Hydroxytyrosol Bioavailability: Unraveling Influencing Factors and Optimization Strategies for Dietary Supplements.

Hydroxytyrosol (HT) is a major phenolic compound in olives and extra virgin olive oil (EVOO), known for its antioxidant, anti-inflammatory, and cardiometabolic properties. The European Food Safety Authority (EFSA) has approved a health claim for the protection of LDL particles from oxidative damage only when HT is consumed within EVOO, which limits its direct use in supplements or functional foods. Since its biological effects depend on absorption, distribution, metabolism, and excretion (ADME), understanding how formulation and delivery strategies influence bioavailability is essential. HT is mainly present as secoiridoid derivatives in EVOO, whereas in supplements, it often appears in its free form, potentially affecting its metabolic fate. This review summarizes human studies on HT bioavailability from EVOO, isolated supplements, and enriched foods, and examines how matrix type, chemical modifications of HT, and advanced delivery systems, such as emulsions, encapsulation, and vesicular carriers, modulate absorption and metabolism. The gut microbiota is highlighted as an emerging factor in HT biotransformation, although its role remains underexplored. Further well-designed human studies are needed to guide the development of nutraceutical formulations capable of replicating the health benefits of EVOO beyond its natural matrix.