The intersection of GLP-1, gut microbiota, and brain connectivity in prodromal Alzheimer’s disease

GLP-1、肠道微生物群和大脑连接在阿尔茨海默病前驱期的交叉作用

• 批准号: 10352498
• 负责人: JOHN R KIRBY
• 金额: $ 39.6万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352498
• 关键词: Address; Affect; Age; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Bacterial Genes; Bioinformatics; Biological Markers; Blood - brain barrier anatomy; Brain; Butyrates; Cognitive; Cognitive aging; Control Groups; Data; Detection; Diagnosis; Diagnostic tests; Disease; Early identification; Epidemic; Evaluation; Failure; Fasting; Functional Magnetic Resonance Imaging; Future; GLP-I receptor; Gene Cluster; Glucose; Goals; Health; Human; Individual; Knowledge; Lead; Link; Longitudinal Studies; Maps; Measures; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolic dysfunction; Methodology; Methods; Nerve Degeneration; Neuropeptides; Onset of illness; Organism; Participant; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Peripheral; Persons; Plasma; Production; Property; Public Health; Research; Ribosomal DNA; Risk; Role; Shotguns; Symptoms; Synapses; Testing; Therapeutic; Time; Visit; Volatile Fatty Acids; amnestic mild cognitive impairment; base; cerebral amyloidosis; cognitive control; cognitive function; cohort; design; effective therapy; genetic risk factor; glucagon-like peptide; glucagon-like peptide 1; glucose transport; gut microbes; gut microbiota; gut-brain axis; improved; insight; insulin signaling; metagenomic sequencing; microbial; microbiome; microbiome research; microbiota; negative affect; neurodegenerative dementia; neurogenesis; neuroimaging; neuron loss; novel; novel therapeutics; prevent; prodromal Alzheimer' s disease; recruit; stool sample; tau Proteins; therapeutic development

Project Summary: Early identification of Alzheimer's disease (AD) is essential for preventing or delaying disease onset. There is currently no effective treatment for AD, which may be attributable to multiple underlying causes. Mounting evidence supports the notion that AD is, in part, a metabolic condition with an array of metabolic perturbations early in the disease, even at the prototypical prodromal stage, i.e. amnestic mild cognitive impairment (aMCI). Animal models indicate that gut- and neuropeptide Glucagon like peptide-1 (GLP-1) is a promising link within the gut-brain axis of AD, although this peripheral-central pathway has yet to be defined in AD. We propose a novel gut-GLP-1 interactome of prodromal AD. We hypothesize that gut specific bacterial strains will influence GLP-1 levels and produce small metabolites that influence brain connectivity patterns in patients with aMCI. We will test this scientific premise in two Specific Aims. In Aim 1, we will determine the relationship between GLP-1 levels and default mode network (DMN) connectivity patterns in aMCI compared to age-matched control cohorts. We will apply rigorous methodological design to measure pre- and post- meal testing GLP-1 levels and assess DMN connectivity patterns using a cutting-edge functional MRI method. In Aim 2, we seek to determine bacterial strains and metabolites associated with DMN connectivity patterns in aMCI and control groups. We will conduct metagenomic sequencing on stool samples collected at similar times from the same individuals assessed in Aim1. We will identify bacterial genes with potential to impact GLP-1 levels. Metabolic markers will be correlated with DMN connectivity patterns. Together, these Aims will elucidate bacterial metabolic biomarkers in a prodromal AD disease state that can negatively affect GLP-1 levels or activity to affect brain functioning. We will use the data collected here to initiate a longitudinal study to follow the progression of metabolic and neuroimaging data along with known AD pathologic biomarkers such as beta- amyloid and tau. Our goal is to determine the specific bacterial strains and their metabolic properties that drive the transition from normal cognitive aging to aMCI to AD.

项目概要： 早期识别阿尔茨海默病 (AD) 对于预防或延缓疾病发作至关重要。有 目前AD尚无有效治疗方法，其原因可能有多种。安装 有证据支持 AD 部分是一种具有一系列代谢扰动的代谢状况的观点 疾病早期，甚至在典型的前驱阶段，即遗忘性轻度认知障碍（aMCI）。 动物模型表明，肠道和神经肽胰高血糖素样肽 1 (GLP-1) 是一个有希望的链接 AD 的肠-脑轴，尽管这一外周-中枢通路在 AD 中尚未被定义。我们提出一个 AD 前驱期的新型肠道-GLP-1 相互作用组。我们假设肠道特定细菌菌株会影响 GLP-1 水平并产生影响 aMCI 患者大脑连接模式的小代谢物。 我们将在两个具体目标中检验这一科学前提。在目标 1 中，我们将确定之间的关系 aMCI 中的 GLP-1 水平和默认模式网络 (DMN) 连接模式与年龄匹配对照相比 队列。我们将采用严格的方法设计来测量餐前和餐后测试 GLP-1 水平 并使用尖端的功能 MRI 方法评估 DMN 连接模式。在目标 2 中，我们寻求 确定与 aMCI 和对照中的 DMN 连接模式相关的细菌菌株和代谢物 组。我们将对在相似时间从同一地点收集的粪便样本进行宏基因组测序。 目标 1 中评估的个人。我们将鉴定可能影响 GLP-1 水平的细菌基因。代谢 标记将与 DMN 连接模式相关。这些目标共同将阐明细菌 AD 疾病前驱状态中的代谢生物标志物可能会对 GLP-1 水平或活性产生负面影响 影响大脑功能。我们将使用此处收集的数据启动一项纵向研究，以跟踪 代谢和神经影像数据以及已知的 AD 病理生物标志物（例如 β- 淀粉样蛋白和 tau 蛋白。我们的目标是确定特定的细菌菌株及其代谢特性 从正常认知老化到 aMCI 再到 AD 的转变。

项目成果

Decreased Cerebrovascular Reactivity in Mild Cognitive Impairment Phenotypes.

轻度认知障碍表型的脑血管反应性降低。

• DOI: 10.3233/jad-221156
• 发表时间: 2023-07-05
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: L. Glass Umfleet;Jessica Pommy;A. Cohen;Margaret Allen;Shawn Obarski;Lilly Mason;Halle Berres;M. Franczak;Yang Wang
• 通讯作者: Yang Wang

A single, peri-operative antibiotic can persistently alter the post-operative gut microbiome after Roux-en-Y gastric bypass.

Roux-en-Y 胃绕道手术后，单一围手术期抗生素可以持续改变术后肠道微生物组。

• 发表时间: 2023-02
• 作者: Fernando, Deemantha G;Saravia, Fatima L;Atkinson, Samantha N;Barron, Matthew;Kirby, John R;Kindel, Tammy L
• 通讯作者: Kindel, Tammy L