Role of IgA-biome in intestinal dysbiosis and brain changes in Alzheimer's disease

IgA 生物组在阿尔茨海默病肠道菌群失调和大脑变化中的作用

• 批准号: 10667011
• 负责人: Suba Nookala
• 金额: $ 21.15万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667011
• 关键词: 16S ribosomal RNA sequencing; APP-PS1; Address; Age; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein; Antibodies; Appearance; Attenuated; Awareness; Bacteria; Behavior; Behavioral; Binding; Biochemical; Biological Markers; Blood; Brain; Burkholderiaceae; C57BL/6 Mouse; Chemosensitization; Clinical; Crohn' s disease; Data; Deterioration; Disease; Disease Progression; Disease model; Enteral; Environmental Risk Factor; Epithelium; Etiology; Family; Female; Functional disorder; Future; Genetic; Genotype; Gliosis; Health; Histologic; Immune; Immune system; Immunoglobulin A; Immunologics; Impairment; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interdisciplinary Study; Intestines; Investigation; Memory; Memory impairment; Meninges; Monitor; Mus; Nerve Degeneration; Oral; Outcome; Pathogenicity; Pathologic; Pattern; Peripheral; Permeability; Phenotype; Population; Reporting; Role; Sampling; Secretory Immunoglobulin A; Sex Differences; Signal Transduction; Sorting; Spleen; Streptococcaceae; System; Testing; Therapeutic; Therapeutic Intervention; Time; Toxin; Transgenic Mice; Transgenic Organisms; Transplantation; Ulcerative Colitis; United States; Wild Type Mouse; Work; absorption; age related neurodegeneration; behavior change; cognitive function; cytokine; diagnostic biomarker; dysbiosis; gut bacteria; gut inflammation; gut microbiota; gut-brain axis; immunoregulation; innovation; intestinal epithelium; intestinal homeostasis; male; microbial; mouse model; neuropathology; novel strategies; pathogen; pathogenic bacteria; prevent; receptor; sex; therapeutic target; tool

Summary An estimated 6.2 million individuals have Alzheimer’s disease (AD) in the US, which is projected to nearly triple by 2050. Although genetic and several environmental factors help explain the etiology of AD, emerging reports recognize significant associations between altered diversity, abundance, and composition of the intestinal microbiota, intestinal dysfunction, loss of epithelial barrier integrity, and the progression of AD. However, it is difficult to distinguish associations from causal relationships. Nevertheless, it is apparent that the dysbiotic gut microbial community elicits inflammatory features extending beyond the enteric system and stimulates aberrant and pathological brain changes. Intestinal homeostasis relies on secreted IgA that coats pathogenic bacteria and blocks their contact with epithelial receptors to avert inflammatory responses. We will test the idea that IgA-coated bacteria (IgA-biome) in the dysbiotic intestine are pathogenic and responsible for the direct potentiation of AD. Our preliminary data using a transgenic AppNL-G-F mouse model of AD demonstrated a significant increase in the levels of IgA-coated fecal bacteria in female mice. Moreover, 16s rRNA sequencing of IgA sorted bacteria (IgA-seq) from 12-month-old female AppNL-G-F and C57BL/6 wild-type mice identified distinct differences in the microbial taxa coated by IgA. These data were concomitant with behavior changes seen only in the female AppNL-G-F mice suggesting a nexus between the IgA-biome, gut, and brain. We will fully characterize the longitudinal changes in the IgA-biome by IgA-seq in Aim one and determine whether distinct IgA coated bacteria correlate with changes in immune phenotype, memory, gliosis, and -amyloid accumulation. In Aim two, we will validate the role of IgA in the dysbiosed AD gut by oral gavage transfer of IgA-biome from old into young mice and assess sex and genotype-dependent changes in behavior, gliosis, - amyloid accumulation, and peripheral and intestinal immunomodulatory changes. Our work will provide a new understanding of the IgA-biome as a contributor to brain changes in AD and may be relevant to other neurodegenerative conditions. We will also identify the unique age and disease patterns of IgA-biome taxa that can be potential diagnostic biomarkers and therapeutic targets.

概括 据估计，美国有 620 万人患有阿尔茨海默病 (AD)，预计这一数字将增加近三倍 到 2050 年。虽然遗传和一些环境因素有助于解释 AD 的病因，但新出现的报告 认识到肠道的多样性、丰度和组成之间的显着关联 微生物群、肠道功能障碍、上皮屏障完整性丧失以及 AD 的进展。 很难区分关联与因果关系，但很明显，肠道菌群失调。 微生物群落引起炎症特征延伸到肠道系统之外并刺激异常 肠道稳态依赖于包被致病菌的分泌型 IgA。 并阻止它们与上皮受体的接触以避免炎症反应我们将测试这一想法。 肠道菌群失调中的 IgA 包被细菌（IgA 生物群落）具有致病性，是直接导致肠道菌群失调的原因。 我们使用 AD 转基因 AppNL-G-F 小鼠模型的初步数据证明了 AD 的增强作用。 此外，16s rRNA 测序显示雌性小鼠粪便中 IgA 包被的细菌水平显着增加。 鉴定出来自 12 个月大雌性 AppNL-G-F 和 C57BL/6 野生型小鼠的 IgA 分选细菌 (IgA-seq) IgA 覆盖的微生物类群存在明显差异，这些数据伴随着行为变化。 仅在雌性 AppNL-G-F 小鼠中观察到，这表明 IgA 生物组、肠道和大脑之间存在联系。 通过目标一中的 IgA-seq 表征 IgA-生物组的纵向变化，并确定是否不同 IgA 包被的细菌与免疫表型、记忆、神经胶质增生和 β-淀粉样蛋白的变化相关 在目标二中，我们将通过口服灌胃转移 IgA 来验证 IgA 在生物失调的 AD 肠道中的作用。 从老年小鼠到年轻小鼠的 IgA 生物组，并评估性别和基因型依赖性行为变化、神经胶质增生、- 我们的工作将提供新的淀粉样蛋白积累以及外周和肠道免疫调节变化。 了解 IgA 生物组是 AD 大脑变化的一个促成因素，并且可能与其他相关 我们还将确定 IgA 生物群落的独特年龄和疾病模式。 可以成为潜在的诊断生物标志物和治疗靶点。