Microbiome Dysbiosis and Postoperative Delirium Pathogenesis

微生物群失调与术后谵妄发病机制

• 批准号: 10055132
• 负责人: Shiqian Shen
• 金额: $ 45.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055132
• 关键词: 16S ribosomal RNA sequencing; Abdomen; Acute; Adult; Age; Aging; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anesthesia procedures; Animal Model; Antibiotics; Attenuated; Behavior; Behavioral; Biochemical; Biological; Biosensing Techniques; Blood; Brain; Butyrates; Caring; Cefazolin; Cognition; Communities; Confusion; Data; Delirium; Development; Disease; Elements; Endocrine; Feces; General Anesthesia; Genus Hippocampus; Germ-Free; Goals; Hour; Human; Immune; Impaired cognition; Inflammation; Interleukin-6; Intervention; Isoflurane; Label; Lead; Measurement; Measures; Methods; Microglia; Mitochondria; Modeling; Morbidity - disease rate; Mus; Neuraxis; Neuropathogenesis; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Postoperative Complications; Postoperative Period; Precipitating Factors; Predisposing Factor; Probiotics; Research; Risk; Risk Factors; Role; Structure; System; Technology; Testing; United States National Institutes of Health; age related; aged; base; behavior test; care costs; cognitive function; confusion assessment method; dysbiosis; extracellular; gut microbiota; high risk; innovation; insight; microbiome; microbiota; mitochondrial dysfunction; mortality; nano; neuroinflammation; new technology; novel; post-operative cognitive dysfunction; postoperative delirium; prevent; tool

Abstract Postoperative delirium (POD), a condition characterized by a state of confusion, is one of the most common postoperative complications among senior patients and is associated with substantially increased rates of morbidity and mortality, increased cost of care, and risk of developing Alzheimer’s disease and related dementias (ADRD). However, even with ongoing POD studies, the pathogenesis of POD is still mostly unknown, which impedes further studies of POD, including the targeted interventions. Thus, there is no treatment for POD at present. Consistent with the notion that gut microbiota dysbiosis (e.g., gut microbiota community structure changes), neuroinflammation and mitochondrial dysfunction are part of ADRD neuropathogenesis and are also associated with cognitive impairments, our preliminary studies showed that the open abdominal surgery under general anesthesia (anesthesia/surgery) induced an age-dependent gut microbiota dysbiosis, neuroinflammation, mitochondrial dysfunction and POD-like behavior in the mice. Thus, we will extend these studies to further define a potential multifactorial model of POD pathogenesis by testing the following hypothesis: anesthesia/surgery-induced neuroinflammation (the precipitating factor and the contributor) is promoted by age-associated microbiota dysbiosis (the predisposing factor and the modulator), leading to mitochondrial dysfunction and POD-like behavior in mice. We will employ biochemical and behavioral tools to accomplish two Specific Aims: (1) we will assess the effects of anesthesia/surgery on gut microbiota and fecal b-amyloid, blood and brain level of IL-6, microglia activation, brain Ab and mitochondrial function, and POD-like behavior in aged mice (18 month-old mice or 3 month-old germ-free mice fed with feces of the 18 months old mice) as compared to those in adult mice (9 months old mice or 3 month- old germ-free mice fed with feces of the 9 months old mice); (2) we will assess whether treatment with butyrate, antibiotic (e.g., cefazolin) and probiotic can mitigate the POD-like behavior and their associated changes in feces, blood, and brain in the mice. We will employ an innovative label-free nano-biosensing system for biomolecular analysis (nanobeam technology) in the proposed studies. This proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses. These studies could ultimately help to develop the targeted interventions of POD by targeting microbiota dysbiosis. These efforts would ultimately promote safer anesthesia and surgical care, leading to better postoperative outcomes for senior patients and, consequently, the development of strategies towards preventing ADRD.

抽象的 术后del妄（POD）是一种以混乱状态为特征的疾病，是最多一种 高级患者的常见术后并发症，并且与大幅增加有关 发病率和死亡率，增加的护理成本以及发展阿尔茨海默氏病及相关的风险 痴呆症（ADRD）。但是，即使进行了正在进行的POD研究，POD的发病机理仍然主要是 未知，这阻碍了对POD的进一步研究，包括靶向干预措施。那没有 目前的POD处理。与肠道菌群营养不良的观念一致（例如，肠道菌群 社区结构变化），神经炎症和线粒体功能障碍是ADRD的一部分 我们的初步研究表明，神经病发生，并且与认知障碍有关 大麻醉下的开放性腹部手术（麻醉/手术）诱导了年龄依赖性肠道 小鼠的微生物群营养不良，神经炎症，线粒体功能障碍和豆荚样行为。那， 我们将扩展这些研究，以进一步定义POD发病机理的潜在多因素模型 以下假设：麻醉/手术诱导的神经炎症（沉淀因子和 贡献者）由年龄相关的微生物群（诱发因子和调节剂）促进。 导致小鼠的线粒体功能障碍和豆荚样行为。我们将采用生化和 实现两个具体目标的行为工具：（1）我们将评估麻醉/手术对 肠道菌群和粪便B-淀粉样蛋白，IL-6的血液和大脑水平，小胶质细胞激活，脑AB和 老年小鼠（18个月大的小鼠或3个月大的细菌小鼠）的线粒体功能和豆荚样行为 与成年小鼠（9个月大的小鼠或3个月 - 用9个月大的小鼠的粪便喂养的旧小鼠）； （2）我们将评估是否处理 丁酸酯，抗生素（例如头孢唑林）和益生菌可以减轻类似豆荚的行为及其相关的行为 小鼠粪便，血液和大脑的变化。我们将采用无创新标签的纳米生物传感 拟议的研究中的生物分子分析系统（纳米束技术）。该建议旨在 通过测试新的假设来研究创新系统中的一个理解主题。这些研究可以 最终，通过靶向微生物群疾病障碍，有助于开发POD的靶向干预措施。这些努力 最终会促进安全性和外科护理，从而为您带来更好的术后结局 高级患者，因此，制定了预防ADRD的策略。