A KETOGENIC DIET PROMOTES BLOOD-SPINAL CORD BARRIER RESEALING TO DECREASE SPINAL CORD IMMUNE CELL INFILTRATION IN A PRECLINICAL MODEL OF MULTIPLE SCLEROSIS

ABSTRACT We previously reported that a medium chain triglyceride and W-3 fatty acid rich ketogenic diet (KD) restores vision and motor functions to mice undergoing experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis (MS). The studies reported here use immune cell profiling to identify the mechanisms underlying this efficacy. We show here that the diet dramatically reduces the infiltration of CD45HI immune cells into the spinal cords of EAE mice when fed for 2 weeks beginning at symptom onset. This reduction was preceded by an increase of myeloid cells in the blood, primarily neutrophils and monocytes. A mechanism underlying this altered distribution was accelerated resealing of the blood-SC barrier (BSCB), which was initially permeabilized at disease onset but was rapidly resealed by the KD in both sexes. This resealing accompanied 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 secreted IL-1β, the primary cytokine associated with compromising the integrity of CNS-blood barriers. As myeloid cells mediate BSCB disruption, we found that although the diet reduced neutrophil SC infiltration by 90%, it preserved subpopulations of neutrophils expressing surface markers associated with inflammation resolution. In parallel, the KD reduced the number of monocyte/macrophages in the SC while preserving non-classical mono/macs associated with healing and tissue repair. Collectively, this work advances a novel mechanistic understanding 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 healing of disrupted blood-CNS barriers and resolving inflammation in multiple neurodegenerative diseases. Competing Interest Statement The authors have declared no competing interest. Footnotes The revised manuscript has been restructured and rewritten.