Effect of Gut Microbiome Dysbiosis in the Pathobiology of Multiple Sclerosis

肠道微生物群失调对多发性硬化症病理学的影响

• 批准号: 10426082
• 负责人: Ashutosh Kumar Mangalam
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426082
• 关键词: Animal Model; Anti-Inflammatory Agents; Bacteria; Biological Markers; Blood Circulation; Cities; Clinic; Clinical; Clinical Medicine; Clinical Research; DNA; Data; Development; Diet; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; Extravasation; Feces; Fiber; Generations; Genes; Goals; Homeostasis; Immune; Immune response; Indigenous; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intestinal permeability; Iowa; Knowledge; Lead; Leaky Gut; Link; Mediating; Mediator of activation protein; Medical; Metabolism; Modeling; Mucous Membrane; Multiple Sclerosis; Outcome; Pathogenesis; Pathway interactions; Patient Recruitments; Patients; Phase; Phytoestrogens; Predisposition; Production; Prognostic Marker; Reporting; Research; Role; Sampling; Serum; Side; Surface; Syndrome; Testing; Therapeutic; Translating; Urine; Veterans; bench to bedside; cohort; commensal bacteria; daidzein; diagnostic biomarker; dietary; dysbiosis; equol; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; in vivo; inflammatory milieu; intestinal epithelium; mouse model; multiple sclerosis patient; novel; novel diagnostics; pathobiont; potential biomarker; stool sample; symbiont; therapeutic target; translational potential

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.

尽管肠道微生物群与多发性硬化症（MS）之间的联系越来越多， 虽然我们认识到，肠道细菌及其代谢产物调节MS疾病的机制很差， 明白我们和其他人已经证明了MS患者肠道微生物群扰动之间的联系。肠道 生态失调是健康肠道微生物群的一种质的改变，其特征在于 炎症促进细菌（致病菌）和有益细菌（共生菌）的消耗。因为MS是一个 炎症性疾病，致病菌的增加和/或共生菌的减少可能会促进促增殖， 炎症环境影响疾病的发展和进展。病原体已知 通过增加肠道渗透性促进促炎环境，从而导致肠道渗漏 通过允许细菌产物（LPS和其他炎症介质）渗漏到全身而引起的综合征 流通肠道通透性相关炎症介质（GPLIMS）的全身水平增加可诱导 通过经典和非经典途径的炎症，包括抑制特化促消退 介质（SPM），一组自然产生的分子在我们的身体内产生，以抑制炎症。它 重要是强调肠道微生物群有助于从饮食中产生SPM。比例的变化 GPLIM和SPM可调节疾病进程和临床结局。此外， 负责维持免疫稳态的共生体也可以促进促炎环境 通过使促炎免疫应答和抗炎免疫应答之间的平衡向促炎应答倾斜。 我们先前报道过，多种肠道细菌与膳食植物雌激素代谢相关， 雌马酚在MS患者中耗尽，从而凸显了植物雌激素代谢在介导MS中的关键作用 肠道微生物组的有益作用。虽然，肠漏和雌马酚之间的负相关性已经被证实， 尽管在一些炎性疾病中有报道，但其在MS的病理生物学中的作用尚不清楚。 我们对MS肠道生态失调机制的理解存在知识缺口 患者为此，我们的建议是重要的和关键的，以填补这一空白，确定相对 致病菌（漏肠综合征）和共生菌（植物雌激素代谢）在MS中的贡献。 长期目标是确定肠道细菌及其代谢物影响保护作用的机制 我们假设肠道生态失调通过以下途径促进MS： 除了消耗有益的雌马酚外，还富集导致肠漏综合征的致病菌 产生肠道细菌。因此，我们建议确定漏肠和雌马酚产生的意义 肠道细菌在MS发病中的作用有以下三个方面。在第一个目标中，我们将测试假设 MS患者的肠道生态失调导致肠漏和促炎性（GPLIM）增加， 抗炎介质，特别是SPM。第二个目标将使我们能够测试的假设， 与HC相比，初治MS患者的雌马酚和产生雌马酚的细菌水平降低。在过去 目的是，我们将检验这样一个假设，即接受疾病修饰疗法（DMT）的MS患者将恢复 和雌马酚/雌马酚合成细菌。在这项研究结束时，我们希望确定潜在的 肠道生态失调影响MS患者临床结局的机制，特别是 GPLIM、SPM和雌马酚产生菌。我们希望找到潜在的治疗生物分子，例如 作为SPMs和肠道细菌，可以抑制MS小鼠模型中的疾病。 有可能发现一组可用于临床医学的生物分子， 潜在的生物标志物。因此，我们的研究数据将使我们能够将一个实验室发现带到床边， MS患者