Therapeutic Mechanisms of Farnesol in Modulating Gut Dysbiosis and Neuroinflammation in Multiple Sclerosis - ABSTRACT Multiple sclerosis (MS) is a prevalent autoimmune disease affecting nearly one million individuals in the United States. MS is characterized by neuroinflammatory demyelination within the central nervous system (CNS), facilitated by immune cell infiltration through a disrupted blood-brain barrier, and is associated with gut dysbiosis. Our previous studies have shown that farnesol (FOL), a metabolite of the mevalonate pathway, delays onset, reduces severity in the experimental autoimmune encephalomyelitis (EAE) model of MS, and reduces neuroinflammatory pathways triggered during disease. This project investigates the cellular mechanisms underlying FOL’s therapeutic effects in EAE. FOL, found in mammalian tissues and produced by bacteria and yeast, possesses protective benefits against cardiac and brain ischemia, neuroinflammation, neurodegeneration, oxidative stress, and disrupted epithelial barriers. We hypothesize that FOL’s protection in EAE is due to its beneficial impact on gut microbiota dysbiosis, intestinal barrier permeability, and intestinal and systemic inflammation. Notably, FOL functions as a neuronal and microvascular voltage-gated Ca2+ channel (VGCC) blocker, which might underpin its broad biological properties. We will evaluate FOL’s impact on gut dysbiosis, intestinal barrier disruption, and inflammation at different stages of disease progression. The specific aims are Aim #1) To determine if FOL prevents the onset and progression of EAE-induced dysbiosis; Aim #2) To determine if FOL prevents the onset and progression of EAE-induced intestinal barrier disruption; Aim #3) To determine if FOL effects on intestinal barrier disruption and dysbiosis predict improved neuroinflammatory and autoimmunity markers and clinical severity throughout the disease. Successful outcomes will elucidate the microbiota's role in MS immunopathogenesis and offer mechanistic insights crucial for translating preclinical knowledge into clinical applications, potentially leading to novel farnesol-based MS therapeutics. Moreover, the project aligns with the goals of R15 proposals, which include supporting meritorious research, involving students in research activities, and strengthening the research environment of our institution. The project that we propose will expose our students to relevant biomedical research and support biomedical interdisciplinary research initiatives at Boise State University.
