• Toxic Effects of Gut Microbial Metabolites TMAO, PAGln, LPS, and Indoles on Cardiovascular Health
  • Roya Gholizadeh,1,* Zohreh Arab,2
    1. Faculty of Medicine, Islamic Azad University, Mashhad Branch, Iran
    2. Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


  • Introduction: Cardiovascular diseases (CVD), including myocardial infarction, stroke, and heart failure, remain the leading cause of global morbidity and mortality. Increasing evidence highlights the role of the gut microbiota in shaping host metabolic and immune responses that influence cardiovascular outcomes. Among microbial-derived products, trimethylamine-N-oxide (TMAO), phenylacetylglutamine (PAGln), lipopolysaccharide (LPS), and indole derivatives have emerged as key mediators linking gut microbial activity with vascular dysfunction, atherosclerosis, and thrombosis. These metabolites contribute to adverse cardiovascular phenotypes by promoting inflammation, oxidative stress, endothelial dysfunction, and platelet hyperreactivity. This review aims to synthesize current knowledge on the mechanistic pathways through which these metabolites exacerbate CVD risk and to discuss their potential utility as biomarkers and therapeutic targets.
  • Methods: This review was conducted through a structured literature search using PubMed, Scopus, and Web of Science databases. The keywords “gut microbiota,” “trimethylamine-N-oxide,” “phenylacetylglutamine,” “lipopolysaccharide,” “indole derivatives,” and “cardiovascular disease” were applied. Articles published in English between 2010 and 2025 were included. Both experimental and clinical studies were reviewed, with emphasis on mechanistic insights, human observational data, and interventional trials where available. Studies exclusively focusing on non-cardiovascular outcomes were excluded.
  • Results: Trimethylamine-N-oxide (TMAO) TMAO is generated from dietary precursors such as choline and carnitine, which are metabolized by gut microbiota into trimethylamine (TMA) and subsequently oxidized in the liver. Elevated plasma TMAO concentrations are consistently associated with heightened CVD risk. Mechanistically, TMAO promotes cholesterol accumulation within macrophages, enhancing foam cell formation and plaque development. It also amplifies platelet reactivity and thrombosis, thereby increasing the likelihood of acute vascular events. In addition, TMAO impairs endothelial function and stimulates pro-inflammatory signaling, exacerbating vascular injury. Phenylacetylglutamine (PAGln) PAGln, a metabolite derived from microbial phenylalanine metabolism, exerts cardiovascular effects primarily through modulation of adrenergic receptor pathways. Elevated PAGln levels enhance adrenergic receptor signaling, leading to increased heart rate, platelet aggregation, and heightened thrombotic potential. Clinical studies demonstrate that higher PAGln concentrations correlate with adverse cardiovascular outcomes independent of traditional risk factors, suggesting its value as a biomarker of heightened sympathetic and thrombotic activity. Lipopolysaccharide (LPS) LPS, a structural component of Gram-negative bacterial membranes, contributes to systemic inflammation when translocated into circulation under conditions of gut barrier dysfunction or dysbiosis. Circulating LPS activates Toll-like receptor 4 (TLR4), initiating cascades of pro-inflammatory cytokine release and endothelial activation. Chronic low-grade endotoxemia has been implicated in the development of hypertension, vascular stiffness, and accelerated atherosclerosis. LPS further aggravates endothelial dysfunction, providing a mechanistic link between gut barrier integrity and vascular pathology. Indole Derivatives Indole-derived metabolites, such as indoxyl sulfate, originate from microbial tryptophan metabolism. These compounds are associated with cardiovascular toxicity via induction of oxidative stress, vascular smooth muscle proliferation, and calcification. Indoxyl sulfate also promotes inflammatory signaling within endothelial cells and macrophages, thereby accelerating vascular remodeling and atherosclerotic progression. Clinical studies in chronic kidney disease populations, where indoxyl sulfate accumulates, reinforce its pathogenic role in vascular dysfunction and CVD events. Integrative Perspective Collectively, TMAO, PAGln, LPS, and indole derivatives create a pro-inflammatory and pro-thrombotic environment that predisposes individuals to CVD. These metabolites exert synergistic effects on vascular biology by converging on pathways involving platelet activation, endothelial injury, and chronic inflammation. Importantly, their detection in circulation highlights their potential as predictive biomarkers of cardiovascular risk. Interventions targeting gut microbial composition, dietary precursors, and metabolic pathways represent emerging therapeutic strategies. Approaches such as probiotics, dietary modification, enzyme inhibitors, and bile acid modulators are under investigation to attenuate the generation or systemic effects of these toxic metabolites.
  • Conclusion: Gut-derived microbial metabolites significantly influence cardiovascular health. TMAO, PAGln, LPS, and indole derivatives promote vascular inflammation, thrombosis, endothelial dysfunction, and atherosclerotic progression. Their mechanistic links to CVD suggest their dual role as biomarkers for early risk prediction and as therapeutic targets for novel intervention strategies. Future research should aim to clarify causal relationships, evaluate interventional efficacy, and translate microbiome-modulating therapies into clinical practice. A better understanding of host-microbiome interactions will open avenues for precision medicine approaches to cardiovascular disease prevention and treatment.
  • Keywords: Gut microbiota, TMAO, Indole derivatives, Cardiovascular disease, Thrombosis