Gut Manifestations in an Experimental Model of Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is an immune-mediated demyelinating and neurodegenerative disease of the central nervous system (CNS). Neuroinflammatory processes in MS are believed to lead to damage and leakage in the blood-brain barrier that protects the CNS and regulates the trafficking of soluble mediators and leukocytes. MS is thought to be triggered in genetically susceptible individuals following exposure to environmental factors, which may be responsible for loss of tolerance and activation of the myelin-reactive T cells. Based on findings in animal models the influence of gut microbiota on disease development has been suggested. In this thesis we aimed to investigate if intestinal barrier and immune function are affected during the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and whether probiotic bacteria could have an impact on the disease. EAE was induced in C57BL/6 mice either by active immunization using myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, or by adoptive transfer of MOG35-55 reactive T cells. A major part of the work focuses on how, in addition to CNS, the bowel is influenced during the development of EAE. The results show increased intestinal permeability and inflammation in the intestinal mucosa, concomitant with activation of the acquired (Th1 and Th17) as well as innate immunity. An increased expression of inflammatory cytokines in antigen presenting cells and also increased activated neutrophils was noted. As a consequence of this activation increased levels of the inflammatory molecule calprotectin was also shown in EAE animals. Interestingly, we found an increased number of mucus-producing goblet cells throughout the intestinal tract. Another part of the thesis is on oral treatment of EAE diseased mice with probiotic bacteria. A screening experiment revealed immunostimulatory properties of some probiotics and a preventive effect on the development of disease. This part focuses on immunoregulatory abnormalities and a synergistic effect of different probiotic lactobacilli. It was shown that a combination of strains could suppress and reverse an ongoing inflammatory condition of diseased animals. Our analysis showed that the therapeutic effect was exerted by activated regulatory T cells in an IL-10 dependent manner. We showed an association between the intestinal mucosa and immune system during development of the disease, however, how local anti-inflammatory activities induced by probiotics can have an influence on the CNS is unclear and remains to be investigated. In addition, our findings show that disruption of intestinal homeostasis is an early and immune-mediated event, and it is proposed that this disruption will support disease progression in MS and thus represent a potential therapeutic target.