Project Grant F32AT013979

INVESTIGATING DIETARY MODULATION OF THE GUT MICROBIOTA DURING PREGNANCY AND ITS IMPACT ON INFANT MICROBIOTA ASSEMBLY AND HEALTH - PROJECT SUMMARY DIET IS A STRONG AND EASILY MODIFIABLE DRIVER OF THE GUT MICROBIOTA DURING PREGNANCY, WITH CONSEQUENCES FOR MATERNAL, FETAL, AND INFANT MICROBIOTA AND METABOLITES THAT MAY CONTRIBUTE TO LIFELONG WELL-BEING. HOWEVER, LITTLE IS KNOWN ABOUT HOW MATERNAL DIET SHAPES THE STRAIN-LEVEL DIVERSITY OR ADAPTATION OF THE MICROBIOTA OR HOW THESE CHANGES MAY INTERACT WITH DIET TO SHAPE MATERNAL AND INFANT HEALTH. THE LONG-TERM OBJECTIVE OF THIS PROJECT IS TO BUILD PREDICTIVE MODELS THAT CONNECT DIET TO THE DEVELOPMENT AND TRANSGENERATIONAL TRANSMISSION OF HEALTHY MICROBIOTAS, ENABLING SAFE, SCALABLE, AND COST-EFFECTIVE INTERVENTIONS AND STRATEGIES FOR LIFELONG DISEASE PREVENTION. THE CENTRAL HYPOTHESIS IS THAT SPECIFIC DIETS DURING PREGNANCY MODULATE THE GUT MICROBIOTA'S COMMUNITY COMPOSITION, EVOLUTIONARY TRAJECTORY, AND FUNCTIONAL CAPACITY DURING PREGNANCY AND THE TRANSMISSION OF BENEFICIAL STRAINS TO OFFSPRING. THREE INTEGRATED AND INDEPENDENT AIMS TEST THIS HYPOTHESIS: AIM 1 APPLIES GENOME-RESOLVED METAGENOMICS TO LONGITUDINAL MATERNAL AND INFANT SAMPLES ACROSS THE FOUR DIET ARMS (HIGH- FIBER, HIGH-FERMENTED FOODS, HIGH-FIBER AND HIGH-FERMENTED FOODS, OR CONTROL WITH NO INTERVENTION) TO DESCRIBE COMMUNITY COMPOSITION, STRAIN STRUCTURE, ALLELE FREQUENCY SHIFTS, FUNCTIONS, AND TRANSMISSION FROM MOTHER TO INFANT. AIM 2 INTEGRATES GLOBAL AND TARGETED METABOLOMICS OF MATERNAL SERUM AND BREASTMILK WITH METAGENOMIC FEATURES TO IDENTIFY DIET- AND MICROBIALLY ASSOCIATED METABOLITES AND THEIR PUTATIVE ORIGINS. AIM 3 USES COMPLEMENTARY GNOTOBIOTIC MOUSE MODELS AND STOOL-DERIVED IN VITRO COMMUNITIES TO IDENTIFY MECHANISMS UNDERLYING OBSERVED INCREASES IN DIVERSITY FOLLOWING A HIGH-FERMENTED FOOD DIET. MY PREVIOUS EXPERIENCE IN ECOLOGY AND EVOLUTIONARY BIOLOGY, METAGENOMICS, BIOINFORMATICS, AND MOUSE HANDLING MAKE ME WELL-EQUIPPED TO ANALYZE THE DATA AND PERFORM THE PROPOSED WORK, AND THE EXPERTISE IN HOST-MICROBE INTERACTIONS, METABOLOMICS, AND IN VITRO ANALYSIS HONED BY MY MENTORING TEAM MAKE STANFORD UNIVERSITY AN IDEAL LOCATION TO LEARN THE SKILLS I WILL NEED TO PERFORM THESE EXPERIMENTS. TOGETHER, THIS WORK WILL GENERATE A DETAILED FRAMEWORK FOR UNDERSTANDING HOW NUTRITIONAL ENVIRONMENTS MODULATE MICROBIAL ADAPTATION AND TRANSMISSION, ADVANCING BOTH OUR FOUNDATIONAL UNDERSTANDING OF PROCESSES GOVERNING THE MICROBIOTA AND THEIR INTERACTION WITH MATERNAL AND EARLY-LIFE SYSTEMS BIOLOGY. AS AMERICAN GUT MICROBIOTA ARE CHARACTERISTICALLY DYSBIOTIC AND LINKED TO THE HIGH PREVALENCE METABOLIC AND IMMUNOLOGICAL DISEASES, CLARIFYING HOW DIET RESTRUCTURES THESE COMMUNITIES AND INFLUENCES HOST METABOLITES IS OF BROAD CLINICAL RELEVANCE. BY CONNECTING DIET-DRIVEN MICROBIAL SHIFTS WITH METABOLITE PROFILES TIED TO WHOLE-BODY PHYSIOLOGY, THIS PROJECT WILL IDENTIFY MECHANISMS THROUGH WHICH SPECIFIC FOODS INFLUENCE MICROBIOTA DEVELOPMENT AND METABOLIC HEALTH. THE ANTICIPATED RESULTS MAY ULTIMATELY INFORM STRATEGIES TO IMPROVE HEALTH OUTCOMES FOR NOT ONLY PREGNANT AND POSTPARTUM INDIVIDUALS AND THEIR INFANTS, BUT ALSO FOR THE BROADER POPULATION.