肠道菌群及其产物在卒中急性期血压调控中的作用机制研究

There is still considerable controversy regarding the management of blood pressure (BP) in acute phase of ischemic stroke (IS). The mechanism of post-stroke BP regulation, especially for the mechanism of BP decline, is not clear. Among patients with acute hypertensive response, 60% experience spontaneous declines in BP over the following few days after stroke, but 40% remain sustained high BP during acute phase. While the body immediately raises BP through sympathetic nervous system and renin-angiotensin system after stroke, whether it also initiates an antagonistic effect from another system? Recent studies have found the important role of gut microbiota on the pathogenesis of hypertension, but it is not clear whether gut microbiota has a role in the short-term BP regulation during acute phase of stroke. Our preliminary study has found that the composition of gut microbiota showed difference at the phylum or genus level between those patients with spontaneous BP decline and those with sustained high BP during acute phase of stroke. This project will further investigate the association of gut microbiota structure and short chain fatty acid (SCFA) with post-stroke BP trajectory in stroke patients and mouse models, and clarify the mechanism of SCFA and its receptors in post-stroke BP regulation, which may provide scientific evidence for exploring the BP management mode with gut microbiota as the therapeutic target in acute phase of IS.

缺血性卒中急性期血压管理一直存在争议。关于卒中后血压水平的调控机制，尤其是卒中后血压自然回落的机制目前并不清楚。60%的应激性血压升高患者数日后血压即可回落，而40%的患者急性期血压持续偏高。卒中发生后机体在通过交感神经和肾素-血管紧张素系统引起血压瞬间升高的同时，是否也启动了另一系统的拮抗效应？近期研究发现肠道菌群在高血压的发病过程中发挥了重要作用，但肠道菌群是否参与了卒中后血压水平的短期调控尚不清楚。我们前期的预试验结果发现卒中急性期血压自然回落的患者和血压持续偏高的患者其肠道菌群在门和属水平均存在显著差异。本课题将在卒中患者及小鼠模型进一步阐明肠道菌群结构及其产物短链脂肪酸（short chain fatty acid，SCFA）与卒中后血压轨迹的关系，揭示SCFA及其受体在卒中后血压调控中的信号机制，为探索以肠道菌群为靶点的缺血性卒中急性期血压管理模式提供科学依据。

肠道菌群及其代谢产物是否与缺血性卒中的临床结局相关、通过何种机制影响缺血性卒中的临床结局目前尚不清楚。本项目分别从卒中复发和神经功能预后两个方面探讨了肠道菌群及其代谢产物对于缺血性卒中临床结局的影响以及可能的机制：①肠道菌群代谢产物和卒中复发：在缺血性卒中患者中，我们发现血浆氧化三甲胺水平与卒中复发事件显著正相关；三甲基赖氨酸与血管事件无显著相关性，但其与心源性死亡呈显著正相关；②肠道菌群代谢产物和神经功能结局：在缺血性卒中患者中，我们发现血浆甜菜碱水平与卒中后神经功能良好结局呈显著正相关，我们进一步在动物水平发现，外源性给予甜菜碱的补充能够减小大脑中动脉闭塞小鼠的脑梗死体积，提示其可能具有神经保护作用。甜菜碱的神经保护作用不依赖于其调节血压的作用，而是通过减轻缺血半暗带的炎症反应及细胞焦亡介导的。本课题从临床水平及动物水平探索了肠道菌群代谢产物对于缺血性卒中复发及神经功能结局的影响，为探索以肠道菌群代谢产物为靶点的缺血性卒中治疗模式提供了证据。