Project Summary A fundamental question in neurobiology is how to protect against Alzheimer’s disease. Emerging evidence reveals a deterministic link between our microbiome, intestine, and neurodegenerative diseases. However, the molecular basis of the interaction between human gut microbiota and the host nervous system is poorly understood, largely because the complexity of the human microbiome makes it extremely hard to determine causal relationships between individual bacteria and neural degeneration. In contrast, C. elegans can be maintained on single or multiple defined bacterial species, has a relatively simple nervous system, and is genetically tractable. We are leveraging these strengths to answer the critical question of how different bacteria, including bacteria isolated from Alzheimer’s patients and healthy adults, influence neurodegeneration. Specifically, we will 1) determine how bacterially produced vitamin B12 protects against TIR-1/SARM1 induced neurodegeneration, 2) determine how Buttiauxella protects against neurodegeneration independently of B12, and 3) identify human bacteria and molecular mechanisms that regulate degeneration in a tractable model of Alzheimer’s disease. Identifying microbiota, their metabolites and molecular mechanisms that protect neuronal integrity is essential to understanding how the microbiome influences neuronal integrity and will significantly enhance our understanding of how to protect against the devastating neurodegeneration that occurs in Alzheimer’s disease.