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

在高达26%的手术患者中，术后会出现微小但持续的学习和记忆障碍， 称为术后认知功能障碍(POCD)。POCD已成为一个严重的公共卫生问题 因为它与更差的临床结果相关，包括增加死亡率。潜在的发病机制 POCD仍不清楚。可修改因素和不可修改因素都可能导致POCD。到目前为止，研究 关于POCD的研究主要集中在手术和麻醉对中枢神经系统的直接影响， 他们认为年龄和遗传因素是POCD的主要危险因素。不幸的是，这些是不可修改的 因素多，难以转化为临床治疗。因此，迫切需要确定 POCD背后的可修改因素。在许多可改变的因素中，饮食影响和肠道微生物区系 与许多具有炎症特征的神经系统疾病有牵连。肠道微生物区系是否 POCD的影响还有待研究。在我们的初步研究中，我们观察到了一种以前未被认识到的 肠道微生物区系在小鼠股动脉异氟醚暴露后POCD发生中的作用 麻醉。具体地说，我们发现：1)肠道微生物区系正常的小鼠没有发生POCD，而肠道微生物区系正常的小鼠 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的变化和吲哚的急剧减少，特别是吲哚-3-硫酸酯 (3)口服吲哚-3-丙酸(IPA)，而不是IS，可阻止POCD 4)POCD小鼠表现出氧化增加和线粒体功能受损。 海马区，由于增加了活性氧物种(ROS)的产生，减少了产生 NADH，并降低NDUFS4(一种关键的线粒体复合体I组分)的蛋白水平 5)口服异丙肾上腺素能减少ROS的生成，增加ROS的生成 氨苄西林处理的小鼠海马区NADH产生和NDUFS4蛋白水平。基于这些 初步发现，我们假设肠道微生物区系对POCD的发展有关键影响。 通过IPA。在这项拨款中提出的研究计划中，我们将通过以下方式检验这一假说 三个关键问题：1)观察到的肠道生物失调对POCD的影响是一种附生现象还是一种 “放任”效应？2)IPA在POCD中起保护作用的机制是什么？以及3)我们可以 开发基于肠道微生物区系和代谢物的策略来预防和治疗POCD？这笔赠款是建立在 我们的新的初步发现和我们建立的结合了尖端技术的研究平台 元基因组学和代谢组学与免疫学和神经行为分析。成功执行 这项提议将建立一个新的概念框架，将饮食和肠道等可改变的因素联系起来 微生物群与POCD，并导致新的治疗策略。

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.