Decoding the Gut–Fat–Heart Axis: From Molecular Communication Networks to Clinical Translation Strategies

The prevention and treatment of cardiovascular disease (CVD) are undergoing a paradigm shift from a lipid-centric approach to a holistic metabolic perspective. Central to this evolution is the gut–fat–heart axis, a sophisticated three-dimensional communication network that integrates neural, endocrine, and immunometabolic signaling to regulate systemic lipid homeostasis. This manuscript systematically explores how the gut microbiota acts as a “metabolic organ” to remotely control host health through the production of bioactive metabolites and the modulation of molecular communication networks. At the physiological level, microbial products such as short-chain fatty acids (SCFAs) and modified bile acids regulate energy balance and lipid synthesis via the FXR-FGF15/19 axis and G protein-coupled receptors. Furthermore, gut hormones like GLP-1 and neuro-reflex pathways involving the vagus nerve provide rapid control over postprandial lipid clearance and feeding behavior. Conversely, pathological dysbiosis triggers the accumulation of harmful metabolites, such as trimethylamine N-oxide (TMAO) and lipopolysaccharides (LPS), which drive lipotoxicity, vascular inflammation, and “dysfunctional HDL” formation. These processes accelerate the progression of atherosclerosis, heart failure, and metabolic syndrome. Finally, the article outlines promising clinical translation strategies, including the development of TMA lyase inhibitors, next-generation probiotics, and the use of phytochemicals to reshape the microbial landscape. By decoding the molecular dialogues within the gut–fat–heart axis, this research provides a novel strategic vantage point for the integrated management of cardiovascular–kidney–metabolic (CKM) syndrome.