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疾病，是最常见的一种。 老年患者中常见的术后并发症， 发病率和死亡率，增加的护理费用，以及发展阿尔茨海默病和相关疾病的风险 痴呆症（ADRD）。然而，即使对POD的研究仍在进行中，POD的发病机制仍主要是 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 目前对POD的处理。与肠道微生物群生态失调（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， 全身麻醉下的开腹手术（麻醉/手术）诱导了年龄依赖性肠道 微生物群失调、神经炎症、线粒体功能障碍和POD样行为。因此，在本发明中， 我们将扩展这些研究，通过测试进一步确定POD发病机制的潜在多因素模型， 以下假设：麻醉/手术诱导的神经炎症（促发因素和 贡献者）由年龄相关的微生物群生态失调（诱发因素和调节剂）促进， 导致小鼠的线粒体功能障碍和POD样行为。我们将使用生物化学和 行为工具，以实现两个具体目标：（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，IL-6的血液和脑水平，小胶质细胞活化，脑Ab和 老年小鼠（18月龄小鼠或3月龄无菌小鼠）的线粒体功能和POD样行为 用18月龄小鼠的粪便喂养）与成年小鼠（9月龄小鼠或3月龄小鼠）相比， 用9个月大的小鼠的粪便喂养的无菌小鼠）;（2）我们将评估用 丁酸盐，抗生素（例如，头孢唑啉）和益生菌可以减轻POD样行为及其相关的 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技术 生物分子分析系统（纳米束技术）在拟议的研究。这项建议旨在 通过测试新的假设来研究创新系统中未充分研究的主题。这些研究可以 最终有助于通过针对微生物群生态失调来开发POD的靶向干预措施。这些努力 最终将促进更安全的麻醉和手术护理，从而改善术后结果， 老年患者，因此，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.