Interrogating the intersection between diet and ocular autoimmunity - 5-8% of the US population suffers from at least one autoimmune disease. An upward trajectory has occurred in the last few decades, implicating diet, lifestyle, environment, and improved diagnostics. The contributions of diet to this increased incidence have been attributed to the excessive consumption of ultra- processed foods that drive systemic inflammation. Just as poor dietary habits can compromise health, diseases can potentially be treated or prevented by diets that promote and restore metabolic homeostasis. Consistent with this notion, we have demonstrated that a well-formulated ketogenic diet (KD), containing medium chain triglycerides as the primary source of fat, can mitigate the visual and motor deficits in a mouse model of autoimmunity called MOG-EAE. This model reconstitutes many of the signature ocular and motor pathologies experienced by patients with Multiple Sclerosis (MS) and Neuromyelitis Optica. The goals of this application are: (1) to identify the immuno-modulatory mechanisms by which a well-formulated KD preserves metabolic homeostasis, gut health, and immune tolerance, (2) to determine if a KD can serve as an adjuvant to enhance the vision-sparing capacity of existing MS treatments and (3) to determine if the KD can repair damaged nerves by promoting remyelination. Our leading hypothesis is that a well-formulated KD promotes immune tolerance and neuroprotection by creating a systemic anti-inflammatory milieu. Specific Aim 1 will identify the mechanisms linking gut integrity and plasma fatty acids to optic neuritis, a painful and often blinding inflammation of the optic nerve experienced by MS patients. Specific Aim 2 will determine if the KD can enhance the vision-sparing capacity of several current MS treatments. Specific Aim 3 will identify novel immunological mechanisms that mediate the efficacy of the KD during autoimmune challenge. This work combines psychophysical measurements of vision, a novel reporter mouse, gut permeability assays, high resolution lipidomics, adoptive transfer assays, and blood analyses for markers of inflammation and metabolic/cardiovascular status. This work is distinguished from previous studies by comparing the anatomic-specific effects of the KD at each of the primary sites of MS lesions (optic nerve, spinal cord, and brain). These studies are designed to overcome the serious adverse effects associated with current MS treatments by empowering patients with a readily-implementable dietary strategy to prevent or reduce flare ups of optic neuritis and other debilitating sequelae. Additionally, these findings will provide a framework to facilitate interpreting outcomes from the numerous clinical trials currently testing the KD across a range of diseases.
