Microbiome Dysbiosis and Postoperative Delirium Pathogenesis

摘要 术后谵妄 (POD) 是一种以精神错乱为特征的病症，是最常见的病症之一。 老年患者常见的术后并发症，与显着增加相关 发病率和死亡率、护理成本增加以及患阿尔茨海默病和相关疾病的风险 痴呆症（ADRD）。然而，即使正在进行 POD 研究，POD 的发病机制仍然主要是 未知，这阻碍了 POD 的进一步研究，包括有针对性的干预措施。因此，不存在 目前治疗POD。与肠道微生物群失调的观点一致（例如，肠道微生物群 群落结构变化）、神经炎症和线粒体功能障碍是 ADRD 的一部分 神经发病机制，也与认知障碍有关，我们的初步研究表明 全身麻醉（麻醉/手术）下的开腹手术诱发了年龄依赖性肠道 小鼠体内微生物群失调、神经炎症、线粒体功能障碍和 POD 样行为。因此， 我们将扩展这些研究，通过测试进一步定义 POD 发病机制的潜在多因素模型 以下假设：麻醉/手术引起的神经炎症（诱发因素和 贡献者）是由与年龄相关的微生物群失调（诱发因素和调节剂）促进的， 导致小鼠线粒体功能障碍和 POD 样行为。我们将采用生化和 行为工具来实现两个具体目标：（1）我们将评估麻醉/手术对 肠道微生物群和粪便 b-淀粉样蛋白、血液和大脑中 IL-6 水平、小胶质细胞激活、大脑抗体和 老年小鼠（18 个月大的小鼠或 3 个月大的无菌小鼠）的线粒体功能和 POD 样行为 用 18 个月大的小鼠的粪便喂养）与成年小鼠（9 个月大的小鼠或 3 个月大的小鼠）相比 用9个月大小鼠的粪便喂养的无菌老小鼠）； (2) 我们将评估治疗是否 丁酸盐、抗生素（例如头孢唑啉）和益生菌可以减轻 POD 样行为及其相关 小鼠粪便、血液和大脑的变化。我们将采用创新的无标记纳米生物传感 拟议研究中的生物分子分析系统（纳米束技术）。该提案旨在 通过测试新颖的假设来研究创新系统中尚未研究的主题。这些研究可以 最终通过针对微生物群失调来帮助制定 POD 的针对性干预措施。这些努力 最终将促进更安全的麻醉和手术护理，从而为患者带来更好的术后结果 老年患者，从而制定预防 ADRD 的策略。

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.