犬尿氨酸代谢异常介导的肠道菌群-肠-脑轴失调——术后认知功能障碍的新机制

Postoperative cognitive dysfunction (POCD) , which can increase the morbidity and mortality, has been an important clinical issue to be solved. However, the mechanism of POCD is not clear yet. Our previous studies demonstrated that injury of the central cholinergic neuron plays an important role in the occurrence of POCD of aged mice. The result of the preliminary experiment of the Transcriptome Sequencing indicates the level of kynurenine aminotransferase (KAT-II) increases in the kynurenine metabolic pathway of the hippocampus post-op. The level of kynurenine in the postoperative blood increases at the same time, and intestinal flora also changes significantly. So we hypothesize that dysbacteriosis caused by the surgery raises the activation of key enzymes of tryptophan metabolism or creates the key enzymes in intestinal tract ,then increasing kynurenine concentration in blood .The kynurenine goes through the blood-brain barrier, which is turned into KYNA by KAT - II enzymes. The increase of KYNA acts on the alpha 7-nAchR receptor in the hippocampus, then reducing the levels of acetylcholine, which results in the down regulation of learning and memory ability. In the present study, with the appendectomy model of aged mice, many methods including KAT-II-gene knock out mice and flora transplantation in GF mice will be adopted to verify our hypothesis. Our study will present a new mechanism of POCD and provide new targets for the therapy of POCD in clinical setting.

术后认知功能障碍（POCD）可以增加围术期死亡率，已经成为一个临床上亟待解决的重要问题，但其发病机制不清楚。我们先前的研究发现老年小鼠术后中枢乙酰胆碱水平降低是POCD发生的重要原因，但其机制不明。预实验转录组测序结果提示术后海马犬尿氨酸代谢途径中的犬尿酸氨基转移酶-II（KAT-II）明显上调，同时发现术后血中犬尿氨酸水平上调，肠道菌群也发生了明显变化。由此提出假说：手术造成了肠道菌群失调，失调的菌群上调或者自身合成色氨酸代谢途径中的关键酶，使得血中犬尿氨酸浓度上调，犬尿氨酸通过血脑屏障后在KAT-II的作用下生成犬尿奎啉酸（KYNA）增加，增加的KYNA 作用于α7 nAchR 受体降低乙酰胆碱的水平，最终造成学习和记忆能力下降。本研究拟采用老年小鼠阑尾切除术模型，应用KAT-II基因敲除和无菌小鼠菌群移植等技术证明上述假说，从而提出POCD的新机制，为临床上防治POCD提供新的靶点。

术后认知功能障碍（POCD）是一种以学习、记忆能力改变为表现的术后并发症，可增加围术期的发病率及死亡率，常见于老年手术患者，是临床上亟待解决的问题。近年来，肠道菌群紊乱已被证明参与多种神经退行性变的发生发展，而围术期的多种因素如肠道手术本身、抗生素的应用等均可影响肠道菌群的组成及功能，然而肠道菌群是否参与老年小鼠术后认知功能障碍的发病且其机制如何尚未明确，为此我们通过16srRNA测序及一系列分子生物学实验、行为学测试来探究其机制。结果显示，老年小鼠麻醉/手术后肠道菌群的组成发生改变，炎症因子水平升高，犬尿氨酸代谢通路显著活化，导致外周及中枢的犬尿氨酸显著增多，与术后的认知功能改变相关；而在给予复合抗生素或益生菌预处理均能改善老年小鼠麻醉/手术后的认知功能，且能逆转炎症因子及犬尿氨酸代谢通路的变化。本研究证明了肠道菌群及犬尿氨酸代谢通路在老年小鼠术后认知功能障碍发生发展中的重要作用，为POCD的防治提供了新的干预靶点及思路。