Multiple sclerosis (MS) is a metabolically demanding disease involving immune-mediated destruction of myelin in the central nervous system. We previously demonstrated a significant alteration in disease course in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS due to diet. Based on the established crosstalk between metabolism and gut microbiota, we took an unbiased sampling of microbiota, in the stool, and metabolites, in the serum and stool, from mice (Mus musculus) on the two different diets, the Teklad global soy protein-free extruded rodent diet (irradiated diet) and the Teklad sterilisable rodent diet (autoclaved diet). Within the microbiota, the genus Lactobacillus was found to be inversely correlated with EAE severity. Therapeutic treatment with Lactobacillus paracasei resulted in a significant reduction in the incidence of disease, clinical scores and the amount of weight loss in EAE mice. Within the metabolites, we identified shifts in glycolysis and the tricarboxylic acid cycle that may explain the differences in disease severity between the different diets in EAE. This work begins to elucidate the relationship between diet, microbiota and metabolism in the EAE preclinical model of MS and identifies targets for further study with the goal to more specifically probe the complex metabolic interaction at play in EAE that may have translational relevance to MS patients.

Objective Many things can impact the reproducibility of results from laboratory to laboratory. For example food from various sources can vary markedly in composition. We examined the effects of two different food sources, the Teklad Global Soy Protein-Free Extruded Rodent Diet (irradiated diet) and the Teklad Sterilizable Rodent Diet (autoclaved diet), on central nervous system disease. Research Methods & Procedures Three preclinical models for human disease: two different experimental autoimmune encephalomyelitis (EAE) models (multiple sclerosis) and the Theiler’s murine encephalomyelitis virus (TMEV)-induced seizure model (epilepsy), were examined for the effects of two different food sources on disease. Results We found that mice fed the irradiated diet had more severe clinical disease and enhanced seizures compared to animals provided the autoclaved diet in both EAE models examined and in the TMEV-induced seizure model, respectively. Conslusions Therefore, just altering the source of food (lab chow) can have marked effects on disease severity and outcome.

Viral encephalitis markedly increases the risk for the development of epilepsy. The Theiler’s murine encephalomyelitis virus (TMEV)-induced model of seizures/epilepsy is a murine model of both viral-induced seizures/epilepsy and human Temporal Lobe Epilepsy. The inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α have been shown to play a role in seizure development in the TMEV-induced model of seizures/epilepsy, and infiltrating macrophages along with microglia have been shown to be major producers of these cytokines. The metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor that has been shown to reduce IL-6 and TNF-α and to provide neuroprotection in other disease models. Therefore, we hypothesized that stimulation of mGluR5 would not only reduce seizures but attenuate IL-6 and TNF-α production in microglia and macrophages in the TMEV model. We found that pharmacological stimulation of mGluR5 with the selective positive allosteric modulator VU0360172 not only reduced acute seizure outcomes, but also reduced the percent of microglia and macrophages producing TNF-α 3 days post infection. Furthermore, treatment with VU0360172 did not alter the level of viral antigen, compared to controls, showing that this treatment does not compromise viral clearance. These results establish that mGluR5 may represent a therapeutic target in the TMEV-induced model of seizures/epilepsy.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Seizures, which are often associated with viral encephalitis, occur in response to imbalances between excitatory and inhibitory inputs within the brain. Patients with viral encephalitis are 16 times more likely to develop epilepsy. It is estimated that around 65 million people worldwide suffer from epilepsy. Although treatments to prevent seizures are available, 30% of the patients do not respond to the medication. In order to develop new immunomodulatory treatments that could lead to an eventual cure for seizures/epilepsy, a better understanding of the seizure development mechanism is required. We have developed an experimental model of virus-induced seizures/epilepsy. In our model, C57BL/6J mice are infected intra-cranially with the Daniels strain (DAV) of Theiler’s murine encephalomyelitis virus. Between 3 and 10 days post infection (d.p.i.), around 50% of the infected mice will develop spontaneous acute seizures and approximately 50% of these mice develop epilepsy. Because seizures begin to develop at 3 d.p.i we believe it happens as a consequence of the activation of the innate immune response. We found that seizures are correlated with an increase in myeloid cells infiltrating into the brain. Also, the pro-inflammatory cytokines IL-6 and TNF alpha were elevated at 3 d.p.i. IL-6 knockout mice infected with DAV experienced significantly fewer seizures. Because infiltrating macrophages are the main producers of IL-6, we depleted macrophages from mice and we infected them with DAV. We did not observed seizures in animals depleted of macrophages, suggesting macrophages are playing a central role in the development of seizures after viral infection.