Effect of Gut Microbiome Dysbiosis in the Pathobiology of Multiple Sclerosis

尽管肠道微生物区系与多发性硬化症(MS)之间的关联越来越大 认识到，肠道细菌及其代谢产物调节多发性硬化症疾病的机制很差 明白了。我们和其他人已经证明了多发性硬化症患者肠道微生物区系紊乱之间的联系。肠 生态失调是健康肠道微生物区系的一种质变，其特征是 促炎细菌(致病细菌)和有益细菌(共生菌)的枯竭。由于MS是一种 炎症性疾病、致病菌的增加和/或共生菌的减少可能会促进亲 炎症环境影响疾病的发生和发展。已知的是，病原体 通过增加肠道通透性来促进促炎环境，从而导致肠道渗漏 允许细菌产物(内毒素和其他炎症介质)渗入全身的综合征 发行量。全身性肠道通透性相关炎症介质(GPLIMS)水平升高可导致 通过规范和非规范途径的炎症，包括抑制专门化的前分解 介质(SPM)，一组在我们体内产生的自然产生的分子，用来抑制炎症。它 强调肠道微生物区系有助于从饮食中产生SPM是很重要的。更改以下比例： GPLIM和SPM可调节病程和临床转归。此外，耗尽了 负责维持免疫动态平衡的共生体也可以促进促炎环境 通过使促炎和抗炎免疫反应之间的平衡向促炎反应倾斜。 我们早些时候已经报道过，多种肠道细菌与饮食中植物雌激素的代谢有关 在MS患者中，Equol被耗尽，因此突出了植物雌激素代谢在调节 肠道微生物群的有益作用。不过，Leaky Gut和Equol之间的负相关关系 据报道，在一些炎症性疾病中，其在MS的病理生物学中的作用尚不清楚。 对多发性硬化症肠道菌群失调的发病机制(S)的认识还存在一定的差距 病人。为此，我们的建议是重要的和关键的，通过确定相对 病原体(肠漏综合征)和共生菌(植物雌激素代谢)在多发性硬化症中的作用 学期目标是确定肠道细菌及其代谢产物影响保护的机制(S) 从多发性硬化症或易患多发性硬化症/发展为多发性硬化症我们假设肠道生物失调通过 除了益气活血素的消耗外，还会导致肠漏综合征的病原菌的丰富 产生肠道细菌。因此，我们建议确定肠漏和Equol生产的重要性 肠道细菌在MS的发病机制中有以下三个目的。在第一个目标中，我们将检验假设 多发性硬化症患者的肠道生物失调会导致肠漏和促炎(GPLIM)增加，并减少 抗炎调节剂，特别是SPM。第二个目标将使我们能够检验治疗的假设 与HCS相比，幼稚的多发性硬化症患者的等量和产生等量的细菌水平将减少。在最后一次 目的：我们将检验这样一种假设，即接受疾病修正疗法(DMT)的多发性硬化症患者将恢复水平 SPM和马儿/马儿合成菌。在这项研究结束时，我们预计将确定潜在的 肠道菌群失调影响多发性硬化患者临床结局的机制，特别是其意义 GPLIM、SPM和Equol产生菌。我们希望确定潜在的治疗生物分子，如 作为SPM和肠道共生菌，可以抑制MS小鼠模型中的疾病。 有可能发现一组本土的生物分子，可以作为临床医学使用 潜在的生物标志物。因此，我们研究的数据将使我们能够将长凳边的发现带到床边。 多发性硬化患者。

Despite the association between gut microbiota and multiple sclerosis (MS) being increasingly appreciated, the mechanism through which gut bacteria and their metabolites modulate disease in MS is poorly understood. We and others have shown a link between perturbations in the gut microbiota in MS patients. Gut dysbiosis, a qualitative alteration in healthy gut microbiota is characterized by an increased abundance of inflammation-promoting bacteria (pathobiont) and depletion of beneficial bacteria (symbionts). As MS is an inflammatory disease, an increase in pathobionts and/or decrease in symbionts might promote pro- inflammatory environment influencing disease development and progression. Pathobionts are known to promote pro-inflammatory environment by causing increased intestinal permeability which leads to leaky gut syndrome by allowing leakage of bacterial products (LPS and other inflammatory mediators) into the systemic circulation. Increased systemic levels of gut permeability linked inflammatory mediators (GPLIMS) can induce inflammation through canonical and non-canonical pathways including suppression of specialized pro-resolving mediators (SPMs), a set of naturally occurring molecules produced within our body to dampen inflammation. It is important to highlight that gut microbiota help in production of SPMs from diet. Alteration in the ratio of GPLIMs and SPMs could modulate the disease course and clinical outcomes. Additionally, depletion of symbionts responsible for maintaining immune homeostasis can also promote a pro-inflammatory environment by tilting balance between pro- and anti-inflammatory immune responses towards pro-inflammatory response. We have earlier reported that multiple gut bacteria associated with metabolism of dietary phytoestrogens into Equol is depleted in MS patients, thus highlighting a critical role of phytoestrogen metabolism in mediating beneficial effect of gut microbiome. Although, an inverse correlation between leaky gut and Equol had been reported in some inflammatory diseases, its role in the pathobiology of MS is unknown. There is a knowledge gap in our understanding about the mechanism(s) of gut dysbiosis in MS patients. To this end, our proposal is significant and critical to fill this void by determining the relative contributions of pathobionts (leaky gut syndrome) and symbionts (phytoestrogen metabolism) in MS. Our long- term goal is to determine mechanism(s) through which gut bacteria and their metabolites influence protection from or predisposition/progression to MS. We hypothesize that gut dysbiosis promotes MS through enrichment of pathobionts which leads to leaky gut syndrome in addition to depletion of beneficial Equol producing gut bacteria. We, therefore, propose to determine the significance of leaky gut and Equol producing gut bacteria in the pathogenesis of MS in the following three aims. In the first aim, we will test the hypothesis that gut dysbiosis in MS patients results in leaky gut and increased pro-inflammatory (GPLIMs) and decreased anti-inflammatory mediators specifically SPMs. Second aim will enable us to test the hypothesis that treatment naïve MS patients will have reduced levels of equol and equol producing bacteria compared to HCs. In the last aim, we will test the hypothesis that MS patients on disease modifying therapies (DMTs) will restore the levels of SPMs and equol/equol synthesizing bacteria. By the end of this study, we expect to identify the potential mechanism by which gut dysbiosis influences clinical outcomes in MS patients, especially the significance of GPLIMs, SPMs, and Equol producing bacteria. We expect to identify potential therapeutic biomolecules such as SPMs and gut commensal bacteria which can suppress disease in the murine model of MS. This project has the potential to discover an indigenous set of biomolecules that can be utilized in clinical medicine as potential biomarkers. Thus, data from our study will enable us to take a bench side discovery to the bedside in MS patients.