A.muciniphila调控ECB系统参与内脏高敏感的机制研究

The triggering factor for most IBS symptoms in the clinic is gastrointestinal infection, called post-infection IBS (PI-IBS).Exploring the mechanism of visceral hypersensitivity in PI-IBS we have confirmed that the endocannabinoids ECB/CB1 receptor at intestinal mucosa involved in the vagus afferent regulation of gastrointestinal visceral pain response；and the ECB/CB1 receptor machanism is the managed key molecular targets in 5-HT3 receptor downstream.However, there is a lack of effective drugs.Probiotics have been found to improve PI-IBS symptoms, and in PI-IBS patients A. muciniphila levels are decreased than healthy people.The studies suggested giving A. muciniphila increases intestinal ECB level. Based on the previous results, the study aimed to explore A. muciniphila how to influence IBS visceral hyperalgesia.We will prove: increasing A. muciniphila mucosal level,can reduce the PI - IBS local lumen increased 5 - HT content, improving the inner lumen of chronic stimulation of 5 - HT, increasing the content of endocannabinoids, and improving the symptoms of abdominal pain.

临床上大多数IBS症状触发因素为胃肠道感染，称为感染后IBS（PI-IBS）。我们在探寻PI-IBS内脏高敏感形成机制中已证实肠粘膜处内源性大麻素ECB/CB1受体参与迷走神经抑制性调控内脏痛反应；而ECB/CB1受体机制是处于5-HT3r下游可干预的关键分子靶点。但目前尚缺乏疗效明确的药物。临床发现予以益生菌可以改善PI-IBS症状，且有研究证实PI-IBS患者肠道内Akkermansia muciniphila水平与健康人群相比较低，而补充A.muciniphila会增加肠道内ECB的水平。因此本课题拟在前期研究基础上探寻A.muciniphila如何影响PI-IBS内脏高敏感形成机制。我们将通过实验证实：增加A.muciniphila的黏膜水平，可以降低PI-IBS原本肠腔局部逐渐升高的5-HT含量，改善肠腔内慢性5-HT的刺激，提高ECB水平，改善腹痛症状。

感染后IBS（PI-IBS）是肠易激综合征（IBS）中常见的一种，常发生于胃肠道感染后。我们之前的研究证实PI-IBS内脏高敏感形成机制中，迷走传入神经5-HT/5-HT3受体通路参与抑制性调控内脏痛，而ECB/CB1R信号通路是迷走传入神经5-HT/5-HT3R途径下游的关键分子机制。但目前尚缺乏有效的针对IBS的ECB相关药物，需要探寻一个可调节的有效生物靶点。Akkermansia muciniphila 在IBS及健康人群中丰度有显著差异，且A. muciniphila水平可能引起内源性大麻素（ECB）含量改变。因此我们制备PI-IBS大鼠模型，通过A. muciniphila干预实验观察到A. muciniphila灌胃可抵消PI-IBS内脏高敏感的作用，减轻内脏痛；同时检测到补充A. muciniphila可引起肠腔局部5-HT水平下调，ECB含量升高；该作用是通过影响ECB降解酶的丰度以及CB1受体水平来实现的。A. muciniphila干预可增加肠道黏液层厚度，改善局部炎症，缓解内脏高敏感。本研究为未来开发A. muciniphila为改善PI-IBS内脏痛提供了一定的科学参考。