Administrative Supplement: Gut Microbiota Influences Postoperative Cognitive Dysfunction through Indole-3-Propionic Acid

行政补充：肠道微生物群通过吲哚-3-丙酸影响术后认知功能障碍

• 批准号: 10388931
• 负责人: Shiqian Shen
• 金额: $ 18.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388931
• 关键词: Address; Administrative Supplement; Age; Ampicillin; Anesthesia procedures; Applications Grants; Biological Assay; Clinical; Clinical Treatment; Communities; Complex; Development; Diet; Generations; Genetic; Grant; Hippocampus (Brain); Immunologics; Impairment; Indoles; Inflammatory; Isoflurane; Lead; Learning; Link; Memory; Metagenomics; Mitochondria; Mus; NADH; Neuraxis; Operative Surgical Procedures; Oral; Oral Administration; Outcome; Pathogenesis; Patients; Postoperative Period; Production; Propionic Acids; Proteins; Public Health; Reactive Oxygen Species; Research; Risk Factors; Role; Structure; Sulfate; Translating; base; dietary; femoral artery; gut dysbiosis; gut microbiota; indoxyl; metabolomics; microbiota metabolites; mortality; nervous system disorder; neurobehavioral; novel; novel therapeutic intervention; oxidation; post-operative cognitive dysfunction; prevent

In up to 26% surgical patients, subtle yet persistent deficits in learning and memory occur postoperatively, referred to as postoperative cognitive dysfunction (POCD). POCD has become a serious public health concern as it is associated with worse clinical outcomes including increased mortality. The pathogenesis underlying POCD remains unclear. Both modifiable and non-modifiable factors may contribute to POCD. To date, studies on POCD have primarily focused on direct influences of surgery and anesthesia on the central nervous system, which have identified age and genetics as major risk factors in POCD. Unfortunately, these are non-modifiable factors and difficult to be translated into clinical treatment. As such, there is an urgent need to identify modifiable factors underlying POCD. Among many modifiable factors, dietary influences and gut microbiota have been implicated in many neurological diseases with inflammatory features. Whether gut microbiota influences POCD has yet to be examined. In our preliminary studies, we observed a previously unrecognized role for gut microbiota in the development of POCD in mice post femoral artery exposure under isoflurane anesthesia. Specifically, we found: 1) mice with normal gut microbiota did not develop POCD while mice with gut dysbiosis developed POCD; 2) oral ampicillin treatment led to a status of gut dysbiosis, characterized by gut microbiota community structure changes and a dramatic decrease of indoles, particularly indoxyl-3-sulfate (IS) and indole-3-propionic acid (IPA); 3) oral administration of IPA, but not IS, deterred the POCD development; 4) mice with POCD displayed increased oxidation and impaired mitochondria function in the hippocampus, suggested by an enhanced production of reactive oxygen species (ROS), decreased production of NADH, and decreased protein levels of NDUFS4 (a critical mitochondria complex I component), when compared with mice without POCD; and 5) Oral administration of IPA decreased ROS generation, increased NADH production and NDUFS4 protein levels in the hippocampus of ampicillin-treated mice. Based on these preliminary findings, we hypothesize that gut microbiota has a key influence on the development of POCD through IPA. In this grant, we will examine this hypothesis by addressing three key questions: 1) Does the observed effect of gut dysbiosis on POCD in the preliminary studies represent an epiphenomenon or a ‘permissive’ effect? 2) What are the mechanisms underlying the IPA’s protective role in POCD? and 3) Can we develop a strategy based on gut microbiota and metabolites to prevent and treat POCD? This grant is built on our novel preliminary findings and our established research platform that combines cutting-edge metagenomics and metabolomics with immunological and neurobehavioral assays. Successful execution of this proposal will establish a novel conceptual framework linking modifiable factors such as diet and gut microbiota with POCD, and lead to new therapeutic strategies.

在多达26％的手术患者中，学习和记忆的微妙而持续的缺陷也出现 称为术后认知功能障碍（POCD）。 POCD已成为严重的公共卫生问题 因为它与临床结果较差有关，包括死亡率增加。基础发病机理 POCD仍然不清楚。可修改和不可修改的因素都可能导致POCD。迄今为止，研究 关于POCD，主要集中于手术和麻醉对中枢神经系统的直接影响， 将年龄和遗传学确定为POCD的主要危险因素。不幸的是，这些是不可修改的 因素和难以翻译成临床治疗。因此，迫切需要确定可修改的 POCD的因素。在许多可修改因素中，饮食影响和肠道菌群已经 在许多具有炎症特征的神经系统疾病中实施。肠道微生物群是否影响POCD 尚未检查。在我们的初步研究中，我们观察到肠道菌群的先前未认识的作用 在异氟烷麻醉下股动脉暴露后小鼠POCD的发展中。具体来说，我们 发现：1）患有正常肠道微生物群的小鼠没有发生POCD，而患有肠道营养不良的小鼠则发展为POCD； 2）口服amicicillin治疗导致肠道营养不良的状态，其特征是肠道菌群结构 吲哚的变化和急剧减少，尤其是吲哚-3-硫酸盐（IS）和吲哚-3-丙酸（IPA）； 3）口服IPA，但不是确定POCD的发展； 4）显示POCD的小鼠 氧化增加和海马中线粒体功能受损，这是由增强的 活性氧（ROS）的产生，NADH的产生改善，并提高了蛋白质水平 与没有POCD的小鼠相比，NDUFS4（一种关键的线粒体复合物I分量）； 5）口服 IPA的给药减少了ROS的产生，NADH产生增加和NDUFS4蛋白水平 amicicillin治疗的小鼠的海马。基于这些初步发现，我们假设肠道 微生物群对通过IPA的POCD发展具有关键影响。在这笔赠款中，我们将检查 通过解决三个关键问题：1）观察到的肠道营养不良对POCD的影响 初步研究代表了epiphenomenon或“宽松”效应？ 2）有什么机制 IPA在POCD中的保护作用是基本的？ 3）我们可以根据肠道菌群制定策略和 用于预防和治疗POCD的代谢产物？这笔赠款建立在我们的小说初步发现和我们已建立的 研究平台将尖端的宏基因组学和宏基因组学与免疫学和 神经行为测定。该提案的成功执行将建立一个新颖的概念框架 将可修改因素（例如饮食和肠道微生物群）与POCD联系起来，并带来新的治疗策略。