Exploring the mechanisms underlying plant (poly)phenols bioactivity via integrating metabolomics and fluxomics

Project Summary Plant (poly)phenolic compounds are widely acknowledged to have health benefits in humans, and diets high in plant-based foods are associated with good health. Phenolic compounds can act as antioxidants, by scavenging free radicals and preventing free radical formation, and can regulate metabolic reactions by binding to various enzymes. Despite epidemiological evidence that these phytochemicals have health-promoting effects, the mechanisms of action behind their bioactivity remain incompletely understood. The overarching goal of this proposal is to elucidate the mechanisms underlying various biological activities of (poly)phenolic compounds including antioxidant, anti-inflammatory, and other medicinal properties. The specific aims are 1) Systems-level analysis of metabolism upon (poly)phenolic compound addition, 2) Exploring the effect of (poly)phenolic compounds in cell lines and animals, and 3) Searching for synergy by paring (poly)phenols, small-molecule drugs, and nutrient conditions. The complexity and diversity of (poly)phenolic compounds and their biological activities necessitate innovative analytical techniques for systems-level quantitation of metabolic effects. The proposed research will innovate i) a widely applicable method for mapping the mechanism of action of natural products and ii) targeted uses of (poly)phenols as a sole preventive and therapeutic strategy and as a complement to other drugs. To this end, a novel method, termed ‘shotgun metabolomics,’ will be developed. Furthermore, a combination of state-of-the-art mass spectrometry, cleverly designed isotope tracing strategies, and a fundamental thermodynamic principle will be used to obtain and integrate metabolomic, fluxomic, and thermodynamic measurements across cellular metabolism. This integrative approach will expand the coverage of quantitative metabolic analysis. Using this approach, this project will generate and test new hypotheses regarding systemic metabolic rewiring, elicited by (poly)phenols, that contributes to preserving energetic homeostasis in terms of ATP and redox molecules. The proposed systems-level analysis will reveal multi-faceted effects of (poly)phenols on various parts of metabolism, which collectively contribute to cells’ ability to fight stressors and maintain homeostasis. Exploring and elucidating the mechanisms underlying (poly)phenols’ biological activities will promote preventive and integrative health care.