Project Grant 20236701140406

THE PREVALENCE OF METABOLIC DISEASES LIKE OBESITY AND TYPE 2 DIABETES (T2D) HAS RISEN UNABATED OVER THE PAST 40 YEARS, DEMONSTRATING A NEED FOR THE DEVELOPMENT OF NEW, ALTERNATIVE THERAPIES. GROWING EVIDENCE HIGHLIGHTS A ROLE FOR THE GUT MICROBIOTA IN THE DEVELOPMENT OF T2D, AND THUS, PROVIDES AN ALTERNATIVE TARGET FOR THERAPEUTIC INTERVENTION THAT COULD BE EASILY IMPLEMENTED THROUGH SUPPLEMENTATION IN THE DIET. DIETS HIGH IN FAT AND SIMPLE SUGAR CREATE A STATE OF DYSBIOSIS WITHIN THE GUT MICROBIOTA, LEADING TO IMPAIRMENTS IN GLUCOSE HOMEOSTASIS, WHICH CAN BE REVERSED BY TREATMENT WITH PLANT-DERIVED FIBERS LIKE OLIGOFRUCTOSE (OFS). HOWEVER, THE MECHANISM THROUGH WHICH OFS-INDUCED SHIFTS IN THE MICROBIOTA DRIVE THE IMPROVEMENTS IN GLUCOSE HOMEOSTASIS IS UNCLEAR. WHILE MOST WORK EXAMINING THE ROLE OF PREBIOTICS ON T2D FOCUSES ON THE LARGE INTESTINE, RECENT WORK HIGHLIGHTS A ROLE FOR THE SMALL INTESTINAL MICROBIOTA IN RESTORING NUTRIENT SENSING TO DECREASE GLUCOSE PRODUCTION VIA A GUT-BRAIN-LIVER AXIS. MY PRELIMINARY DATA SUPPORTS THAT OFS BENEFICIALLY SHIFTS THE SI MICROBIOTA OF HIGH FAT (HF)-FED RATS AND THAT THESE SHIFTS IMPROVE SMALL INTESTINAL NUTRIENT SENSING MECHANISMS TO REGULATE GLUCOSE PRODUCTION FOLLOWING A SMALL INTESTINAL NUTRIENT INFUSION. THEREFORE, I HYPOTHESIZE THAT RAPID SHIFTS IN THE SI MICROBIOTA FOLLOWING OFS TREATMENT RESTORE THE GUT-BRAIN-LIVER AXIS TO DECREASE GLUCOSE PRODUCTION, WHICH IS IMPAIRED WITH HF-FEEDING. I WILL USE BASAL INSULIN EUGLYCEMIC PANCREATIC CLAMPS IN CONJUNCTION WITH MANIPULATION OF THE GUT-BRAIN-LIVER SIGNAL AND THE SMALL INTESTINAL MICROBIOTA TO DEMONSTRATE THE ABILITY OF OFS-MEDIATED SHIFTS IN THE SMALL INTESTINAL MICROBIOTA TO IMPROVE SMALL INTESTINAL NUTRIENT SENSING TO DECREASE GLUCOSE PRODUCTION. ADDITIONALLY, I WILL DETERMINE WHETHER TREATMENT WITH THE PROBIOTIC BACTERIUM, BIFIDOBACTERIUM PSEUDOLONGUM, WHICH IS INCREASED FOLLOWING OFS SUPPLEMENTATION CAN IMPROVE WHOLE BODY GLUCOSE HOMEOSTASIS ALONE AND IN CONJUNCTIONWITH OFS SUPPLEMENTATION. UNDERSTANDING HOW PLANT-BASED FIBERS CAN IMPROVE GLUCOSE HOMEOSTASIS VIA SHIFTS IN THE GUT MICROBIOTA COULD LEAD TO THE DEVELOPMENT OF SPECIFICALLY DESIGNED CROPS THAT BETTER TARGET THESE HOST NEURONAL SIGNALING PATHWAYS TO IMPROVE HUMAN HEALTH WHILE PROVIDING SUSTAINABLE IMPROVEMENTS IN THE US AGRICULTURE AND FOOD SYSTEM.