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

肠道微生物群通过吲哚-3-丙酸影响术后认知功能

• 批准号: 10475064
• 负责人: Shiqian Shen
• 金额: $ 40.02万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475064
• 关键词: Address; 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; programs

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 the research program proposed in this grant, we will examine the hypothesis by addressing three key questions: 1) Does the observed effect of gut dysbiosis on POCD 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.

高达 26% 的手术患者术后会出现微妙但持续的学习和记忆缺陷， 术后认知功能障碍（POCD）已成为严重的公共卫生问题。 因为它与更差的临床结果（包括死亡率增加）相关。 迄今为止，研究尚不清楚可改变的因素和不可改变的因素都可能导致 POCD。 POCD 主要关注手术和麻醉对中枢神经系统的直接影响， 不幸的是，这些因素是不可改变的。 难以转化为临床治疗的因素，因此迫切需要确定。 POCD 背后的可改变因素包括饮食影响和肠道微生物群。 是否与许多具有炎症特征的神经系统疾病有关。 POCD 的影响尚未得到检验。在我们的初步研究中，我们观察到了一个以前未被认识到的现象。 股动脉暴露于异氟烷下的小鼠 POCD 发展中肠道菌群的作用 具体来说，我们发现：1）肠道菌群正常的小鼠不会出现 POCD，而肠道菌群正常的小鼠则不会出现 POCD。 肠道菌群失调发展为 POCD；2) 口服氨苄西林治疗导致肠道菌群失调状态，其特征为 肠道微生物群落结构发生变化，吲哚（特别是 3-硫酸吲哚酚）急剧减少 (IS) 和吲哚-3-丙酸 (IPA) 3) 口服 IPA 可阻止 POCD，但 IS 则不然。 4) 患有 POCD 的小鼠表现出氧化增加和线粒体功能受损 海马体，活性氧 (ROS) 产量增加，产量减少 NADH 的减少，以及 NDUFS4（线粒体复合物 I 的关键成分）蛋白质水平的降低 与没有 POCD 的小鼠相比；5) 口服 IPA 减少了 ROS 的产生，增加了 氨苄青霉素治疗小鼠海马中 NADH 的产生和 NDUFS4 蛋白水平 基于这些。 初步研究结果表明，肠道微生物群对 POCD 的发展具有关键影响 在本次资助提出的研究计划中，我们将通过解决这一问题来检验这一假设。 三个关键问题：1）观察到的肠道菌群失调对 POCD 的影响是一种附带现象还是一种现象？ “许可”效应？2）IPA 在 POCD 中发挥保护作用的机制是什么？3）我们可以吗？ 制定基于肠道微生物群和代谢物的策略来预防和治疗 POCD 这笔赠款是建立在？ 我们新颖的初步发现和我们建立的结合了尖端技术的研究平台 宏基因组学和代谢组学以及免疫学和神经行为测定的成功执行。 该提案将建立一个新颖的概念框架，将饮食和肠道等可改变因素联系起来 微生物群与 POCD，并导致新的治疗策略。