** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** DIETARY LONG-CHAIN (LC) POLYUNSATURATED FATTY ACIDS (PUFAS) ARE IMPORTANT NUTRIENTS IN THE HUMAN DIET OBTAINED VIA CONSUMPTION OF FOODS OF MARINE AND ANIMAL ORIGIN. LC PUFA INTAKE IMPROVES HUMAN HEALTH, IN PART, VIA STIMULATORY EFFECTS ON SKELETAL MUSCLE METABOLISM. THE RESIDENT MICROBES THAT INHABIT THE GASTROINTESTINAL TRACT MEDIATE SOME OF THE BENEFICIAL EFFECTS OF LC PUFAS ON THEIR HUMAN HOST, ALTHOUGH THE CHEMICAL SIGNALS INVOLVED REMAIN UNKNOWN. MANY OF THE BIOLOGICAL ACTIONS OF LC PUFAS ARE ELICITED SECONDARY TO THEIR ENZYMATIC CONVERSION TO OXYGENATED LIPID METABOLITES (OXYLIPINS). GUT MICROBE-HOST CELL INTERACTIONS METABOLIZE LC PUFA SUBSTRATES TO FORM A VARIETY OF OXYLIPINS, BUT THE ROLE OF THESE POTENTIALLY BIOACTIVE LIPID MEDIATORS IN MODULATING HOST METABOLISM IS POORLY UNDERSTOOD. IN THE PROPOSED RESEARCH PROJECT ADDRESSING THE AFRI PROGRAM PRIORITY AREA FOOD AND HUMAN HEALTH, WE WILL INVESTIGATE THE ROLE OF LC PUFAS AS IMPORTANT FOOD COMPONENTS ON THE HUMAN GUT MICROBIOME, ITS METABOLITES, AND THE SUBSEQUENT IMPACT ON HUMAN HEALTH VIA THE GUT-MUSCLE AXIS. TO ACCOMPLISH THIS, WE WILL UTILIZE WELL-ESTABLISHED MOUSE MODELS OF GUT MICROBIOTA DYSBIOSIS AND ORAL FECAL TRANSPLANTATION. WE WILL FIRST TEST THE EFFECT OF LC PUFAS AND ORAL ANTIBIOTICS ON THE GUT MICROBIAL COMMUNITY AND ITS INTERRELATIONSHIP WITH BLOOD AND MUSCLE OXYLIPINS. WE WILL THEN TEST THE POTENTIAL ROLE OF THE GUT-MUSCLE AXIS IN MEDIATING THE PROTECTIVE EFFECTS OF LC PUFAS IN DIET-INDUCED OBESITY. ULTIMATELY, THIS WORK WILL PROVIDE A SCIENTIFIC FOUNDATION REGARDING THE NUTRIENTS IN FOOD AND THEIR IMPACT ON THE GUT MICROBIOTA TO IMPROVE HUMAN HEALTH.