慢性肾脏病肠道菌群紊乱导致过量三甲胺产生风险研究

Cardiovascular disease (CVD) is a leading cause of death in Chronic Kidney Disease (CKD) patients, in which the mechanism remains to be explored. Trimethylamine (TMA), the gut microbiota metabolite of L-carnitine orally taken by CKD patients, is converted to Trimethylamine oxide (TMAO), promoting the progress of atherosclerosis. Our research group have demonstrated that the CKD patients exhibited significantly elevated serum TMAO levels and dysbiosis of gut microbiota, which further led to significantly increased TMAO levels in mice that received fecal microbiota transplantation from these patients. Therefore, we suppose that TMA produced by gut microbiota plays an important role in development of cardiovascular diseases and a personalized risk assessment model can be established based on gut microbiota in CKD patients. In this study, firstly, we plan to verify the causality relationship and functional consistency between gut microbiota and serum TMAO levels in CKD patients through experiments in vitro and in vivo, and explore microbial metabolic pathways of TMA by metagenomics. Then, the mechanism of the progress of cardiovascular diseases caused by TMA produced by gut microbiota will be explored in CKD patients, through the ApoE -/- mice experiments. Finally, a follow-up cohort of CKD patients will be collected to evaluate the consistency between their experimental results of fecal samples in vitro and TMAO levels of those patients taking L-carnitine orally, and to establish a risk assessment model of TMA induced by L-carnitine in CKD patients. Our study is designed to elucidate the risk of TMA produced by orally taken L-carnitine in the development of cardiovascular diseases, and to establish a new approach for personalized nutrition programs in CKD patients.

慢性肾脏病（CKD）首要死亡原因为心血管疾病，机制有待探索。CKD患者口服补充肉碱，被肠道菌群代谢为三甲胺（TMA），之后转化为TMAO促进动脉粥样硬化进展。课题组发现CKD患者血浆TMAO显著升高，CKD肠菌移植显著升高小鼠血浆TMAO水平。本课题假设：CKD患者肠菌生成TMA是其心血管疾病的重要机制，并可依据肠菌建立个性化风险评价模型。本研究拟首先通过体内外实验验证CKD肠菌特征与血清TMAO升高的因果关系与功能一致性，通过宏基因组学探索TMA主要微生物代谢途径；其次通过ApoE-/-小鼠实验探索CKD肠菌通过TMA途径影响心血管疾病机制；最后建立CKD患者随访队列评估其粪便样本体外实验结果与口服肉碱后TMAO水平一致性，建立CKD患者肠菌代谢肉碱产TMA风险评价模型。本研究有望为阐明CKD患者口服肉碱产生TMA在心血管疾病中的风险奠定实验基础，为建立CKD患者个体化营养方案探索新途径

研究按照课题计划书顺利执行，主要完成并取得进展如下：（1）探究了脑卒中后大脑与肠道的互作关联：缺血性脑卒中可引发特征一致的肠道菌群紊乱，即肠杆菌科的过度增殖；且紊乱的菌群可进一步促进脑损伤的进展，并与脑卒中的不良结局相关。文章发表于Gut杂志（IF=23.059）；（2）发现合并糖尿病的急性缺血性卒中患者肠道菌群紊乱程度大于糖尿病患者或急性缺血性卒中患者，其中糖尿病特征菌群与合并糖尿病的急性缺血性卒中患者的不良临床结局相关，糖尿病特征的肠道菌群可加重卒中后脑损伤的严重程度。文章发表于mSystems杂志（IF=6.496）；（3）发现脑卒中患者肠道宏病毒组的整体多样性与健康志愿者相似，但宏病毒组的组成及其与菌群的相互作用模式不同，文章发表于南方医科大学学报；（4）发现慢性肾脏病患者肠道菌群发生紊乱，慢性肾脏病患者在并发脑血管疾病期间体现出更差的临床预后。上述论文在进一步整理投稿中；（5）期间参与多项学术会议，进行学术汇报，并获得2021年中国脑卒中防治百篇优秀论文一等奖与2021中国肠道大会优秀口头报告奖。