THE EFFECTS OF A MODIFIED KETOGENIC DIET ON CLINICAL, BEHAVIORAL, GENETIC, AND DEMYELINATING INFLAMMATORY IMMUNE RESPONSES IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MODEL OF MULTIPLE SCLEROSIS

(Graduate Research Thesis)

ABSTRACT

Multiple sclerosis (MS) remains one of the most elusive neurological autoimmune disorders for  which there is no established cause or cure. Single-target disease modifying therapies (DMTs)  aim to slow disease progression via immunosuppressive and/or immunomodulatory  mechanisms but are associated with significant side effects and not effective for many MS  patients. In contrast, systems-based dietary interventions are noninvasive, have fewer adverse  effects, and may have as profound an impact on MS pathophysiology as DMTs. This hypothesis  was tested in a previous pilot study by the author using the experimental autoimmune  encephalomyelitis (EAE) model of MS following prophylactic dietary treatments where  C57BL/6J mice were fed either a rodent standard diet (SD) or a modified ketogenic diet (mKD)  rich in medium-chain triglycerides and omega-3-6-9 fatty acids. The present study was designed  to confirm and expand on the pilot study by including a larger sample size with greater  statistical power and two additional cohorts of mice, including sham controls and a group of  mice fed the mKD with added sucrose (mKS). The mKS group tested the hypothesis that  disaccharides combined with the mKD promote inflammation, demyelination, and reduce  efficacy of the mKD. Results for mKD indicate delayed onset of EAE, reduced preclinical  sensorimotor deficits and clinical disability scores, and induced EAE remission in every animal by end of study (EOS). However, treatment with mKS produced similar results as mice fed the  SD, who exhibited increased preclinical sensorimotor asymmetry, early EAE onset, and  sustained elevated clinical scores. Data analyzing mKS response to EAE indicates that sucrose  supplementation negated the therapeutic benefits of mKD treatment, but two distinct  response-type sub-populations were observed: severe (s) having similar symptoms to SD mice,  and mild (m) less impacted than SD mice. Although mKS response to EAE indicates highly  significant overall reduction of mKD benefits, further analyses are ongoing. In-progress  histological work is evaluating neuroimmune mechanisms that contributed to these behavioral  and clinical outcomes. 

NOTE: Jenny owns the copyright on this research. Her thesis was published but is under embargo because she is pursuing patent and intellectual property rights for aspects of her research and the treatment she developed… be on the lookout because she will release her work to the public soon!

A MODIFIED KETOGENIC DIET ATTENUATES MOTOR DISABILITY AND COGNITIVE IMPAIRMENT IN A MURINE MODEL OF MULTIPLE SCLEROSIS (MS)

(Undergraduate Research Thesis)

ABSTRACT

Multiple Sclerosis (MS) is a progressive demyelinating disease of the Central Nervous System (CNS)  characterized by neuro-inflammation resulting in symptoms ranging from optic neuritis to weakness,  vertigo, numbness, tremors, paralysis, and cognitive dysfunction. Treatment protocols for MS typically  consist of pharmaceutical intervention even though diet, particularly one rich in omega-3 fatty acids,  and exercise are considered to be non-invasive approaches to stimulating neuronal repair. In this study,  mice fed a Modified Ketogenic Diet (mKD) high in fats from medium chain triglycerides and omega-3-6-9  fatty acids but restricted for carbohydrates exhibited significantly delayed onset, progression, and  severity of Experimental Autoimmune Encephalomyelitis (EAE), a murine model of MS. Control animals  induced to develop EAE but fed a Standard Rodent Diet (SD), unlike those fed the mKD, exhibited  substantial motor disability as well as spatial learning and memory deficits in Morris Water Maze and Y Maze cognitive and behavioral analyses. Molecular analyses demonstrated that Peptidylarginine  deiminase 2 (Padi2) gene expression was significantly downregulated in the brain and spinal cord of  mice fed the mKD relative to controls. Padi2 is overexpressed in the brain and CNS of MS patients and is  known to induce hypercitrullination of arginine residues in myelin basic protein, leading to  autoimmunity and demyelination. Further, bisulfite conversion analysis revealed hypermethylation of  the Padi2 promoter region for animals with EAE fed the mKD, while animals with EAE on the SD showed patterns of hypomethylation, suggesting an influence on epigenetic controls. These data strongly  suggest that a diet high in omega-3-6-9 fatty acids, medium chain triglycerides, and plant oils, but low in  carbohydrates, can exert protective effects against autoimmune-based neuro-inflammatory events  consistent with human MS.