Effects of sex-dependent susceptibility to CNS inflammatory demyelination on the intestinal mucosa

More women suffer multiple sclerosis (MS) than men. The female-to-male ratio is 2:1, with some studies broadening it to 3:1. A similar pattern is observed in experimental disease models, although the sex-dependent susceptibility is subjected to the genetic background. Another biological variable that affects the disease establishment and progression is the gut microbiota. Studies from our lab and others showed that the significant reduction or complete absence of gut microbiota reduces the severity and progression of experimental autoimmune encephalomyelitis (EAE). Reciprocally, disease onset alters the gut microbiota composition and increases intestinal permeability suggesting that the gut-microbiota-brain axis acts bidirectionally. While most microbiota studies compare the fecal microbial composition, the effects of disease on the microbiota composition of the mucosal layer remain unknown. Exploring this knowledge gap is significant because gut microbes modulate the production and integrity of the gut mucus, an extracellular matrix (ECM), and tight junction expression in epithelial cells. Since sex-dependent microbiota differences have been described in EAE mice, we hypothesize that disease susceptibility in females and males is directly associated with changes in the microbiota associated with the intestinal mucosal ECM, resulting in increased microbial translocation to the lamina propria, local and systemic inflammation, which subsequently leads to increased neuroinflammation and disease severity. We propose evaluating the effects of the sex-dependent EAE susceptibility in the microbiota composition of the gut lumen and ECM, intestinal permeability, systemic and CNS inflammation, and the effects of microbiota interventions in the intestinal ECM and disease progression. We will use two different EAE models with different sex-dependent susceptibility: the SJL/J EAE model with only female mice being susceptible to the disease and the C57BL/6J model with both females and males susceptible to EAE. We recently showed that the oral treatment with the isoprenoid farnesol, a microbial biofilm regulator protected EAE mice against the disease. We now hypothesize that the treatment with farnesol regulates biofilm formation in the microbiota-ECM resulting in increased overall intestinal integrity in sex-dependent EAE susceptible mice. We propose three specific aims to determine whether the disease in sex-dependent EAE susceptible mice promotes a microbiota-ECM architecture that contributes to local, systemic, and CNS inflammation and whether the oral treatment with farnesol reverses the effects of disease on microbiota and integrity of the gut epithelium and mucosa. The project would extend our understanding of the protective effects of isoprenoids against neuroinflammation by directly targeting MS and studying the gut mucosal layer, an extracellular glycoproteinbased matrix.