Interactions between the microbiome, metabolome, and immune system as underlying mechanisms of ALS pathogenesis

摘要 肌萎缩侧索硬化症(ALS)是一种以进行性运动为特征的致死性神经退行性疾病 神经元丢失。几乎没有疗效有限的治疗选择；因此，新的治疗方法至关重要。 需要的。然而，必须更好地了解疾病发病的潜在机制才能确定 疾病生物标志物和治疗靶点。肌萎缩侧索硬化症涉及多种生物系统和途径 包括肠道微生物组、代谢组和免疫系统。我们自己的研究表明，这些 外周系统不仅随着时间的推移而变化，而且与疾病的进展有关。尤其是， 肠道微生物组与临床、代谢和免疫指标有关，这表明有一个完整的 导致肌萎缩侧索硬化症的疾病途径网络。在拟议的研究中，我们将检查潜在的 这些外周通路影响肌萎缩侧索硬化症进展的机制以加强未来试验的设计 和治疗。更具体地说，我们将研究肠道变化的潜在机制 微生物组改变ALS的外周代谢产物和免疫细胞。这项方案B研究的总体目标 是使用R01资助的两项正在进行的ALS研究的现有基础设施和数据管道来确定 肌萎缩侧索硬化症微生物组与临床、代谢组学和 疾病的免疫指标。我们假设ALS受试者的微生物组成--无论是个体 细菌群落或细菌种群-将与ALS的进展相关，因为 由ALS功能评定量表修订(ALSFRS-R)(目标1)测量。此外，我们假设 特定的细菌种群或种群集群将与这两种代谢谱的变化相关联 (目标2)以及免疫指标(目标3)，代谢和免疫变化将与 改变了疾病的进程。这项研究的完成将确定微生物、代谢和免疫的集成 可作为生物标记物或治疗靶点用于未来临床试验的通路。

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Few treatment options with limited efficacy are available; therefore, new therapies are critically needed. However, the underlying mechanisms of disease pathogenesis must be better understood to identify disease biomarkers and therapeutic targets. Numerous biological systems and pathways are implicated in ALS including the gut microbiome, the metabolome, and the immune system. Our own studies show that these peripheral systems not only change over time but are associated with disease progression. In particular, the gut microbiome is linked to clinical, metabolomic, and immune metrics, suggesting that there is an integrated disease pathway network contributing to ALS. In the proposed research, we will examine the underlying mechanisms by which these peripheral pathways impact ALS progression to enhance the design of future trials and therapies. More specifically, we will examine the potential mechanisms by which changes in the gut microbiome alter peripheral metabolites and immune cells in ALS. The overall objective of this Option B study is to use the existing infrastructure and data pipelines from two ongoing R01-funded ALS studies to identify cross-sectional and longitudinal associations between the ALS microbiome and clinical, metabolomic, and immune metrics of disease. We hypothesize that the microbial composition of ALS subjects – either individual bacterial communities or clusters of bacterial populations – will be associated with ALS progression as measured by the ALS functional rating scale-revised (ALSFRS-R) (Aim 1). In addition, we hypothesize that specific bacterial populations or population clusters will be associated with changes in both metabolic profiles (Aim 2) as well as immune metrics (Aim 3) and that metabolic and immune changes will be associated with altered disease progression. Completion of the study will identify integrated microbial, metabolic, and immune pathways that can be used as biomarkers or therapeutic targets for future clinical trials.