Grape-derived (poly)phenols: influence of bioavailability and food matrix on circulating metabolites and endothelial function

Abstract

Cardiovascular disease (CVD) is a leading cause of mortality worldwide with endothelial dysfunction being recognized as an early predictor of cardiovascular outcomes. (Poly)phenols continue to emerge as a potential dietary strategy to mitigate disease-risk via its impact on endothelial function. This thesis critically evaluates the efficacy of (poly)phenols and their microbial-derived metabolites on macrovascular circulation measured through using flow mediated-dilation (FMD) whilst exploring the impact of food matrices on bioavailability. Chapter 1 provides a comprehensive overview of all topics covered within this thesis.

A narrative review (Chapter 2) included within this thesis highlights the positive yet variable impacts of (poly)phenol-rich foods and extracts, with berries, cocoa and tea consistently improving endothelial function, whereas grape and citrus (poly)phenols produced less consistent results. Both acute and chronic dietary interventions suggest beneficial effects, although these are influenced significantly by health status, the complexity of food matrices and the consequent differences in bioavailability and metabolism. Microbiota-mediated derived metabolites, including phenolic acids and phenyl-y-valerolactone, may underpin many of the observed vascular benefits attributed to dietary polyphenols.

A randomised, double-blind, placebo-controlled, 4-way cross-over clinical trial (Chapter 3) compared3 individual dosages of grape derived (poly)phenols (156mg, 222mg, 333mg) and placebo in an at risk population for endothelial dysfunction (n=20). Although a null effect (FMD) was observed, the bioavailability data indicated presence of conjugated forms of epicatechin suggesting phase Imetabolism occurred within the 2-hour timeframe, which may explain the lack of FMD response observed as the unconjugated forms of epicatechin are more bioactive and generally associated with FMD improvements. Additionally, a randomised, double-blind, 4-way cross-over clinical trial (Chapter4) comparing 4 interventions of flavanol monomers with a total (poly)phenol content of 300 mg: <2%hard-shell capsule, 15% hard-shell capsule, 26% hard-shell capsule and 15% gummy in a healthy population (n=15). This study investigated how (poly)phenols delivered through various matrices affect their pharmacokinetics and bioavailability. The results from this chapter indicate that food matrix of the gummy did not impact the pharmacokinetic parameters nor bioavailability albeit some insignificant differential absorption patterns were observed. Future research should develop specific intake guidelines and fortification methods to optimize (poly)phenol intake, overcoming inherent dietary variability and limited consumption of diverse (poly)phenol sources.

Thesis is embargoed until 31st December 2027

Date of Award	Dec 2025
Original language	English
Supervisor	Patrick Richardson (Supervisor), Sumantra Ray (Supervisor), Kirsty Pourshahidi (Supervisor) & Chris Gill (Supervisor)