Project Grant F32HD118812

A BIOACTIVE MILK COMPONENT PROMOTES COGNITION THROUGH THE GUT MICROBIOME-BRAIN AXIS. - PROJECT SUMMARY/ABSTRACT MILK IS AN INVALUABLE, NATURAL SOURCE OF UNIQUE MILK FAT GLOBULE MEMBRANE (MFGM) GLYCOCONJUGATES THAT PROMOTE COGNITIVE FUNCTION IN INFANTS. THESE FUNCTIONS ARE ATTRIBUTED IN PART TO SIALYLATED GLYCOCONJUGATES, WHICH CONTAIN SIALIC ACID (SIA), A CRUCIAL MOLECULE FOR NEURODEVELOPMENT. USING A NOVEL BIOACTIVE DAIRY COMPONENT (WHEY PROTEIN PHOSPHOLIPID CONCENTRATE, WPPC) ENRICHED WITH BOVINE MFGM AS A PROXY FOR BREAST MILK, THE FIRST GOAL OF THIS WORK IS TO IDENTIFY THE GENETIC ELEMENTS ENABLING SELECT BIFIDOBACTERIA WITH THE METABOLIC CAPACITY TO CONSUME WPPC AND RELEASE SIA. AIM 1 WILL INVOLVE SYSTEMATIC, HIGH-THROUGHPUT SCREENING TO IDENTIFY BIFIDOBACTERIA SPECIES IN VITRO GROWTH ON WPPC AND MEASURING SIA RELEASE INTO THE CULTURE MEDIA. RNA SEQUENCING WILL BE PERFORMED TO DISCOVER GENETIC DIFFERENCES BETWEEN SPECIES THAT RELEASE SIA AND THOSE THAT DO NOT, AND KNOCK-OUT STRAINS AND STRAINS WITH THE NECESSARY GENETIC ELEMENTS CLONED IN WILL VALIDATE ESSENTIAL GENETIC ELEMENTS FOR SIA RELEASE. SEQUENTIAL FECAL ENRICHMENT EXPERIMENTS USING ADULT FECES AND WPPC WILL ENABLE THE IDENTIFICATION OF BIFIDOBACTERIA STRAINS THAT PERSIST IN A STABILIZED GUT MICROBIOME AND QUANTIFICATION OF SIA RELEASE. NEXT, THIS PROPOSAL WILL DETERMINE IF SIA RELEASE FROM WPPC-CONSUMING BIFIDOBACTERIA CAN PROMOTE COGNITIVE FUNCTION IN RATS. IN AIM 2, I WILL ALSO ORALLY ADMINISTER BIFIDOBACTERIA +/- WPPC TO AN INFANT MODEL OF WISTAR RATS TO DETERMINE IF WPPC PROMOTES BIFIDOBACTERIA PERSISTENCE (FECES), ENABLES THE RELEASE OF SIA FROM WPPC (FECES, BLOOD, HIPPOCAMPUS AND FRONTAL CORTEX), AND PROMOTES COGNITION THROUGH BEHAVIOR TESTS. I WILL ALSO INFUSE LABELED SIA INTO RATS TO DETERMINE THE EFFECT OF DIETARY TREATMENTS ON BRAIN MYELINATION KINETICS, WHICH IS IMPORTANT FOR COGNITION. I ANTICIPATE ENZYMATICALLY CAPABLE BIFIDOBACTERIA WILL BE ABLE TO RELEASE SIA, WHICH WILL IMPROVE COGNITIVE FUNCTION IN RATS. THESE EXPERIMENTS WILL IDENTIFY A MECHANISM FOR HOW NATURAL MILK MFGM GLYCOCONJUGATES MAY PROMOTE NEURODEVELOPMENT IN INFANTS. IN THE LONG-TERM, THESE FINDINGS COULD CONTRIBUTE TOWARDS DEVELOPING AN INTEGRATIVE FOOD-FOR-HEALTH SYNBIOTIC TO PROMOTE COGNITIVE DEVELOPMENT IN EARLY LIFE. THE FELLOWSHIP TRAINING WILL BE GUIDED BY NIH FUNDED CO-SPONSORS PROFESSORS DAVID MILLS (MICROBIOLOGY) AND AMEER TAHA (NEUROBIOLOGY), AND PROFESSOR DANIELA BARILE (GLYCOCHEMISTRY) IN THE DEPARTMENT OF FOOD SCIENCE AND TECHNOLOGY AT UC DAVIS. THE MILLS LABORATORY HAS AN ESTABLISHED, OVER 20-YEAR-OLD UC DAVIS MILK BIOACTIVES GROUP WHICH HAS FACILITATED NUMEROUS COLLABORATIVE RESEARCH PROJECTS AMONGST 100'S OF ACADEMICS RESULTING IN 100'S OF PUBLICATIONS. DR. MILLS HAS GRADUATED 24 GRADUATE STUDENTS AND MENTORED 18 POSTDOCTORAL RESEARCHERS, THREE OF WHOM WERE AWARDED AN F32. TWELVE OF DR. MILLS FORMER MENTEES ARE NOW ACADEMIC FACULTY. THE MILLS LABORATORY IS PART OF THE UC DAVIS FOOD FOR HEALTH INSTITUTE, WHICH AIMS TO BRING PERSONALIZED HEALTH TO PRACTICE BY UNDERSTANDING HOW DIET CONTROLS HEALTH. AS SUCH, THE LABORATORY AND BROADER INSTITUTIONAL ENVIRONMENT AT UC DAVIS HAS THE PERSONNEL AND EXPERTISE FOR THIS RESEARCH TRAINING PLAN AND PROJECT TO BE SUCCESSFULLY COMPLETED.