** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** TRIMETHYLAMINE N-OXIDE (TMAO) IS A HARMFUL METABOLITE DERIVED FROM GUT BACTERIA. CIRCULATING LEVELS OF TMAO ARE POSITIVELY ASSOCIATED WITH ATHEROSCLEROSIS RISK. CARDIOVASCULAR DISEASE, INCLUDING ATHEROSCLEROSIS, IS THE LEADING CAUSE OF DEATH WORLDWIDE. NO DRUGS ARE APPROVED TO LOWER TMAO. STRATEGIES SUCH AS DIET REPRESENT OUR BEST BET FOR CONTROLLING TMAO. DIETARY PHENOLICS HAVE SHOWN POTENTIAL FOR BENEFICIALLY ALTERING GUT BACTERIAL COMMUNITIES AND METABOLISM. ONE SUCH COMPOUND IS CHLOROGENIC ACID, FOUND IN FOODS SUCH AS BLUEBERRIES. OUR PRELIMINARY DATA SUGGEST THAT CHLOROGENIC ACID-RICH BLUEBERRIES REDUCE TMO LEVELS IN VIVO. HOWEVER, CHLOROGENIC ACID CONTENT VARIES WIDELY IN BLUEBERRY CULTIVARS. WE HYPOTHESIZE THAT THE CHLOROGENIC ACID CONTENT OF BLUEBERRIES CORRESPONDS TO THEIR TMAO-LOWERING AND CARDIOPROTECTIVE EFFECTS. WE PROPOSE TO USE IN VITRO AND IN VIVO STUDIES TO DETERMINE THE RELATIONSHIP BETWEEN THE CHLOROGENIC ACID CONTENT OF BLUEBERRIES AND THEIR TMAO-LOWERING AND ANTI-ATHEROSCLEROSIS ACTIVITIES. THE RATIONALE FOR THIS WORK IS THAT UNDERSTANDING WHETHER THE CHLOROGENIC ACID CONTENT OF FOODS CORRESPOND TO THEIR EFFICACY FOR LOWERING TMAO CAN LEAD TO HEALTHIER DIETARY PATTERNS IN AT-RISK INDIVIDUALS AND THE POPULATION, AND THAT BREEDERS CAN USE THESE DATA TO BREED CHLOROGENIC ACID-RICH CULTIVARS. THE LONG-TERM EFFECTS OF SUCH PATTERNS MAY REDUCE CARDIOVASCULAR DISEASE BURDEN AND INCREASE QUALITY OF LIFE AT THE INDIVIDUAL AND POPULATION LEVELS. THIS APPLICATION RESPONDS TO PROGRAM AREA PRIORITY 3D (FOOD AND HUMAN HEALTH) BY INVESTIGATING THE IMPACT OF FOOD COMPONENTS (BLUEBERRY CHLOROGENIC ACID) ON THE GUT MICROBIOME AND ITS METABOLITES (BACTERIAL-DERIVED TMAO) AND HOW THIS RELATES TO HUMAN HEALTH (PREVENTION OF ATHEROSCLEROSIS).