(Poly)phenols a complex class of naturally occurring compounds have garnered increasing attention due to their putative bioactive effects. Flavan-3-ols a subgroup of polyphenols, predominantly found in cocoa, various teas (including black and green tea), and grape seed extracts (GSE), have been associated with various health benefits including cardioprotective, neuroprotective, and anti-inflammatory effects. Moreover, their monomeric forms catechin and epicatechin have been increasingly investigated for their antioxidant properties, which may contribute to the prevention of chronic diseases such as cardiovascular disorders, diabetes, and neurodegenerative conditions. Increasing number of large-scale intervention trials have reported an inverse correlation between a flavan-3-ol intake in range of 400 - 800 mg/d and the risk of cardiovascular disease. A finding that has been supported by the recent COSMOS trial which included \>20,000 participants who consumed 600 mg/d, reporting a significant 15% reduction in total CVD events when compared to the placebo group.

Despite these benefits, the efficacy of flavan-3-ols is heavily dependent on their bioavailability. However, this is severely influenced by various factors including the chemical structure, dosage, and the food matrix. Moreover, after ingestion, very few (poly)phenols are readily absorbed within the small intestine and subsequently not present in the circulation as the parent compound but as simpler phenolics, derived from the colonic fermentation within the large intestine where they are metabolised by the local microbiota through a series of chemical modifications such as ring fission, and cleavage of ester and/or glycosidic bonds. The newly formed simple phenolics may then undergo a various transformations mediated in part by local epithelial cell producing phase I/II metabolites such as, phenyl-y-valerolactones (PVLs) and their related phenylvaleric acids (PVAs), indicating that it is these secondary metabolites that offer the described benefits post-absorption. Although these metabolites are thought to play significant roles in health outcomes, their identification and quantification remains a challenge due to the lack of reference standards in biological fluids. Moreover, the metabolic fate of these compounds is characterized by a high degree of inter-individual variability, which is further complicated by factors such as enterohepatic recirculation and the diverse metabolic capabilities of the gut microbiota. Research has demonstrated that encapsulation technologies can influence the bioavailability of polyphenols, with different delivery systems such as hard capsules and soft gummies affecting the dissolution rates and systemic exposure of these bioactive compounds. Given these complexities, there is an increasing need to further elucidate the pharmacokinetic profiles of flavan-3-ols and their metabolites to optimize their health benefits. To this end, the investigators seek to conduct an open-label, randomized, 4-way crossover design with the aim to explore the bioavailability of GSE-derived flavan-3-ols from GSE and their related microbial metabolites and advance understanding of the bioactive properties of flavan-3-ols contributing to the development of more effective dietary strategies and functional food products.