Examining Gut Microbiome as a Determinant of Blueberry Polyphenol Bioavailability to Optimize Dose and Phytochemical Standardization for Functional Effects in Humans - PROJECT ABSTRACT Blueberries are a polyphenol-rich food that has been shown to confer cardiovascular- and neuro-protective benefits in a wide range of human populations, including individuals with metabolic syndrome and middle-aged/older adults. However, data from blueberry feeding studies are equivocal and even when there are overall improvements observed with blueberry interventions, there is variability in individual responses within the population. We hypothesize that the gut microbiome is a source of this variability. Most blueberry polyphenols are poorly absorbed in the intestines and therefore most are metabolized by the gut microbiota. These metabolites can have altered bioavailability and bioactivity relative to the parent compounds found in the whole food. Individual-level differences in the gut microbiome influence the suite of blueberry metabolites that are produced, ultimately impacting an individual’s exposure and mediating functional outcomes. In addition, while the benefits of blueberry are thought to be primarily mediated by the anthocyanin component of blueberries, through reductions in oxidative stress, the activity of many microbially produced metabolites that make it into the circulation is poorly understood. We have assembled a strong multi-disciplinary team of clinical and translational nutrition researchers, data scientists, and natural products chemists to untangle interactions between the microbiome and blueberry components. Specifically, the first Aim will assign individuals to “metabotypes”, assemblages of the gut microbiome with distinct polyphenol-metabolizing capabilities and use this categorization to develop machine learning models predictive function of circulating blueberry metabolites. Aim 2 will link these circulating metabolites to functional outcomes such acute modulation of brachial-artery increased flow-mediated dilation (FMD) and reduced vascular oxidative stress and increased nitric oxide production. Aim 3 will examine the specific components of blueberry (e.g., blueberry polyphenol extract, anthocyanins) responsible for functional benefits that lead to increased resilience to oxidative stress and other factors that increase cardiovascular disease risk with aging. In addition to targeted approaches, we have also included a discovery element, non-targeted metabolomics profiling, throughout the project that will help identify novel or understudied bioactive blueberry components. These studies address several gaps in knowledge regarding mediators of blueberry polyphenol intervention responses, including the source of variation in individual responses and specific dosing and components for optimized intervention delivery. Addressing these gaps will permit design of an optimized blueberry polyphenol delivery systems and design dietary intervention efficacy trials that utilize precision nutrition approaches. The knowledge from these studies will provide valuable new resources to researchers and the proposed studies are necessary for the optimal design and interpretation of a future clinical trial examining the effects of blueberries and blueberry polyphenols on cardiovascular and cognitive/brain health.
