Investigating the Microbe-Specific Effects in Multiple Sclerosis and CNS Autoimmunity

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) resulting in the demyelination of neurons. The gut microbiome consists of commensal and opportunistic pathogenic bacteria, viruses and fungi and is emerging as a potent modulator of the immune system contributing either to inflammatory or regulatory responses. Patients with MS have significant differences within their gut microbiome as compared to healthy controls; however more research is needed to fully understand specific microbe contributions to CNS autoimmunity. Antibiotics are commonly used to deplete the microbiome of pathogens but more often than not, cause a complete wipeout of commensal organisms, leaving the body vulnerable to pathogenic infection. Commensal microbes are essential to promote proper gut health and homeostasis, but may be altered in MS. I hypothesize that certain microbes that are altered in MS may contribute to the disease by regulation of CNS autoimmunity. I tested my hypothesis by colonizing mice with bacteria that we have identified as altered MS, then induced experimental autoimmune encephalomyelitis (EAE) to model disease onset and progression in both the C57BL/6 and NOD mouse strains, which model the acute and progressive forms of the disease, respectively. In AIM I, I investigated whether the course of experimental autoimmune encephalomyelitis differs between animal vendors in the acute C57BL/6 (abbrev. C57) and progressive NOD/ShiLtJ (abbrev. NOD) animal models, because previous studies have shown differences in pro-inflammatory Th17 cells in mice from Jackson laboratories and Taconic Farms. I found that while mice from both animal vendors showed EAE symptoms, mice from Jackson Laboratories had worse disease in the C57 model and mice from Taconic Farms had worse disease in the NOD EAE model. To test whether microbes associated with clinical disease in MS patients contribute to CNS autoimmunity, in AIM II, I colonized C57 and NOD mice with Anaerotruncus colihominis and Clostridium bolteae, associated with worse disease, and Faecalibacterium prausnitzii and a combination of butyrate producing bacteria, associated with improved clinical parameters, then induced EAE. I found that A. colihominis had a protective effect blunting the severity of EAE in C57 and NOD models of disease. F. prausnitzii had a protective effect in the NOD animal model of disease. Finally, to identify potential mechanisms by which these bacteria may affect MS, in AIM III, I characterized peripheral and central immune responses. I found that treatment with Anaerotruncus colihominis decreased the secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory cytokines, which may contribute to lower disease burden. Treatment with Faecalibacterium prausnitzii produced limited effects on immune responses however, we found some increases in the levels of regulatory immune cells which may limit host immune responses and produce better disease outcomes. These studies are important to biologically validate correlations that we identified to be associated with differential disease outcomes in our MS patient population. This new information can allow for more targeted treatment opportunities in patients with the disease.