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

Background With growing evidence implicating gut dysbiosis in the initiation and progression of heart failure, microbial metabolites hold promise as novel prognostic biomarkers and therapeutic targets. Purpose This systematic review and meta-analysis summarises the prognostic utility of gut microbial metabolites, namely trimethylamine-N-oxide (TMAO), phenylacetylglutamine (PAGln), indoxyl sulfate, imidazole propionate and short-chain fatty acids (SCFAs), across different phenotypes of heart failure. Methods Medline, Embase, Cochrane Library, Web of Science and Google Scholar were systematically searched through February 2025 for non-randomised diagnostic studies investigating the association between gut microbial metabolites and clinical outcomes in heart failure. Prespecified study characteristics, baseline covariates and outcome data were extracted by two independent, blinded reviewers. The prespecified primary outcome was all-cause mortality, prespecified secondary outcomes were cardiovascular mortality and major adverse cardiac events (MACE). Random-effect models were applied to pool hazard ratios (HR) and 95% confidence intervals (CI). Subgroup analysis was performed with respect to heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF), and ischaemic (ICM) or non-ischaemic cardiomyopathy (NIDCM). This study was registered on PROSPERO. Results Following screening of 2991 abstracts, 19 studies comprising 17484 patients were included in meta-analysis; a further 6 studies were synthesised narratively. The median follow-up duration was 32.4 months (IQR 23.2-60.0 months). Higher TMAO levels were associated with increased all-cause mortality in the overall population (HR 1.66, 95%CI 1.41-1.96, p<0.001) and in HFrEF (HR 2.29, 95%CI 1.74-3.01), HFpEF (HR 1.88, 95%CI 1.09-3.23) and ICM (HR 1.48, 95%CI 1.07-2.05). There was evidence supporting a greater hazard of death with higher TMAO levels in HFrEF compared to HFpEF (pinteraction=0.04). Higher TMAO levels were also associated with MACE (HR 1.57, 95%CI 1.41-1.75, p<0.001), consistent across heart failure phenotypes (HRHFrEF 1.46, 95%CI 1.14-1.86; HRHFpEF 1.87, 95%CI 1.33-2.62; HRICM 1.58, 95%CI 1.22-2.03). In the overall cohort, increased all-cause mortality risk was observed with higher PAGln levels (HR 1.60, 95%CI 1.33-1.94, p<0.001). Similarly, increased MACE risk was seen at higher PAGln levels in the overall cohort (HR 1.56, 95%CI 1.29-1.89, p<0.001) and in HFrEF patients (HR 1.53, 95%CI 1.21-1.93). Paucity of data precluded quantitative synthesis for cardiovascular mortality and NIDCM subgroups, while only narrative synthesis was feasible for indoxyl sulfate, imidazole propionate and SCFAs. Conclusion The gut microbial metabolites TMAO and PAGln are strongly associated with adverse outcomes across various phenotypes of heart failure. The prognostic role of indoxyl sulfate, imidazole propionate and SCFAs in heart failure requires further investigation.