Exploring the Underlying Mechanisms of Aerobic Exercise-Improving Cardiovascular Function by Integrating Microbiome, Metabolome, and Proteome Analysis in a High-Fat Diet-Induced Obesity Rat Model.

Objective: This study aimed to investigate the potential mechanisms by which moderate-intensity aerobic exercise improves cardiovascular dysfunction in high-fat diet-induced obese rats through integrated multi-omics analysis. Methods: Animals were assigned to three groups: normal diet, HFD, and HFD with exercise. Cardiovascular function was assessed by echocardiography and vascular tension measurement. Gut microbiota, serum metabolites, and protein expression were analyzed using 16S rRNA sequencing, untargeted metabolomics, and proteomics, respectively. Integrated multi-omics analysis was performed using Mantel tests and mediation effect analysis. Results: Eight weeks of aerobic exercise significantly improved cardiovascular function in obese rats, including enhanced acetylcholine-induced vasodilation and increased left ventricular ejection fraction. Furthermore, exercise also reshaped the gut microbiota composition, notably altering the relative abundances of Lactobacillus and Ruminiclostridium_9. Metabolomics revealed that exercise shifted the metabolic phenotype from high-fat diet-induced basal metabolic disorder toward beneficial pathways, including fatty acid biosynthesis and ubiquinone biosynthesis. Proteomics identified key differentially expressed proteins such as APOE, FN1, and Lap3. Integrated multi-omics analysis for the first time revealed a core regulatory axis: exercise may influence Lap3 expression, modulate the abundance of Lactobacillus, and thereby systematically regulate the level of palmitoyl lysophosphatidylcholine, ultimately improving cardiovascular function. Conclusions: Aerobic exercise counteracts HFD-induced cardiovascular dysfunction through systemic remodeling of the gut microbiota-host metabolism-protein network. The discovery of the Lap3-Lactobacillus-palmitoyl lysophosphatidylcholine axis provides new molecular insights into the exercise-mediated protective mechanisms of the gut-cardiovascular system axis.