RECENT STUDIES INDICATE GUT MICROBIOTA IS INVOLVED IN DEVELOPMENT OF CARDIOVASCULAR DISEASE. GUT MICROBIOTA TRANSFORM CHOLINE AND CARNITINE, COMMONLY FOUND IN MEAT OR EGG YOLK, TO TRIMETHYLAMINE (TMA), WHICH CAN THEN BE CONVERTED INTO TRIMETHYLAMINEN-OXIDE (TMAO) BY HEPATIC ENZYMES. TMAO ACCELERATES ATHEROSCLEROSIS AND IS ASSOCIATED WITH MAJOR ADVERSE CARDIAC EVENTS. THERE IS SOLID REASONING FOR INVESTIGATING ORANGE PEEL TO MODULATE GUT MICROBIOTA SUBSEQUENTLY INHIBITING TMAO FORMATION: 1) OUR PRELIMINARY STUDY SHOWED ORANGE PEEL CAN INHIBIT TMAO FORMATIONIN VIVOVIAALTERATION OF GUT MICROBIOTA AS WELL AS INHIBIT A MICROBIAL CARNITINE-SPECIFIC TMA ENZYME TO PREVENT CARNITINE TRANSFORMING INTO TMAIN VITRO. 2) APPROXIMATELY FIVE MILLION TONS OF ORANGE PEEL ARE GENERATED ANNUALLY IN THE US; 3) NATURAL ORANGE PEEL EXTRACTS ARE CONSIDERED SUBSTANCES GENERALLY RECOGNIZED AS SAFE (GRAS) BY THE FDA; 4) INCREASED USAGE OF ORANGE PEEL DIRECTED AT IMPROVING HEART HEALTH COULD POTENTIALLY PROVIDEADDITIONAL ECONOMIC RETURNS BENEFITING US AGRICULTURE AND FOOD SYSTEMS. THE HYPOTHESES OF THIS PROJECT ARE ORANGE PEEL CAN EFFECTIVELY PREVENT DEVELOPMENT OF ATHEROSCLEROSIS VIA MODIFYING GUT MICROBIOTA, AND ORANGE PEEL CONTAINS BIOACTIVE COMPONENTS THAT INTERFERE WITH ACTIVITY OF CARNITINE-SPECIFIC TMA ENZYMES. TO TEST THESE HYPOTHESES, OUR INTERDISCIPLINARY TEAM WILL COMBINE ANIMAL STUDIES AND NATURAL PRODUCTS CHEMISTRY WITHIN VITROENZYME ASSAYS TO ASSESS PATHWAYS ASSOCIATED WITH ORANGE PEEL CONSUMPTION, TMA/TMAO METABOLISM AND PREVENTION OF ATHEROSCLEROSIS AS WELL AS IDENTIFY TMA INHIBITORS, RESPECTIVELY.