Gut microbiome-derived metabolites as prognostic biomarkers in heart failure: a systematic review and meta-analysis.

BACKGROUND: Growing evidence implicates gut dysbiosis in heart failure (HF) pathogenesis. This systematic review and meta-analysis synthesises prognostic associations of microbial metabolites in HF. METHODS: Electronic databases were searched through February 2026 for studies investigating associations between gut microbial metabolites and HF outcomes. Study characteristics, baseline covariates and outcomes were extracted in duplicate. The prespecified primary outcome was all-cause mortality; the secondary outcome was major adverse cardiac events (MACE). Random-effects models were applied to pool hazard ratios. Subgroup analyses stratified cohorts by HF phenotype and aetiology; meta-regression explored potential effect modifiers. This study was preregistered on PROSPERO (CRD42025631114). RESULTS: Twenty studies comprising 17,715 patients were included in meta-analysis; six studies were synthesised narratively. Median follow-up was 31.7 months. Elevated trimethylamine-N-oxide (TMAO) was associated with all-cause mortality in the overall population (HR 1.72, 95%CI 1.42-2.08, p=0.0002, I2 37.3%) and across HF phenotypes (HRHFrEF 2.17, 95%CI 1.68-2.81, I2 0%; HRHFpEF 1.55, 95%CI 0.92-2.61, I2 0%). Higher TMAO was also associated with MACE (HR 1.60, 95%CI 1.44-1.78, p<0.0001, I2 0%), consistent across HF phenotypes (HRHFrEF 1.43, 95%CI 1.15-1.78, I2 0%; HRHFpEF 1.76, 95%CI 1.21-2.55, I2 31.6%). Elevated phenylacetylglutamine (PAGln) was associated with mortality (HR 1.60, 95%CI 1.33-1.94, p<0.0001, I2 0%) and MACE (HR 1.65, 95%CI 1.37-1.99, p<0.0001, I2 2.1%) in the overall population. Meta-regression demonstrated no significant effect modification by baseline age, NT-proBNP, renal function or BMI. CONCLUSION: Elevated TMAO and PAGln are consistently associated with adverse outcomes across diverse HF cohorts, highlighting their potential relevance as indicators of residual risk in HF.