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

摘要 肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种以进行性运动障碍为特征的神经退行性疾病 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。 needed.然而，必须更好地了解疾病发病机制的基本机制，以确定 疾病生物标志物和治疗靶点。许多生物系统和途径与ALS有关 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， 外周系统不仅随时间变化，而且与疾病进展有关。特别是 肠道微生物组与临床、代谢组学和免疫指标有关，这表明存在一个综合的 导致ALS的疾病通路网络。在拟议的研究中，我们将研究潜在的 这些外周通路影响ALS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中的外周代谢物和免疫细胞。本方案B研究的总体目标 是利用现有的基础设施和数据管道，从两个正在进行的R 01资助的ALS研究，以确定 ALS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 细菌群落或细菌群簇-将与ALS进展相关， 通过ALS功能评定量表-修订版（ALSFRS-R）（目标1）测量。此外，我们假设， 特定的细菌种群或种群簇将与两种代谢谱的变化相关 (Aim 2）以及免疫指标（目标3），代谢和免疫变化将与 改变疾病进展。研究完成后，将确定整合的微生物、代谢和免疫 可用作未来临床试验的生物标志物或治疗靶点的途径。

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.