Are metabolites of flavonoids responsible for the health benefits of fruit and vegetable consumption?

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Finding strategies to maintain population health during ageing represents a major challenge. Flavonoids are plant compounds found in fruits, vegetables, berries, wine, chocolate, tea, etc., and scientific reports reveal associations between intake and increased likelihood of surviving to old age in optimal health. In addition, the news, internet and food and health magazines contain countless reports describing the health effects of flavonoid-rich foods. However, flavonoid-rich foods do not have official health claims associated with them and the government does not endorse their increased intake for providing population health benefit. Why is this the case, when flavonoid-rich foods may be able to help delay the onset of age-related diseases and disorders? Oddly enough it's because we actually know very little about how flavonoids work, despite their extensive study. In fact, we are just now forming a basic understanding of their metabolism (i.e., how the body breaks them down and processes them), and the impact this has on their activity. Unfortunately, presently we don't even have the basic tools to study the products of flavonoid metabolism (i.e., commercially available metabolites) and therefore, are unable to establish the extent to which metabolism impacts their biological activity. In the present study, we hope to remedy this by producing flavonoid metabolites using organic synthesis techniques. These metabolites can then be used as a tool for investigating the physiological abundance of flavonoid metabolites, their correlation with dietary consumption (i.e., markers of intake), the impact of metabolism on their activity and their molecular mechanisms of action.Considering recent reports proposing the importance of flavonoid metabolites (Rodriguez-Mateos et al., 2014), this project is particularly timely, and our group is well-situated to lead this research, as we are one of a few groups globally who are exploring the activity of flavonoid metabolites. After identifying a 40-fold higher abundance of flavonoid metabolites relative to their unmetabolised counterparts (Czank et al., 2012; De Ferrars et al., 2013 & 2014), we have recently been investigating the activity of a select number of these metabolites in vascular and inflammatory cell culture models (di Gesso et al., 2015; Amin et al., 2015). We have observed often greater and differential bioactivity relative to their unmetabolised forms found in food. It's clear that the key to unlocking the functional activity of flavonoids lies with their metabolites. However, flavonoids are metabolised to an extensive array of metabolites, and studying each individually would be a mammoth undertaking; particularly as over 4000 unique flavonoid structures have been identified and one individual flavonoid could be metabolised to form greater than 20-30 distinct metabolic by-products. A technique called structure activity relationship (SAR) analysis, which is commonly used for drug discovery can speed this process along. SAR establishes the data necessary to predict the effect of metabolism on bioactivity without having to test all the metabolites individually. This will provide valuable information required to drive future clinical validation of flavonoids, which is paramount to establishing how these compounds contribute to health. In this project we will: develop flavonoid metabolites using synthetic chemistry and identify metabolite activity (Objective 1, synthesis and activity screening); further synthetically modify the metabolites to establish the effect of altering their structure on their function (Objective 2, SAR analysis); establish the effects of metabolism on biological mechanism of action by identifying the impact of the active compounds (identified in Objective 1 & 2) on biological pathways associated with inflammation and vascular function.