Hydroxytyrosol Enhances Plasma Extracellular Vesicle Secretion, Modulates Their miRNAs Cargo, and Reduces LDL Oxidation in Humans: Postprandial and 1‐Week Effects

Hydroxytyrosol (HT) consumption is associated with healthy outcomes. Specifically, its ability to modulate microRNA (miRNA) expression has been described. However, whether HT influences the secretion of extracellular vesicles (EVs) and their transported miRNAs remains unknown. Here, following HT administration, we explored the potential changes in EV secretion and in their miRNA cargo during postprandial state and after 1 week of daily intake. Twelve healthy participants received, first, a single 25 mg dose of HT (postprandial study) and then 25 mg HT daily, for one week (sustained study). Plasma and circulating plasma-isolated EVs were analyzed for HT and derived metabolites using UPLC-qTOF-MS and miRNAs by RNA-seq. HT induced the secretion of EVs 1-h post-ingestion and a 1-week daily administration of HT increased fasting EVs and reduced circulating oxidized LDL levels. RNA-seq analysis identified 55 modulated miRNAs (30 upregulated and 25 downregulated) related to response to oxygen level and gland development, following 1-week HT supplementation. This pilot study sheds light on the effects of HT consumption on EV secretion and modulation of exosomal miRNAs in humans, which has been scarcely studied to date. Further research is warranted to elucidate the molecular mechanisms underlying the observed effects.