肠道菌群代谢物TMAO及其前体物与缺血性脑卒中病后认知功能障碍的关联及风险预测模型构建

Post-stroke cognitive impairment (PSCI) is a common complication of stroke that seriously reduces the quality of life. Intestinal metabolite trimethylamine N-oxide (TMAO) is regarded as an important driver of cardiovascular disease. Experimental studies indicate that intestinal flora disturbance and elevated TMAO levels play a role in the progression of stroke and cognitive decline. Prior studies have indicated that TMAO can change intestinal epithelial permeability, affect systemic immune response, aggravate inflammatory response, induce endothelial cell dysfunction and stimulate mitochondrial oxidative stress, while all these pathological processes could cause neurological damage. However, no prospective study on the association between plasma TMAO and PSCI has been reported. This project is conducted among the ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Plasma TMAO concentrations will be measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). We will first investigate the associations of plasma TMAO and precursor (choline, betaine and L-carnitine) with PSCI, and then explore the role of inflammation and endothelial functional mechanisms in the relationships between TMAO and precursors with PSCI. In addition, we will further construct a PSCI prediction model by combining plasma TMAO and precursors, multiple biomarkers covering distinct pathways, and traditional risk factors. This model involves multiple pathologic pathways leading to the onset of PSCI, which is more comprehensive, and can accurately screen and identify high-risk PSCI patients. Our project will provide important epidemiological evidence for the use of plasma TMAO and precursors as predictive markers of PSCI, and will provide new insights for the prevention and control of PSCI.

卒中后认知障碍（PSCI）是严重影响脑卒中患者生存质量的常见并发症。肠道菌群代谢物氧化三甲胺（TMAO）被认为是心血管疾病的重要驱动因子。基础研究发现肠道菌群紊乱及TMAO异常在脑卒中进展和认知功能衰退过程中发挥作用。而血液中TMAO与PSCI关联的前瞻性研究未见报道。本项目依托已建立的缺血性脑卒中队列，采用高效液相色谱串联质谱法检测血浆TMAO和前体物（胆碱、甜菜碱和L-肉毒碱）水平，分析血浆TMAO及前体物与PSCI的关联；探讨炎症和内皮功能机制在TMAO及前体与PSCI关联之间的作用；进一步联合TMAO及前体物、前期工作发现的反映不同病理通路的缺血性脑卒中不良预后预测蛋白和传统危险因素构建PSCI预测模型，模型同时考虑导致PSCI发病的多病理途径，可精准地识别PSCI高危患者。本研究将为血浆TMAO及前体物作为PSCI预测标志提供重要的流行病学证据，为PSCI的预防和控制提供新思路。

卒中后认知障碍（PSCI）是严重影响脑卒中患者生存质量的常见并发症。肠道菌群代谢物氧化三甲胺（TMAO）被认为是心血管疾病的重要驱动因子。基础研究发现肠道菌群紊乱及TMAO异常在脑卒中进展和认知功能衰退过程中发挥作用。体内代谢物可反映脑卒中急性发作期的病理变化，提供疾病和临床表型高分辨率的生物学特征。因此，肠道代谢物用于脑卒中预后风险预测具有天然优势。本项目基于缺血性脑卒中预后前瞻性队列，采用靶向代谢组学技术检测血浆TMAO、胆碱、甜菜碱和L-肉毒碱浓度，采用Logistic回归模型结合限制性立方样条模型发现血浆TMAO与PSCI存在正相关剂量反应关系，而胆碱、甜菜碱和L-肉毒碱与PSCI存在负相关剂量反应关系。在传统危险因素模型的基础上增加TMAO通路代谢物可显著提高模型对PSCI的预测能力，改善风险分层。此外，我们发现血浆胆碱、甜菜碱与卒中后抑郁、脑卒中复发和血管事件的风险存在负相关剂量反应关系。通过项目的开展，为TMAO通路代谢物作为PSCI预测标志提供流行病学证据，为充分理解缺血性脑卒中进展的病理生理机制、改善风险分层和个体化治疗提供新思路。