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Th 1/Th 17 T细胞）和调节性T细胞之间的失调引起的。与MS相关的因素，包括疾病发作，复发和进展知之甚少，尽管流行病学研究表明饮食，季节性变化，感染和遗传因素的作用。我们假设MS可能与肠道微生物组有关，因为现在人们逐渐认识到肠道微生物组可能在塑造免疫库以及各种效应和调节T细胞群之间的平衡方面发挥关键作用。人体所有T淋巴细胞的近80%被区室化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产生重大影响。尽管迄今为止，肠道微生物组之间的界面尚未得到广泛研究，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，尽管肠道微生物组的影响并不局限于局部自身免疫过程。类风湿性关节炎患者的粪便微生物群与健康对照组不同。关于微生物组和MS的研究很少。日本研究人员认为，H.幽门螺杆菌是日本人群中针对MS的潜在保护因子，并且已经报道了MS中双歧杆菌的减少。在MS的EAE小鼠模型中，益生菌的施用减少了疾病活动性，并且在近交系SJL和C57 BL/6小鼠中使用抗生素消耗微生物群落损害了EAE的发展，并且这种保护与促炎细胞因子的减少有关，潜在地提示通过改变肠粘膜诱导外周耐受的作用。他们还报告了口服肠道成分治疗的动物对EAE的积极影响。我们相信对MS中肠道微生物组的调查是及时的，并与Broad Foundation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项目。我们将致力于以下具体目标：1。与健康对照组相比，复发缓解型MS患者的肠道微生物组是否存在差异？2.与健康对照组和复发缓解型MS相比，继发性进展型MS患者的肠道微生物组是否存在差异？3. MS患者血液中的抗原阵列和其他免疫指标（氧化固醇、骨桥蛋白、热休克蛋白）测量的免疫特征与肠道微生物组之间是否存在联系？总之，我们认为，对MS肠道微生物组的研究符合R21机制，因为它是探索性的和新颖的，并寻求开拓新的方向和应用。它首次应用了一项重要的新开发技术，以获得对自身免疫性疾病的潜在基本见解，其潜在的发病机制仍然未知。 公共卫生相关性：多发性硬化症（MS）是一种影响年轻人的神经系统疾病。身体的免疫系统在MS中起着关键作用，现在人们认识到肠道中大量的细菌会影响免疫系统。我们将研究多发性硬化症患者的肠道植物群，以确定多发性硬化症患者的肠道植物群是否不同，是否以某种方式与疾病有关。

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. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a disease of the nervous system that affects young adults. The body's immune system plays a key role in MS and it is now recognized that the large number of bacteria in the gut can affect the immune system. We will be studying the gut flora in MS patients to determine if the gut flora is different in MS patients and is in some way linked to the disease.