Multi-Omic Analysis and Platelet Function Distinguish Treatment Responses to Hydroxytyrosol in Cardiovascular Risk

Many polyphenols have been recognized for their antioxidant and health benefits. The present study attempted, for the first time, to determine the effects of daily oral intake of β-cyclodextrin-encapsulated hydroxytyrosol (HT) on plasma platelet reactivity and proteomic and metabolomic profiles of patients at cardiovascular risk and correlated it with biomarkers of cardiovascular (CV) status. The results showed that 28-day regular HT intake improved the lipid profile and lowered platelet function ex vivo (n=26). The suppression of platelet reactivity and agonist-induced platelet activation observed after diet intervention were measured by CD61/CD62P expression and apoptotic microparticles. Microbiota analysis revealed HT treatment significantly increased and decreased the abundance of Ruminiclostridium sp. and Desulfovidrio sp., respectively. Proteomic and metabolic responses were heterogeneous within two distinct ̶ responder and non-responder ̶ subgroups, associated mainly with thrombotic and hemostatic signals. Metabolomic analysis further confirmed the differentially expressed metabolites within the two subgroups, highlighting an improvement in glutathione metabolism after HT treatment. The correlations between biomarkers, proteins, and metabolites offer a more comprehensive representation of the glutathione and coagulation pathways affected by HT treatment. These findings have important implications for the development of novel therapeutic strategies aimed at preventing CV diseases by targeting HT-mediated platelet dysfunction and lipid changes, which are important for the primary prevention of CV diseases. The current approach has the potential to improve the diagnosis and categorization of therapeutic responses in the medical field.