SPACEFLIGHT HAS DEMONSTRATED CONCERNING IMPACTS TO HUMAN PHYSIOLOGY, INCLUDING WELL DOCUMENTED IMMUNE SYSTEM DYSREGULATION. DIET, IMMUNE FUNCTION, AND THE MICROBIOME ARE INTERLINKED, BUT DIET IS THE ONLY ONE OF THESE FACTORS THAT WE HAVE THE ABILITY TO EASILY, AND SIGNIFICANTLY, ALTER ON EARTH OR DURING FLIGHT. IT IS EXPECTED THAT AS WE UNDERSTAND DIETARY IMPACTS MORE THOROUGHLY, WE MAY CONTINUE TO IMPROVE THE SPACEFLIGHT DIET IN DIRECT SUPPORT OF CREW HEALTH. WE PROPOSE HERE AN INTERDISCIPLINARY STUDY THAT WILL DETERMINE THE EFFECT OF THE CURRENT SPACEFLIGHT DIET COMPARED TO AN "ENHANCED" SPACEFLIGHT DIET (25% MORE FOODS RICH IN OMEGA-3 FATTY ACIDS, LYCOPENE, FLAVONOIDS, FRUITS, AND VEGETABLES), WITH COMPLETE DIETARY TRACKING, ON IMMUNE FUNCTION, GUT MICROBIOTA COMPOSITION, AND NUTRITIONAL STATUS OF CREW IN GROUND-CONTROL ANALOGS, AND ON ISS MISSIONS. WE HYPTHESIZE THAT BY INCREASING CONSUMPTION OF FRUITS AND VEGETABLES AND BIOACTIVE COMPOUNDS (E.G., OMEGA-3 FATTY ACIDS, LYCOPENE, FLAVONOIDS) AND ENHANCING OVERALL NUTRITIONAL INTAKE DURING SPACEFLIGHT (OR A GROUND-BASED ANALOG OF SPACEFLIGHT) WE WILL IMPROVE HUMAN IMMUNOLOGICAL PROFILES, THE TAXONOMIC PROFILE OF THE GUT MICROBIOTA, AND NUTRITIONAL STATUS BIOMARKERS. POSITIVE ASSOCIATIONS BETWEEN BENEFICIAL IMPROVEMENTS WILL PROVIDE EVIDENCE TO BETTER PREDICT THE IMPACT OF DIET ON CREW HEALTH AND ADAPTATION TO SPACEFLIGHT AND TO DESIGN TARGETED MORE-EFFICIENT DIETARY INTERVENTIONS. SPECIFICALLY, WE PROPOSE TO 1) IMPLEMENT A PILOT GROUND-CONTROL STUDY WITH ANALOG CREW RANDOMIZED BETWEEN TWO SPACEFLIGHT DIETS, AND DETERMINE DIET EFFECTS ON IMMUNE DYSREGULATION, INCLUDING LEUKOCYTE DISTRIBUTION, INFLAMMATORY CYTOKINE PROFILES, T CELL FUNCTION, AND OTHER RELEVANT IMMUNOLOGICAL MARKERS, THE TAXONOMIC AND METATRANSCRIPTOMIC PROFILE OF THE GUT MICROBIOME, AND NUTRITIONAL BIOMARKERS AND METABOLITES AT SELECTED INTERVALS, AND STATISTICALLY EVALUATE TO ASSOCIATE SHIFTS ACROSS EACH MEASURE AND IN RELATION TO NUTRIENT INTAKE; AND 2) DETERMINE EFFECTS OF DIET ON IMMUNE DYSREGULATION, INCLUDING LEUKOCYTE DISTRIBUTION, INFLAMMATORY CYTOKINE PROFILES, T CELL FUNCTION, AND OTHER RELEVANT IMMUNOLOGICAL MARKERS, THE TAXONOMIC AND METATRANSCRIPTOMIC PROFILE OF THE GUT MICROBIOME, AND NUTRITIONAL BIOMARKERS AND METABOLITES AT SELECTED INTERVALS IN SPACEFLIGHT AND STATISTICALLY EVALUATE TO ASSOCIATE SHIFTS ACROSS EACH MEASURE, AND IN RELATION TO GROUND-CONTROL DATA. THIS STUDY SPECIFICALLY ADDRESSES THE B.4 RESEARCH EMPHASIS 3 - UNDERSTANDING HOW COMPLEX ORGANISMS ADAPT TO SPACEFLIGHT, BY PROVIDING DETAILED COMPREHENSIVE ANALYSIS OF THE EFFECT OF DIET ON THE HUMAN IMMUNE SYSTEM, GUT MICROBIOTA, AND NUTRITIONAL STATUS DURING HUMAN ADAPTATION TO SPACEFLIGHT.