑α may reduce HBsAg. This review proposes biomarker‑guided stratification and multi‑target strategies to improve functional cure rates.

Introduction

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‑α (HBsAg clearance rates: 1.4–5.1% for NAs, 2.1–20% for PegIFN‑α). Most patients need lifelong therapy. The gut‑liver axis offers new targets via SCFAs and BAs, which regulate viral replication and hepatic immunity.

SCFAs in HBV infection

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.

Immunologically, SCFAs act through GPR41/43 and GPR109A: they can promote antiviral responses (T cells, NK cells, macrophages) and reduce hepatic stellate cell inflammation. Conversely, they may promote Treg differentiation and IL‑10/TGF‑β, reinforcing immune tolerance-particularly concerning in the immune‑tolerant phase. The net effect depends on disease stage and immune context.

Bile acids in HBV infection

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‑dose 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‑κB but has no direct antiviral effect; dual FXR/TGR5 agonists like INT‑767 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.

SCFA‑BA synergies and therapeutic strategies

BAs can suppress butyrate‑producing bacteria, further reducing SCFAs in advanced fibrosis; SCFAs regulate BA synthesis via the FXR‑FGF19 axis and strengthen gut barrier. Thus, a self‑reinforcing cycle of dysbiosis, BA dysregulation, and SCFA depletion is a key therapeutic target.

Therapeutic approaches include direct SCFA supplementation, prebiotics/probiotics/FMT, and FXR agonists (vonafexor, ASC42) in early trials. Combinations with PegIFN‑α may improve HBsAg decline. Future strategies include intestinal‑targeted FXR modulators and dual FXR/TGR5 agents. Metabolic‑immune combinations (e.g., SCFA prodrug + NA + immunotherapy) may target multiple mechanisms. Patient stratification by disease phase and gut microbiota/metabolic profiles is essential.

Limitations and risks

Evidence is predominantly preclinical; clinical data are scarce and small‑scale. 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‑term viral adaptation and durability of HBsAg loss are unknown.

Conclusion and outlook

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‑target combination strategies. Future work should focus on multi‑omics profiling for stratification, humanised models, rigorous RCTs, and next‑generation delivery platforms. With careful development, metabolic‑immune combinations may improve functional cure rates and patient outcomes.