Bioactive Peptides in Probiotic Fermented Foods: Structure-Activity Relationships and Cardiometabolic Protective Effects.

Bioactive peptides generated during probiotic fermentation have emerged as a complex class of food-derived molecules with multifaceted physiological effects relevant to cardiometabolic health. Recent advances in peptidomics, structural analysis, and mechanistic evaluation have revealed that fermentation with lactic acid bacteria, Bacillus species, or mixed cultures produces highly diverse peptide profiles whose activities depend on sequence motifs, hydrophobicity, charge distribution, and resistance to gastrointestinal degradation. These peptides modulate key pathways involved in vascular regulation, glucose metabolism, lipid handling, and inflammatory signaling. Evidence from cellular and animal models consistently demonstrates that selected short sequences inhibit angiotensin converting enzyme, enhance incretin bioactivity through dipeptidyl peptidase IV inhibition, reduce oxidative stress via direct radical scavenging and Nrf2 activation, attenuate inflammatory cascades by neutralizing endotoxin or interfering with immune receptor interactions, and influence lipid metabolism by interacting with bile acids or receptor-regulated transcription factors. Human trials, although heterogeneous in design and outcomes, suggest modest improvements in blood pressure, glucose tolerance, and lipid measures in specific populations, with notable geographical and genetic variability. Controversy remains regarding effect size, reproducibility, and translation of in vitro potency to physiological relevance due to variability in peptide abundance, digestion stability, and differences in habitual diet. Despite such limitations, emerging strategies in controlled fermentation, peptide enrichment, in silico prediction, and combined functional formulations indicate strong potential for targeted development of peptide-rich foods that support cardiometabolic resilience. Continued integration of structural analysis, mechanistic validation, and rigorously designed clinical studies will be essential to clarify their role within food-based preventive strategies.