Flavonoids and Their Influence on the Gut Microbiome: Implications for Cardiovascular Health.

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide, necessitating effective preventive and therapeutic strategies. Flavonoids and polyphenols, which are abundant in colourful fruits and vegetables, have emerged as promising bioactive compounds for mitigating CVD. This study elucidates the mechanisms by which flavonoids exert cardioprotective effects through their antioxidant, prebiotic, and mitochondrial restorative properties. Flavonoids function as hydrogen donors, scavenging free radicals such as nitric oxide (NO•), superoxide anions (O•), and hydroxyl radicals (OH•), thereby reducing oxidative stress by decreasing inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) activity while enhancing endothelial nitric oxide synthase (eNOS) functionality to promote vasodilation and prevent hypertension. Additionally, flavonoids act as prebiotics, fostering the symbiotic gut microbiota (GM), including Bifidobacteria and Lactobacillus, which produce short-chain fatty acids (SCFAs) and suppress pathogenic trimethylamine-N-oxide (TMAO)-producing bacteria. This enhances gut epithelial barrier integrity, reduces inflammation mediated by lipopolysaccharide (LPS), and protects against heart failure, ischaemia, and atherosclerosis. Under ischemic and heart failure conditions, flavonoids inhibit apoptosis, necrosis, ferroptosis, and fibrosis by restoring hypoxia-damaged mitochondrial function and cardiac energy metabolism. Furthermore, flavonoids prevent arteriosclerosis by inhibiting low-density lipoprotein (LDL) oxidation, reducing cholesterol absorption, promoting bile salt-hydrolysing bacteria, and decreasing vascular cell adhesion molecule (VCAM)-1 expression on coronary vessels. Here, we aim to advance the understanding of flavonoid-mediated cardioprotection by considering their antioxidant, anti-inflammatory, and gut microbiome-modulating effects, offering novel insights into dietary interventions for CVD prevention and management. The findings underscore the potential of flavonoids as accessible, natural agents to address global health disparities in CVD burden.