基于肠嗜铬细胞探讨肠道菌群对术后肠麻痹的影响及机制研究

Postoperative ileus is one of the most common postoperative complications, which is characterized by the dysfunction of gut motility and affects patient recovery after surgery. The methods to prevent and improve gut motility after surgery are important during perioperative period. Our previous findings demonstrated that alterations of the microbiome might affect gut motility via altered 5-HT by microbial-derived metabolites in the development of constipation. Furthermore, the composition of the intestinal microbiota was different between patients with postoperative ileus and controls, and the symptoms of decreased gastrointestinal motility in mice with postoperative ileus could be transferred to mice through their fecal microbiota in the cohousing model. Based on these findings, the aim of our study is to find out the characteristic of intestinal microbiota in patients with postoperative ileus. And the relationship between gut microbiota and postoperative ileus will be discussed by a mouse model of postoperative ileus and humanized mice model. What`s more, the mechanism will also be discussed from the microbial-derived metabolites, intestinal inflammatory response, and enteric nervous system. In addition, under the guide of high-throughput sequencing, we will try to separate some key strains and let them individually colonize in normal mice in order to judge their effects. The results of this study will help to demonstrate the potential role of fecal microbiota from patients with postoperative ileus in the regulation of gastrointestinal motility, and the alterations of the microbiome from patients with postoperative ileus could affect gut motility of mice in humanized mice model. In addition, we try to draw the conclusion which indicates that the changes of gut motility are due to altered 5-HT by microbial-derived metabolites. The important experiments include analyzing the intestinal microbiota from patients with postoperative ileus, finding mechanisms of intestinal microbiota affect the gut motility. From this study, we want to deepen our knowledge of the pathophysiology in postoperative ileus, and explore the potential therapies based on the gut microbiota.

术后肠麻痹主要表现为肠道动力减弱，其严重影响患者术后恢复，如何改善术后肠道动力障碍是围手术期的重要研究内容。在慢传输型便秘患者肠道菌群相关研究中，证实其菌群结构发生改变，且菌群代谢产物通过5-HT通路参与调控肠道蠕动。进一步研究发现，术后肠麻痹患者的肠道菌群可发生类似便秘患者肠道菌群改变，动物实验表明术后肠麻痹小鼠的肠道菌群可导致正常小鼠的肠道动力减弱。本项目主要研究内容包括深入挖掘术后肠麻痹患者的肠道菌群变化特点；结合“术后肠麻痹小鼠”和“人源化鼠”从不同角度探讨肠道菌群与术后肠麻痹的关系；从菌群代谢产物、肠道炎症反应、肠道神经系统进一步分析相关机制；寻找可能影响肠道动力的相关功能菌种。通过本项目研究拟得出术后肠麻痹患者改变的肠道菌群是影响术后肠道动力恢复的重要影响因素之一，术后肠麻痹患者的肠道菌群可通过干扰肠嗜铬细胞产生5-HT的功能导致小鼠出现肠道动力减弱现象。本项目关键实验在于分析术后肠麻痹患者的肠道菌群变化特点，以及研究肠道菌群改变后通过何种途径影响肠道动力。本课题的意义在于揭示术后肠麻痹的病理生理变化并寻找潜在的治疗靶点，进而为基于肠道微生态理念防治术后肠麻痹提供理论依据。

术后肠麻痹在胃肠道手术后较为常见，主要表现为排气排便时间延迟，严重影响患者出院时间。尽管目前加速康复外科理念已在临床普遍开展，但如何将这个理念实施开展是围手术期的重要研究内容。肠道菌群及菌群代谢产物在肠道疾病中的作用逐渐受到重视，越来越多的证据也表明其在术后肠麻痹中发挥重要作用。本研究主要揭示肠道菌群与术后肠麻痹的关系，为肠道微生态治疗在术后肠麻痹中的作用提供理论依据。本研究发现了术后肠麻痹患者的肠道菌群丰度和多样性发生了改变，且利用“人源化鼠”模型发现其可通过短链脂肪酸和胆汁酸菌群代谢产物影响肠嗜铬细胞产生5-HT，从而导致肠道动力减弱的现象。另外，本研究发现对于胃肠道手术患者围手术期补充益生菌有利于促进术后排气排便恢复。本课题的结果揭示了肠道菌群及菌群代谢产物在术后肠麻痹病理生理中的作用，为防治术后肠麻痹提供了新的治疗途径及理论依据。