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

在高达26%的手术患者中，术后发生轻微但持续的学习和记忆缺陷， 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，包括死亡率增加。潜在的发病机制 POCD仍然不清楚。可改变和不可改变的因素都可能导致POCD。迄今为止，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， 他们已经确定年龄和遗传是POCD的主要危险因素。不幸的是，这些是不可修改的 这些因素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群一直是 与许多具有炎症特征的神经系统疾病有关。肠道微生物群是否影响POCD 还有待检验。在我们的初步研究中，我们观察到肠道微生物群以前未被认识到的作用， 在异氟烷麻醉下股动脉暴露后小鼠发生POCD。我们特别 发现：1）肠道菌群正常的小鼠不发生POCD，而肠道菌群失调的小鼠发生POCD; 2)口服氨苄青霉素治疗导致肠道菌群失调，其特征在于肠道微生物群结构 吲哚类，特别是吲哚基-3-硫酸酯（IS）和吲哚-3-丙酸（IPA）的变化和急剧减少; 3)经口给予IPA，而不是IS，阻止了POCD的发展; 4）POCD小鼠显示 海马中氧化增加和线粒体功能受损，这是由增强的 活性氧（ROS）的产生，NADH的产生减少， NDUFS 4（一种关键的线粒体复合物I组分），与无POCD的小鼠相比;和5）口服 给予IPA减少了ROS的产生，增加了NADH的产生和NDUFS 4蛋白水平， 氨苄青霉素治疗小鼠的海马体。根据这些初步发现，我们假设肠道 微生物群通过IPA对POCD的发展具有关键影响。在这份研究报告中，我们将研究 这一假说通过解决三个关键问题：1）观察到的肠道生态失调对POCD的影响， 初步研究是一种附带现象还是一种“放任”效应？2)有哪些机制 IPA在POCD中的保护作用和3）我们能否制定一项基于肠道微生物群的策略， 代谢物来预防和治疗POCD这项资助是建立在我们新颖的初步发现和我们既定的 研究平台，将尖端的宏基因组学和代谢组学与免疫学和 神经行为测定。这一建议的成功实施将建立一个新的概念框架 将饮食和肠道微生物群等可变因素与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.