Gut micro biota in patients with multiple sclerosis

描述（由申请人提供）：多发性硬化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。尽管流行病学研究表明饮食、季节变化、感染和遗传因素与MS发病、复发和进展等因素有关，但对MS的相关因素了解甚少。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库以及各种效应和调节性T细胞群之间的平衡中发挥关键作用。体内近80%的T淋巴细胞被划分为肠道相关淋巴组织（GALT）。越来越多的人认识到肠道可能对全身免疫系统有重要影响。虽然到目前为止，肠道微生物组之间的界面尚未被广泛研究，但肠道微生物组与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，尽管肠道微生物群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群与健康对照不同。关于微生物组和多发性硬化症的研究很少。日本研究人员认为，幽门螺杆菌是日本人群中对抗多发性硬化症的潜在保护因子，双歧杆菌在多发性硬化症EAE小鼠模型中被报道减少。在近系SJL和C57BL/6小鼠中，益生菌给予乳酸菌可降低疾病活性，而使用抗生素的微生物群消耗会损害EAE的发展，这种保护作用与促炎细胞因子的减少有关。可能提示通过改变肠道共生体诱导外周耐受性的作用。他们还报告了口服肠道成分治疗动物EAE的积极作用。我们认为对多发性硬化症的肠道微生物组进行调查是及时的，并与Broad基金会建立了合作关系，该基金会有一个与人类微生物组计划相关的重大项目。具体目标如下：1。与健康对照相比，复发缓解型多发性硬化症患者的肠道微生物群有差异吗？2. 继发性进展性多发性硬化症患者的肠道微生物组与健康对照组和复发缓解型多发性硬化症患者相比有差异吗？3. 抗原阵列测量的免疫特征和MS患者血液中的其他免疫测量（氧甾醇、骨桥蛋白、热休克蛋白）与肠道微生物群之间是否存在联系？综上所述，我们认为对MS肠道微生物组的研究符合R21机制，因为它具有探索性和新颖性，并寻求在新的方向和应用方面取得突破。它首次应用了一项重要的新开发技术，以获得潜在的基本见解，以了解潜在的自身免疫性疾病，其潜在的发病机制仍然未知。

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.