肠道微生态在高血压病发生发展中的作用及其机制研究

Essential hypertension is a most prevalent cardiovascular diseases, and becomes a serve global public health issue because of the high morbidity and potential risk to other cardiovascular diseases. Recently, several animal studies reported that the disorder of gut microbiome correlated with hypertension. Based on our previous work findings of metagenomics analysis, fecal transplantation and metabonomics changes in hypertension and pre-hypertension patients, we raised our hypothesis "Disorder of gut microbiome is a novel environmental pathogenic factor of essential hypertension". In this project, we plan to analyze the metagenomics in other two cohorts for conforming the universality of this pathogenic factor in human. Using isolated conditional pathogenic bacterium or its components to inoculatetransplant sterile germ-free mice, we aim to identify the key pathogenic bacterium for inducing hypertension. Next, we plan to observe the possible immunological injury by pathogen-associated molecular pattern pathway or damage-associated molecular pattern while giving pathogenic bacterium; or to observe vascular injury by the metabolic production to elucidate the pathophysiologcial mechanism of gut microbiome. Last, we plan to interference the disorder of gut microbiome to treat hypertensive rats, aim to evaluate the efficiency of therapy addressing gut microbiome as target. In the present project, we aim to give some evidences to support our hypothesis by these studies. By performing this project, we offer a novel common pathogenic factor of hypertension, and a novel preventive and therapeutic target of essential hypertension.

高血压病是最常见的慢病，是中国乃至全球重要的公共卫生问题。近期有动物实验研究提示肠道微生物失调与高血压相关。本项目是申请人前一个国家自然基金课题的延续和深入，即在高血压、高血压前期及健康人肠道菌群宏基因组测序、高血压病人粪菌移植无菌小鼠诱发小鼠血压升高以及高血压病人血清代谢组学研究的基础上，进一步采集不同区域高血压病人标本扩大样本量进行肠道宏基因组分析，以明确高血压病人肠道菌群紊乱分子分型特征的普遍性；筛选代表性条件致病菌株进行无菌小鼠移植试验明确因果关系；并观察条件致病菌是否通过抗原介导的分子模式或损伤介导的分子模式活化机体免疫炎症反应；评估肠道菌群调节相关血清代谢小分子的血管损伤机制；观察干预肠道菌群对高血压防治的有效性，从而探讨肠道菌群微生态紊乱是高血压发病新的环境致病因素，明确肠道菌群导致血压调节障碍的病理生理机制。本项目的开展将对临床早期防治高血压提供新的靶点，具有重要的意义。

高血压病是最常见的慢病，是中国乃至全球重要的公共卫生问题。课题组在国家自然科学基金的资助下，选取正常血压组，高血压前期组，高血压组人群，结合宏基因组和代谢组学，发现高血压及高血压前期患者的肠道菌群物种组成及代谢特征显著区别于健康人，揭示了高血压病人肠道菌群紊乱失调特征。通过菌群移植实验，证实高血压病人的肠道菌群可诱发无菌小鼠血压升高，获得了肠道微生物直接影响宿主血压的详实证据。我们明确了高血压患者肠道中优势的克雷伯杆菌促进小鼠血压升高，血管收缩和肠道损伤的作用。探究了肠道菌群调节的代谢小分子琥珀酸，琥珀酸导致免疫系统的激活，促使炎症因子、细胞因子释放损伤血管内皮，血管舒张功能下降，诱发高血压的机制。明确CD4+T细胞内源性CSE/H2S系统促进调节性T细胞的分化和增殖，改善肾脏和血管的炎症，发挥高血压保护作用。进一步探索了高血压患病率较低的彝族原住民肠道菌群和代谢特征。基于其饮食习惯开发了靶向肠道菌群的苦荞配方饮食，阐明了对高血压防治的有效性。建立了高通量微生物组学培养平台和人工智能生物信息算法平台，完成全国多中心、前瞻性、随机对照临床试验-中国老年高血压患者降压靶目标的干预研究。启动口服FMT胶囊治疗原发性高血压的临床研究和益生菌治疗原发性高血压有效性和安全性的临床研究。在该国家自然科学基金项目的资助下，以通讯作者发表论文27篇，影响因子合计256.085，单篇影响因子最高91.245。获批专利2项，主编专著2本。培养博士后及研究生4名。获得国家自然科学基金杰出青年基金 1项，科技部中青年科技领军人才，北京市卓越青年科学家计划等。