The gut microbiota-aromatic amino acid axis in cardiovascular disease: pathophysiological roles, translational biomarkers, and therapeutic targeting
Abstract
Background Cardiovascular disease (CVD) remains a leading global health burden, with conventional risk factors lacking sufficient predictive power. Gut microbiota-derived aromatic amino acid (AAA) metabolites and oxidative tyrosine post-translational modifications (PTMs) have emerged as novel pathophysiological regulators of CVD, but their integrated mechanistic roles, clinical biomarker value, and therapeutic potential remain to be systematically elucidated. Methods A review on gut microbiota-AAA axis in CVD was conducted, synthesizing mechanistic, clinical, and translational evidence of AAA metabolites (phenylalanine, tryptophan, tyrosine derivatives) and tyrosine PTMs in the pathogenesis of CVD. We also analyzed the diagnostic potential of multi-omics identified combinatorial biomarkers and the preclinical/clinical evidence for targeted therapeutic strategies. Results Phenylacetylglutamine (PAGln) activates α2A/α2B/β2-adrenergic receptors, induces platelet hyperreactivity and myocardial injury, and is associated with increased major adverse cardiovascular events (MACE) risk. Tryptophan metabolism's pro-atherogenic kynurenine axis and gut-derived indoxyl sulfate (IS) promote endothelial dysfunction, while indole-3-propionate (IPA) exerts vasculoprotective effects. Tyrosine PTMs (sulfotyrosine, 3-nitrotyrosine) regulate leukocyte recruitment and impair endothelial enzymes, with elevated 3-nitrotyrosine predicting adverse cardiac events. The integration of combinatorial biomarkers, including PAGln, IS, Kyn/Trp ratio, 3-nitrotyrosine, and sulfotyrosine, may enhance the predictive capacity of conventional risk models, though their clinical utility requires rigorous validation across diverse populations. Gut microbiota modulation, enzymatic inhibition, and receptor antagonism show preclinical/early clinical potential for CVD intervention. Conclusions The gut microbiota-AAA axis integrates dysbiosis, inflammation, and oxidative stress to drive CVD pathogenesis, with its metabolites and PTMs providing complementary diagnostic value. If validated, interventions targeting this axis may improve CVD risk assessment and therapeutic development.