** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** CADMIUM (CD), A TOXIC HEAVY METAL PRESENT IN MANY FOODS, AFFECTS REDOX STATUS IN DIFFERENT ORGANS, CAUSING MISREGULATION OF CELLULAR PROCESSES, LEADING TO SKELETAL, RENAL, GASTROINTESTINAL, METABOLIC, AND COGNITIVE DISORDERS. CD HAS DIFFERENTIAL EFFECTS ON THE GUT MICROBIOME, WHICH REGULATES CD BIOAVAILABILITY, WITH ALTERED METABOLITE POOLS OF LACTATE AND BUTYRATE IN CD-SENSITIVE MICROBIOMES. THE OVERALL OBJECTIVE OF THIS PROPOSAL IS TO DEVELOP MICROBIOTA-BASED STRATEGIES THAT PROTECT THE HOST FROM CD TOXICITY. WE HYPOTHESIZE THAT HOST DIET AND CD-TOLERANT BACTERIA REGULATE THE VULNERABILITY OF THE GUT MICROBIOTA TO CD DAMAGE, AND THAT DIETARY FIBER OR CD-TOLERANT BACTERIA CAN RESTORE COMPOSITION AND FUNCTION TO CD-SENSITIVE MICROBIOTAS, THEREBY DECREASING HOST ABSORPTION OF CD AND INCREASING HOST HEALTH. WE WILL EMPLOY HUMAN MICROBIOTA-ASSOCIATED MICE HARBORING MICROBIOTAS THAT DIFFER IN CD SENSITIVITY TO DETERMINE THE ROLE OF 1) CD TOLERANCE OF THE GUT MICROBIOTA AND 2) CD-TOLERANT BACTERIA, IN MEDIATING CD ACCUMULATION AND OXIDATIVE STRESS IN HOST TISSUES. WE WILL ALSO IDENTIFY THE ROLE OF DIET IN CONFERRING CD TOLERANCE TO A MICROBIOME BY EXAMINING THE PROTECTIVE EFFECT OF DIETARY FIBER ON THE GUT MICROBIOTA AGAINST CD TOXICITY. THIS PROJECT ADDRESSES THE PRIORITY AREAS OF THIS AFRI PROGRAM BY INVESTIGATING THE TERNARY INTERRELATIONSHIP AMONG FOODS, CD, AND THE HUMAN GUT MICROBIOME. WE WILL LINK THE FUNCTIONAL OUTCOMES OF METABOLITES OF THE GUT MICROBIOME TO OUTCOMES THAT ARE RELEVANT TO HUMAN HEALTH, INCLUDING DECREASING CD DEPOSITION AND OXIDATIVE STRESS IN HOST TISSUES. OUR STUDY WILL HELP SHAPE DIETARY RECOMMENDATIONS TO PROTECT THE PUBLIC FROM CD TOXICITY.