Gut micro biota in patients with multiple sclerosis

描述(申请人提供)：多发性硬化症是一种自身免疫性疾病，被认为是由效应T细胞(包括Th1/Th17 T细胞)和调节性T细胞之间的失调引起的。虽然流行病学研究表明饮食、季节变化、感染和遗传因素在多发性硬化症发病、复发和进展中的作用，但与多发性硬化症相关的因素知之甚少。我们假设MS可能与肠道微生物组有关，因为现在人们认识到肠道微生物组可能在形成免疫系统以及各种效应器和调节性T细胞群之间的平衡方面发挥关键作用。人体内近80%的T淋巴细胞被分隔成肠道相关淋巴组织(GalT。人们越来越认识到，肠道可能对系统免疫系统产生重大影响。虽然到目前为止，肠道微生物群之间的界面还没有被广泛研究，但肠道微生物群和自身免疫性疾病之间的关系已经被发现。大多数研究都是在炎症性肠病中进行的，尽管肠道微生物区系的影响并不局限于局部自身免疫过程。类风湿关节炎患者的粪便微生物区系与健康对照组不同。关于微生物组和MS的研究一直很少。日本研究人员认为，在日本人群中，幽门螺杆菌是预防MS的一个潜在保护因素，据报道，在MS的EAE小鼠模型中，双歧杆菌减少了；在MS的EAE小鼠模型中，益生菌的应用减少了近交系SJL和C57BL/6小鼠中使用抗生素的疾病活动性和微生物群的枯竭，从而损害了EAE的发育；这种保护与促炎细胞因子的减少有关，可能是通过改变肠道共生性而诱导外周耐受的作用。他们还报告了口服肠道成分对动物EAE的积极影响。我们相信对多发性硬化症肠道微生物群的调查是及时的，并已与布罗德基金会建立了合作关系，该基金会有一个与人类微生物组项目相关的主要计划。我们将针对以下具体目标：1.复发缓解期MS患者的肠道微生物组与健康对照组相比有差异吗？2.继发性进展性MS患者的肠道微生物组与健康对照组和复发缓解期MS患者相比是否有差异？3.MS患者血液中的抗原芯片检测的免疫信号和其他免疫指标(氧类固醇、骨桥蛋白、热休克蛋白)与肠道微生物组之间是否存在联系？综上所述，我们认为对多发性硬化症肠道微生物群的研究符合R21机制，因为它是探索性的和新颖的，并寻求朝着新的方向和应用开创性地发展。它首次应用了一项新开发的重要技术，以获得对一种潜在的自身免疫性疾病的基本见解，其潜在的发病机制尚不清楚。

DESCRIPTION (provided by applicant): Multiple sclerosis is an autoimmune disease thought to be caused by a dysregulation between effector T cells, including Th1/Th17 T cells, and regulatory T cells. The factors associated with MS including disease onset, relapses and progression are poorly understood, although epidemiological studies have suggested a role for diet, seasonal variation, infection, and genetic factors. We hypothesize that MS may be linked to the gut microbiome, as it is now becoming recognized that the gut microbiome may play a key role in shaping the immune repertoire and the balance between various effector and regulatory T cell populations. Nearly 80% of all T lymphocytes of the body are compartmentalized to the gut associated lymphoid tissues (GALT. It is becoming increasingly recognized that the gut may have a major influence on the systemic immune system. Although to date, the interface between the gut microbiome has not been extensively studied, relationships between the gut microbiome and autoimmune illness have been found. Most studies have been carried out in inflammatory bowel disease, though the effect of gut microbiota is not restricted to local autoimmune processes. The fecal microbiota in patients with rheumatoid arthritis differs from healthy controls. Studies on the microbiome and MS have been few. Japanese investigators suggest that H. pylori is a potential protective factor against MS in Japanese populations and Bifidobacteria have been reported decreased in MS. In the EAE mouse model of MS, probiotic administration of lactobacillus reduces disease activity and depletion of microflora using antibiotics in inbred SJL and C57BL/6 mice impaired the development of EAE, and that this protection was associated with a reduction of proinflammatory cytokines, potentially suggesting a role for induction of peripheral tolerance through alterations of gut commensals. They also reported positive effects on EAE in animals treated with gut components orally. We believe an investigation of the gut microbiome in MS is timely, and have established collaboration with the Broad Foundation which has a major program related to the Human Microbiome Project. We will address the following Specific Aims: 1. Do patients with relapsing remitting MS have differences in the gut microbiome compared to healthy controls? 2. Do patients with secondary progressive MS have differences in the gut microbiome compared to healthy controls and to relapsing-remitting MS? 3. Is there a link between immune signatures as measured by antigen arrays and other immune measures in the blood of MS patients (oxysterols, osteopontin, heat shock proteins) and the gut microbiome? In summary, we believe that the investigation of the gut microbiome in MS fits with the R21 mechanism as it is exploratory and novel and seeks to break ground towards new directions and applications. It applies for the first time an important newly developing technology to gain potential basic insights into an autoimmune disease whose underlying pathogenesis remains unknown.