A KETOGENIC DIET ACCELERATES BLOOD-SPINAL CORD BARRIER RESEALING AND DECREASES SPINAL CORD IMMUNE CELL ACCUMULATION IN A PRECLINICAL MODEL OF MULTIPLE SCLEROSIS

ABSTRACT We previously reported that a medium chain triglyceride and ω -3 fatty acid enriched ketogenic diet (KD) restored vision and motor functions to mice undergoing experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis (MS). In the mechanistic studies reported here we show that the KD dramatically reduces the infiltration of CD45 HI immune cells into the spinal cords of EAE mice when initiated at symptom onset and fed for 2 weeks. Two mechanisms contributed to this reduced accumulation of infiltrates. First, the KD accelerated resealing of the blood-SC barrier (BSCB) in both sexes. This resealing accompanied motor score functional recovery and occurred whether KD feeding was initiated the day of symptom onset or 1 week after symptom onset. Consistent with this resealing, the KD reduced SC levels of soluble IL-1β, a primary cytokine associated with compromising the integrity of CNS-blood barriers. A second mechanism was that the KD increased the percentage of spinal cord infiltrates undergoing apoptosis. Beyond reducing the total abundances of immune cell infiltrates by these two mechanisms, the KD also preserved subpopulations of neutrophils and non-classical mono/macs expressing surface markers associated with inflammation resolution, healing, and tissue repair. Studies leveraging global knockout mouse strains showed unexpectedly that the efficacy of the KD in this interventional paradigm was independent of both the hydroxycarboxylic acid receptor 2 (HCA 2 ) and the anti-stress transcription factor, Nrf2. Collectively, this work advances novel insights by which a KD ameliorates autoimmune-mediated MS-like pathologies to promote functional recovery and more broadly, implies that this dietary strategy has potential benefit for facilitating the healing of disrupted blood-CNS barriers and resolving inflammation in multiple neurodegenerative diseases.