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: 9759966
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759966
• 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; Translating; Unspecified or Sulfate Ion Sulfates; base; dysbiosis; femoral artery; gut microbiota; indoxyl; metabolomics; microbiota metabolites; mortality; nervous system disorder; neurobehavioral; novel; novel therapeutic intervention; novel therapeutics; 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.

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 POCD的可修改因素。在许多可修改因素中，饮食影响和肠道菌群 在许多具有炎症特征的神经系统疾病中隐含。是否肠道微生物群 影响POCD尚待研究。在我们的初步研究中，我们观察到了以前未被认可的 肠道微生物群在异氟烷下股动脉暴露的小鼠POCD发展中的作用 麻醉。特别是，我们发现：1）肠道菌群正常的小鼠没有患有POCD 肠道营养不良发生了POCD； 2）口服杏仁饼治疗导致肠道营养不良的状态，其特征是 肠道菌群群落结构的变化和吲哚的急剧减少，尤其是Indoxyl-3-硫酸盐 （IS）和吲哚-3-丙酸（IPA）； 3）IPA的口服给药，但没有确定POCD 发展; 4）具有POCD的小鼠的氧化增加和线粒体功能受损 海马，通过增强的活性氧（ROS）的产生提出，生产降低 NADH的NDUFS4（一种关键的线粒体复合物I）的蛋白质水平，当 与没有POCD的小鼠相比； 5）口服IPA降低ROS的产生，增加 NADH的产生和NDUFS4蛋白水平在接受amicillin治疗的小鼠的海马中。基于这些 初步发现，我们假设肠道菌群对POCD的发展有关键的影响 通过IPA。在本赠款中提出的研究计划中，我们将通过解决该假设来解决该假设 三个关键问题：1）观察到的肠道营养不良对POCD的作用是否代表Epiphenomenon或A “允许”效果？ 2）IPA在POCD中的保护作用是什么机制？ 3）我们可以吗 制定基于肠道菌群和代谢产物的策略来预防和治疗POCD？这笔赠款建立在 我们新颖的初步发现和我们既定的研究平台，结合了尖端 具有免疫学和神经行为测定法的宏基因组学和代谢组学。成功执行 该建议将建立一个新的概念框架，将可修改因素（例如饮食和肠道）联系起来 带有POCD的微生物群，并导致新的治疗策略。