Microbiome and intestinal barrier in ALS therapy

ALS 治疗中的微生物组和肠道屏障

• 批准号: 9884176
• 负责人: Jun Sun
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884176
• 关键词: ALS patients; Address; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Bacteria; Bacteroidetes; Biochemical; Biological; Brain; Butyrates; Caring; Central Nervous System Diseases; Cessation of life; Communication; Complex; Diagnosis; Disease; Disease Progression; Engineering; Enteric Nervous System; Environment; Epithelial Attachment; Evaluation; Experimental Animal Model; Experimental Models; FDA approved; Firmicutes; Functional disorder; Future; General Population; Goals; Health; Histopathology; Homeostasis; Human; Immune system; Intestinal permeability; Intestines; Leaky Gut; Link; Longevity; Military Personnel; Modeling; Molecular; Motor Neurons; Mus; Muscular Atrophy; Neuraxis; Neuromuscular Diseases; Neurons; Neurosecretory Systems; Onset of illness; Parkinson Disease; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Physiological; Play; Population; Prevention; Probiotics; Production; Protocols documentation; Publications; Quality of life; Research; Riluzole; Risk; Risk Assessment; Role; Services; Spinal Cord; Structure; System; Therapeutic; Therapeutic Effect; Time; Transgenic Animals; Veterans; War; Wild Type Mouse; base; clinically relevant; combat; design; dysbiosis; fecal transplantation; feeding; gastrointestinal; gut microbiome; host-microbe interactions; improved; inflammatory disease of the intestine; innovation; intestinal barrier; intestinal homeostasis; microbial; microbiome; motor neuron function; mouse model; nervous system disorder; neuromuscular; neuromuscular function; neuroprotection; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oral microbiome; overexpression; patient population; peace; preservation; protein TDP-43; stem cells; therapeutic target; tool

The goal of this application is to investigate the important role of intestinal microbial homeostasis in ALS, meanwhile investigating a novel approach that can potentially treat ALS by restoring host-microbe relationships and combining with FDA approved drugs. Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by progressive death of motor neurons and muscle atrophy. Most patients die within 5 years after the disease onset. Currently, treatment with Riluzole and Radicava only extends patient life span for a few months. Therefore, there are significant needs to develop novel treatments for ALS and improving the life quality of ALS patients. Emerging evidence has demonstrated that microbiome and intestinal homeostasis plays essential roles in neurological diseases, such as Alzheimer's disease and Parkinson's disease. However, little is known about the intestinal microbiome in patients with ALS. Our lab is the first to discover the link between intestinal homeostasis and the disease progression in an ALS mouse model G93A. Our study in human ALS further reveals the dysbiosis and intestinal inflammation. ALS mice had damaged intestinal structure and increased intestinal permeability (leaky gut). Remarkably, restoring the intestinal homeostasis by feeding the ALS model mice with a bacterial product butyrate significantly delayed the disease onset and prolonged the life span of ALS mice. We hypothesize that targeting gut microbiome and combining with FDA approved drugs to improve the intestinal barrier function and restore microbiome, thus slowing disease progression of ALS. The studies are designed to rigorously examine the hypotheses and address two main objectives. Aim 1 is to determine the mechanisms that contribute to dysbiosis and barrier dysfunction in ALS. We will define the mechanism for abnormal epithelial junction structure and dysbiosis (e.g. loss of butyrate- producing bacteria) in ALS mice. We will investigate roles of butyrate and butyrate-producing bacteria, using novel molecular tools, enteroid cultures, and transgenic animal models (SOD1G93 mice and a novel gut-specific overexpression of SOD1G93 model). We will determine mechanisms underlying the benefits of bacterial product butyrate on intestinal permeability and neuroprotection. Aim 2 is to conduct proof-of-principle studies with restoring gut microbiome and intestinal barrier for preserving neuromuscular function in ALS. ALS mice at different stages of ALS will be treated with beneficial bacteria (probiotics that promote butyrate production) or combining with FDA drugs (Riluzole or Radicava). ALS mice will have fecal microbiota transplantation (FMT) using health wild-type mice as donors. Physiological and molecular biological assessments of intestinal integrity, microbiome, and neuromuscular performance will be used to evaluate the therapeutic effects. Histopathology and biochemical evaluations will be used to determine changes at the cellular level of intestinal and neuromuscular function at different stages of ALS. We will optimize the efficacy of restoring intestinal microbiome combining with FDA drugs in slowing ALS progression using different ALS mouse models (SOD1G93A and TDP43). Veterans are twice as likely to be diagnosed with ALS as the general population. Military veterans, regardless of the branch of service, the era in which they served, or whether they served during a time of peace or war, are at a greater risk of dying from ALS than if they had not served in the military. Our study is significant because of the health burden of ALS in VA population and the novel role of the microbiome on neuromuscular function in health and disease, especially in Veterans' care. Innovation of this project lies in its: (a) therapeutic potential for ALS, (b) conceptual frame-work to discover early changes and dysbiosis and the gut barrier effects before onset of ALS, and (c) state-of–the-art experimental models that allow us to understand novel mechanisms underlying the beneficial effect of probiotics and/or bacterial products that improve the motor neuron function. It has significant translational implications for developing new therapeutic strategies for combating this devastating disease and improving the health of veterans.

该应用的目的是研究肠道微生物稳态在ALS中的重要作用， 在研究一种可以通过恢复宿主微子关系来治疗ALS的新型方法时的平均值 并与FDA批准的药物结合使用。肌萎缩性外侧硬化症（ALS）是致命的神经肌肉疾病 以运动神经元和肌肉萎缩的进行性死亡为特征。大多数患者在5年内死亡 疾病发作后。目前，利鲁唑和Radicava的治疗仅延长患者的寿命 月份。因此，为ALS开发新颖的治疗方法并改善了生活，有很大的需求 ALS患者的质量。新兴证据表明，微生物组和肠内稳态 在神经疾病中起着重要作用，例如阿尔茨海默氏病和帕金森氏病。然而， 关于ALS患者的肠道微生物组知之甚少。我们的实验室是第一个发现链接的实验室 在ALS小鼠Model G93A中的肠内稳态和疾病进展之间。我们的研究 人类ALS进一步揭示了营养不良和肠炎。 ALS小鼠肠损坏了 结构和肠渗透性增加（肠道渗漏）。值得注意的是，恢复了肠内稳态 用细菌产物给ALS模型小鼠喂食丁酸酯显着延迟了疾病的发作和 延长了ALS小鼠的寿命。我们假设靶向肠道微生物组并与FDA结合 批准的药物以改善肠道屏障功能并恢复微生物组，从而减慢疾病 ALS的进展。这些研究旨在严格检查假设并解决两个主要 目标。目的1是确定导致ALS失调和障碍功能障碍的机制。 我们将定义异常上皮结构和营养不良的机制（例如，丁酸酯的丧失 在ALS小鼠中产生细菌）。我们将使用使用丁酸酯和丁酸酯的细菌的作用 新颖的分子工具，肠培养和转基因动物模型（SOD1G93小鼠和一种新型肠道特异性 SOD1G93模型的过表达）。我们将确定细菌产物益处的基础机制 丁酸肠渗透性和神经保护作用。目标2是通过 恢复肠道微生物组和肠壁，以保留ALS中的神经肌肉功能。 ALS小鼠在 ALS的不同阶段将用有益细菌（促进丁酸酯产生的益生菌）或 与FDA药物（Riluzole或Radicava）结合。 ALS小鼠将具有粪便菌群移植（FMT） 使用健康野生型小鼠作为捐助者。肠道生理和分子生物学评估 完整性，微生物组和神经肌肉性能将用于评估治疗作用。 组织病理学和生化评估将用于确定肠细胞水平的变化 和神经肌肉功能在ALS的不同阶段。我们将优化恢复肠的效率 微生物组与FDA药物结合使用不同的ALS小鼠模型减慢ALS进展 （SOD1G93A和TDP43）。退伍军人被诊断为ALS的可能性是普通人群的两倍。 退伍军人，无论服役分支如何 在和平或战争的时期，与没有在军队中服役相比，ALS死亡的风险更大。 我们的研究意义重大，因为VA人口中ALS的健康伯恩（ALS）的健康和 关于健康和疾病的神经肌肉功能的微生物组，尤其是在退伍军人护理中。创新 项目在于：（a）ALS的治疗潜力，（b）概念框架 - 发现早期变化 ALS发作之前的营养不良和肠道障碍作用，以及（c）最新的实验模型 这使我们能够理解益生菌和/或细菌的有益作用的基础的新型机制 改善运动神经元功能的产品。它对开发新的具有重大的翻译意义 打击这种毁灭性疾病并改善退伍军人健康的治疗策略。