Resveratrol and vascular health: evidence from clinical studies and mechanisms of actions related to its metabolites produced by gut microbiota

Abstract

Cardiovascular diseases are among the leading causes of mortality worldwide, with dietary factors being the main risk contributors. Diets rich in bioactive compounds, such as (poly)phenols, have been shown to potentially exert positive effects on vascular health. Among them, resveratrol has gained particular attention due to its potential antioxidant and anti-inflammatory action. Nevertheless, the results in humans are conflicting possibly due to interindividual different responses. The gut microbiota, a complex microbial community that inhabits the gastrointestinal tract, has been called out as potentially responsible for modulating the biological activities of phenolic metabolites in humans. The present review aims to summarize the main findings from clinical trials on the effects of resveratrol interventions on endothelial and vascular outcomes and review potential mechanisms interesting the role of gut microbiota on the metabolism of this molecule and its cardioprotective metabolites. The findings from randomized controlled trials show contrasting results on the effects of resveratrol supplementation and vascular biomarkers without dose-dependent effect. In particular, studies in which resveratrol was integrated using food sources, i.e., red wine, reported significant effects although the resveratrol content was, on average, much lower compared to tablet supplementation, while other studies with often extreme resveratrol supplementation resulted in null findings. The results from experimental studies suggest that resveratrol exerts cardioprotective effects through the modulation of various antioxidant, anti-inflammatory, and anti-hypertensive pathways, and microbiota composition. Recent studies on resveratrol-derived metabolites, such as piceatannol, have demonstrated its effects on biomarkers of vascular health. Moreover, resveratrol itself has been shown to improve the gut microbiota composition toward an anti-inflammatory profile. Considering the contrasting findings from clinical studies, future research exploring the bidirectional link between resveratrol metabolism and gut microbiota as well as the mediating effect of gut microbiota in resveratrol effect on cardiovascular health is warranted.

Keywords: gut microbiota; metabolites; polyphenols; resveratrol; vascular.

FIGURE 1

An overview of endothelial dysfunction. Different oxidative factors can contribute to eNOS uncoupling leading to the production of ROS and the reduction of NO bioavailability. Abbreviations; Ang-II, Angiotensin II; AT1, angiotensin one receptor; BH4, tetrahydrobiopterin; ET1, endothelin-1; ETA, endothelin A receptor; NO, nitric oxide; NOX, nicotinamide adenine dinucleotide phosphate oxidase; O2-, superoxide anion; ONOO-, peroxynitrite; ROS, reactive oxygen species.

FIGURE 2

Main mechanisms by which resveratrol exerts its cardioprotective effects. Resveratrol activates AMPK/Sirt1/PGC-1 pathway resulting in the deacetylation/phosphorylation of PGC-1. As a coactivator, PGC-1 results in the activation of downstream genes, comprising multiple genes involved in regulation of mitochondrial function. AMPK and SIRT1 activation results in the nuclear translocation of FOXO and upregulation of eNOS. Resveratrol modulates the Nrf2/KEAP1 pathway through Nrf2 dissociation from KEAP1 and its translocation into nucleus that in turn activates ARE, which modulates the transcription of antioxidant enzymes. AMPK, AMP kinase; ARE, antioxidant response element; CAT, catalase; eNOS, endothelial nitric oxide synthase; FOXO, Forkhead box O; Keap1, Kelch-like ECH-associated protein 1; NAD, nicotinamide adenine dinucleotide; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PGC-1, peroxisome proliferator-activated receptor gamma coactivator 1; SIRT1, sirtuin 1; SOD2, superoxide dismutase 2.