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

患多发性硬化症(MS)的女性比男性多。女性和男性的比例是2：1，一些研究表明 将其扩大到3：1。在实验疾病模型中观察到类似的模式，尽管性别依赖 易感性受制于遗传背景。另一个影响疾病的生物变量 建立和发展是肠道微生物区系。我们实验室和其他实验室的研究表明， 肠道微生物区系减少或完全缺失可降低实验性肠炎的严重程度和进展 自身免疫性脑脊髓炎(EAE)。反过来，疾病的发作改变了肠道微生物区系的组成和 增加肠道通透性，表明肠道-微生物区系-脑轴是双向作用的。虽然大多数人 微生物区系研究比较了粪便微生物组成、疾病对微生物区系组成的影响 粘膜层的位置尚不清楚。探索这一知识鸿沟意义重大，因为肠道微生物 调节肠道粘液、细胞外基质(ECM)和紧密连接的产生和完整性 在上皮细胞中表达。由于已经在EAE小鼠中描述了性别相关的微生物区系差异，我们 假设女性和男性的疾病易感性与 与肠粘膜ECM相关的微生物区系，导致微生物移位增加到 固有层，局部和全身炎症，随后导致增加 神经炎症和疾病严重程度。我们建议评估性别依赖的EAE的影响 肠腔和细胞外基质的微生物区系组成、肠道通透性、全身和中枢神经系统的敏感性 炎症，以及微生物区系干预对肠道ECM和疾病进展的影响。我们会 使用两种具有不同性别相关易感性的不同EAE模型：仅含女性的SJL/J EAE模型 对疾病敏感的小鼠和雌性和雄性都易患EAE的C57BL/6J模型。 我们最近表明，口服类异戊二烯法尼醇，一种微生物生物膜调节剂，保护 EAE小鼠对抗这种疾病。我们现在假设，法尼醇治疗调节生物膜的形成。 在微生物区系-ECM中，导致性别依赖型EAE易感小鼠的整体肠道完整性增加。 我们提出了三个特定的目标来确定性别依赖的EAE易感小鼠是否患有这种疾病 促进促进局部、全身和中枢神经系统炎症的微生物区系-ECM架构，以及 口服法尼醇可逆转疾病对肠道上皮微生物区系和完整性的影响 和粘膜。该项目将扩大我们对异戊二烯类化合物保护作用的理解。 直接靶向MS并研究以细胞外糖蛋白为基础的肠黏膜层的神经炎症 矩阵。

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.