Understanding the regulation of the intestinal epithelium in Alzheimer’s disease by commensal bacteria and the role it plays in preventing neurocognitive decline

了解共生细菌对阿尔茨海默病肠上皮的调节及其在预防神经认知衰退中的作用

• 批准号: 10680057
• 负责人: Ethan Bailey Loew
• 金额: $ 3.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680057
• 关键词: Adaptive Immune System; Address; Affect; Age; Alternative Therapies; Alzheimer' s Disease; American; Anti-Inflammatory Agents; Antibiotics; Antigens; B-Lymphocytes; Bacteria; Behavioral; Biological Assay; Biological Response Modifiers; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; C57BL/6 Mouse; Cell Line; Cells; Central Nervous System; Chemicals; Citrulline; Clinical; Coculture Techniques; Colon; Data; Deterioration; Development; Dextrans; Disease Progression; Elderly; Electrical Resistance; Engraftment; Epithelial Cells; Epithelium; Extravasation; Feces; Functional disorder; Germ-Free; Goals; Human; Immune; Immune Tolerance; Immune system; Immunoglobulin Class Switching; Immunohistochemistry; Impaired cognition; Individual; Infection; Inflammaging; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Intestinal permeability; Intestines; Investigation; Knowledge; Lamina Propria; Leukocyte L1 Antigen Complex; Link; Lipopolysaccharides; Lymphatic; Maintenance; Measures; Mediator; Metabolic; Modeling; Morphology; Mucous Membrane; Mus; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Pathogenesis; Peripheral; Peripheral Blood Lymphocyte; Permeability; Phytoestrogens; Plasma; Play; Population; Process; Property; Proteins; Publishing; Regulation; Research; Rest; Role; Sampling; Senile Plaques; Serum; Shapes; System; Testing; Time; Transgenes; Work; adaptive immune response; cognitive testing; cohort; commensal bacteria; cytokine; disorder risk; equol; gastrointestinal epithelium; genome sequencing; gut bacteria; gut inflammation; gut microbiome; gut microbiota; immunosenescence; intestinal barrier; intestinal epithelium; lipopolysaccharide-binding protein; microbial; microbial community; microbiome; microbiome analysis; microbiome composition; microbiota; microbiota-gut-brain axis; mouse model; myelination; neurogenesis; neuroinflammation; novel; peripheral blood; prevent; random forest; stool sample; systemic inflammatory response; theories; whole genome; zonulin

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as causative in the development of neuroinflammation, immunosenescence, and inflamm-aging seen in AD. Our own research has demonstrated a decrease in gut microbiota with anti-inflammatory properties and higher abundances of pro-inflammatory gut microbiota in AD elders. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in blood, serum cytokine profiling, and cognitive assessments of AD elders at 90-day intervals. This analysis identified changes in B cell populations with an increased abundance of class-switched and decreased abundance of naïve B cells at levels of greater cognitive impairment. To better understand how the microbiome may control AD progression, we propose to investigate the connection between the AD microbiome and the adaptive immune system with a focus on regulation of the intestinal epithelium by commensal gut bacteria. Specifically, we intend to use stool and plasma samples collected from our AD cohort to measure makers of intestinal permeability and determine whether metabolites secreted by the AD gut microbiome cause disruptions in the intestinal epithelium. We will directly study the disruptive effects of AD stool by applying stool supernatants to intestinal epithelial cells, quantifying changes in epithelial permeability using established assays, and determining whether specific taxa depleted in AD are sufficient to cause epithelial disruption. In our previously published data, we have observed the loss of the phytoestrogen-metabolizing bacteria, Adlercreutzia equolifaciens (AE), in the microbiome of AD elders. My preliminary studies reveal that a metabolic product of AE, (S)-equol, prevents epithelial damage in the setting of inflammation. Therefore, we aim to determine whether AE or its metabolic products protect the intestinal epithelium. To untangle the role of the AD microbiome on our observed changes in class switched and naïve B cells, I have collected preliminary data which demonstrates that colonization of mice with the microbiome of AD elders promotes B cell class switching when compared with colonization of cognitively impaired elders without AD. This application proposes to expand this finding and characterize the changes in the adaptive immune system caused by the AD microbiome. This continuing work will further establish the connection between AD related neurocognitive decline, the microbiome, and immune system.

抽象的 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征是淀粉样蛋白β斑块 大脑中的神经原纤维缠结以及大脑中的感染。这已经引起了 对于微生物群落或感染的理论，在神经炎症的发展中谨慎 免疫衰老和AD中看到的炎症。我们自己的研究表明肠道有所减少 具有抗炎特性的微生物群和AD中促炎型微生物群的较高丰度 长者。但是，目前尚不清楚AD微生物组如何对中枢神经系统产生影响。解决 在知识上，我们进行了肠道微生物组分析，分析血液中的免疫细胞种群， 血清细胞因子分析和AD长老的认知评估时间为90天。该分析确定了 B细胞种群的变化，班级切换的丰度增加，丰度增加 幼稚的B细胞在更大的认知障碍水平下。更好地了解微生物组如何控制 AD进展，我们建议研究AD微生物组与自适应免疫的联系 系统的重点是通过共生肠道细菌调节肠上皮。具体来说，我们打算 使用从我们的广告群中收集的粪便和血浆样品来测量肠道通透性和 确定AD肠道微生物组分泌的代谢产物是否会导致肠上皮的干扰。 我们将通过将粪便上清液应用于肠上皮细胞，直接研究AD粪便的破坏性作用， 使用既定测定法量化上皮通透性的变化，并确定特定的分类单元是否 在AD中耗尽的足以引起上皮干扰。在我们先前发布的数据中，我们已经观察到 AD的微生物组中的植物雌激素代谢细菌（AE）的丧失 长者。我的初步研究表明，AE（S） - Equol的代谢产物可防止上皮损害 炎症的设​​置。因此，我们旨在确定AE或其代谢产品是否保护 肠上皮。为了解开AD微生物组在我们观察到的类切换中观察到的变化中的作用， 天真的B细胞，我收集了初步数据，这表明小鼠与微生物组的定殖 与认知障碍长者的定殖相比 没有广告。此申请提案以扩展此发现并表征自适应的变化 AD微生物组引起的免疫系统。这项持续的工作将进一步建立联系 在与AD相关的神经认知下降，微生物组和免疫系统之间。