Cardiovascular–kidney–metabolic syndrome through the lens of gut‑derived uremic toxins

Cardiovascular–Kidney–Metabolic (CKM) syndrome represents a complex, interconnected cluster of cardiovascular disease, chronic kidney disease, and metabolic disorders such as obesity and type 2 diabetes. These conditions share overlapping metabolic, inflammatory, and vascular pathways, with the gut microbiome increasingly recognised as a key contributor and common underlying risk factor. Uremic toxins, traditionally considered waste products of host and microbial metabolism, are now recognised as active mediators of tissue damage across the CKM spectrum, particularly in the context of impaired renal function. Their production and accumulation are amplified by disrupted intestinal barrier integrity, chronic inflammation, and reduced renal clearance, collectively driving systemic toxicity throughout the CKM continuum. This review explores the origins and impact of gut-derived uremic toxins, including trimethylamine-N-oxide (TMAO), indoxyl sulfate (IS), p-cresol sulfate (PCS) and its associated metabolites, p-cresol and p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln), and imidazole propionate (ImP) within the context of CKM syndrome. These toxins originate from an imbalanced gut microbiome, often shaped by poor diets, such as low-fibre and high-meat intake. We discuss their production by the microbiome and their roles from cardiovascular, renal, and metabolic perspectives and highlight emerging microbiome-targeted strategies to mitigate their pathogenic effects.