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The recently conceptualized Cardiovascular–Kidney–Metabolic (CKM) syndrome represents a pressing global health burden, characterized by a vicious cycle of dysfunction among the cardiac, renal, and metabolic systems. Growing evidence suggests that gut microbiota dysbiosis, specifically, a loss of butyrate-producing bacteria (BPB) and the resulting systemic butyrate deficiency, may be an important but previously overlooked driver of CKM progression. In this review, we synthesize available evidence linking butyrate to the integrated, multi-organ pathophysiology of CKM and propose a conceptual framework we term the gut-butyrate-CKM axis. We discuss the multiple mechanisms by which butyrate and BPB exert protective effects, including targeting key pathophysiological features of CKM, such as insulin resistance (IR), metabolic inflammation, oxidative stress, endothelial dysfunction, renin–angiotensin–aldosterone system (RAAS) overactivation, and gut dysbiosis itself. Through a critical appraisal of human studies, we bring together findings from direct butyrate supplementation, dietary interventions, and microbiota-directed strategies. Based on this, we argue that butyrate serves as a central hub linking gut homeostasis to systemic metabolic and cardiorenal health. By integrating previously fragmented observations into a coherent framework, this review addresses a conceptual gap in our understanding of CKM pathogenesis and points to actionable, microbiota-targeted therapeutic strategies that could help break the disease cycle. Given the current lack of integrated management options for CKM, our work offers insights for future translational research and clinical practice, highlighting butyrate-centered approaches as a potential paradigm shift in CKM care.
Huang et al. (Sun,) studied this question.