The gut-heart axis in atrial fibrillation: a systematic review and meta-analysis of microbiome composition and trimethylamine N-oxide concentration

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with over 59.7 million cases globally. The interaction between the intestinal microbiota and the cardiovascular system has emerged as a possible factor associated with AF pathogenesis. Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been recently proposed as a potential mediator of this interaction. No prior meta-analysis has jointly examined both TMAO levels and microbiota composition in AF patients. The goal of the following work was to analyse alterations in TMAO concentrations, gut microbial diversity, and compositional changes in patients with AF. This is a dual-arm systematic review and meta-analysis following PRISMA 2020 guidelines, with prospective PROSPERO registration. Search of three databases (PubMed, Embase, and Web of Science) was performed. Random-effects meta-analyses were performed for TMAO levels (mean difference) and the α-diversity expressed by Shannon diversity index (Hedges' g). For gut microbiota abundance alteration, a vote-counting analysis based on the direction of effect was conducted. Statistically significant genus-level alterations reported in the included articles were extracted and pooled. Results were analyzed when at least three studies reported a consistent direction of change (increase or decrease in AF compared to control). Sixteen studies (6 TMAO, 10 microbiota) comprising 12,152 participants were included. TMAO levels were significantly higher in AF patients (MD = 1.24 µmol/L, 95% CI: 0.70 to 1.79, p < 0.001; I 2 = 77.5%). Shannon diversity did not differ significantly between groups (Hedges' g = 0.33, 95% CI: − 0.17 to 0.82, p = 0.197; I 2 = 85.0%). Vote-counting identified five genera consistently enriched in AF: Enterococcus spp. , Ruminococcus spp. , Dorea spp. , Oscillibacter spp. and Streptococcus spp., and three consistently depleted: Prevotella spp., Bacteroides spp., and Faecalibacterium spp. The TMAO meta-analysis demonstrated significantly elevated concentrations in AF patients, while Shannon α-diversity did not differ significantly between groups, and the inconsistent direction of effects across studies indicates that current evidence does not support a reproducible difference in microbial diversity in AF. Despite the very low certainty of the evidence (GRADE), the convergence of metabolomic and compositional findings supports the biological plausibility of a gut–heart axis in AF. Further prospective studies are needed to establish causality.