Administrative Supplement: 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，迫切需要确定可修改的 POCD的潜在因素。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影响POCD 还有待检验。在我们的初步研究中，我们观察到了肠道微生物区系以前未被认识到的作用。 异氟醚麻醉下小鼠股动脉暴露后POCD的发生。具体来说，我们 发现：1)肠道微生物区系正常的小鼠不发生POCD，而肠道菌群失调的小鼠发生POCD； 2)口服氨苄西林可导致肠道微生物区系结构紊乱。 吲哚的变化和急剧减少，特别是吲哚-3-硫酸酯(IS)和吲哚-3-丙酸(IPA)； 3)口服IPA，而不是IS，可阻止POCD的发展；4)POCD小鼠表现出 海马区氧化增加和线粒体功能受损，提示 产生活性氧(ROS)，减少NADH的产生，并降低 NDUFS4(一种关键的线粒体复合体I成分)，与没有POCD的小鼠相比；以及5)口服 给予IPA可减少ROS的产生，增加NADH的产生和NDUFS4的蛋白水平 氨苄西林处理的小鼠的海马体。基于这些初步发现，我们假设直觉 微生物区系通过IPA对POCD的发生发展有重要影响。在这笔赠款中，我们将审查 这一假设解决了三个关键问题：1)观察到的肠道生物失调对POCD的影响 初步研究代表的是一种附带现象还是一种“允许”效应？2)机制是什么？ IPA在POCD中的保护作用是什么？3)我们能否开发一种基于肠道微生物区系和 代谢产物预防和治疗POCD？这笔赠款是建立在我们新颖的初步发现和我们建立的 将尖端的元基因组学和代谢组学与免疫学和 神经行为分析。这项提议的成功执行将建立一个新的概念框架 将饮食和肠道微生物区系等可调节因素与POCD联系起来，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 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.