Yu Fang, Li Xi, Feng Xianjing, Wei Minping, Luo Yunfang, Zhao Tingting, Xiao Bo, Xia Jian
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, China.
Front Cardiovasc Med. 2021 Dec 23;8:798765. doi: 10.3389/fcvm.2021.798765. eCollection 2021.
To discover novel metabolic biomarkers of ischemic stroke (IS), we carried out a two-stage metabolomic profiling of IS patients and healthy controls using untargeted and targeted metabolomic approaches. We applied untargeted liquid chromatography-mass spectrometry (LC-MS) to detect the plasma metabolomic profiles of 150 acute IS patients and 50 healthy controls. The candidate differential microbiota-derived metabolite phenylacetylglutamine (PAGln) was validated in 751 patients with IS and 200 healthy controls. We evaluated the associations between PAGln levels and the severity and functional outcomes of patients with IS. Clinical mild stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score 0-5, and moderate-severe stroke as NIHSS score >5. A favorable outcome at 3 months after IS was defined as the modified Rankin Scale (mRS) score 0-2, and unfavorable outcome as mRS score 3-6. In untargeted metabolomic analysis, we detected 120 differential metabolites between patients with IS and healthy controls. Significantly altered metabolic pathways were purine metabolism, TCA cycle, steroid hormone biosynthesis, and pantothenate and CoA biosynthesis. Elevated plasma PAGln levels in IS patients, compared with healthy controls, were observed in untargeted LC-MS analysis and confirmed by targeted quantification (median 2.0 vs. 1.0 μmol/L; < 0.001). Patients with moderate-severe stroke symptoms and unfavorable short-term outcomes also had higher levels of PAGln both in discovery and validation stage. After adjusting for potential confounders, high PAGln levels were independently associated with IS (OR = 3.183, 95% CI 1.671-6.066 for the middle tertile and OR = 9.362, 95% CI 3.797-23.083 for the highest tertile, compared with the lowest tertile) and the risk of unfavorable short-term outcomes (OR = 2.286, 95% CI 1.188-4.401 for the highest tertile). IS patients had higher plasma levels of PAGln than healthy controls. PAGln might be a potential biomarker for IS and unfavorable functional outcomes in patients with IS.
为了发现缺血性中风（IS）的新型代谢生物标志物，我们采用非靶向和靶向代谢组学方法，对IS患者和健康对照进行了两阶段代谢组学分析。我们应用非靶向液相色谱-质谱联用（LC-MS）检测了150例急性IS患者和50例健康对照的血浆代谢组学图谱。在751例IS患者和200例健康对照中验证了候选差异微生物衍生代谢物苯乙酰谷氨酰胺（PAGln）。我们评估了PAGln水平与IS患者的严重程度和功能结局之间的关联。临床轻度中风定义为美国国立卫生研究院卒中量表（NIHSS）评分为0 - 5分，中度至重度中风定义为NIHSS评分>5分。IS后3个月的良好结局定义为改良Rankin量表（mRS）评分为0 - 2分，不良结局定义为mRS评分为3 - 6分。在非靶向代谢组学分析中，我们检测到IS患者和健康对照之间有120种差异代谢物。显著改变的代谢途径有嘌呤代谢、三羧酸循环、类固醇激素生物合成以及泛酸和辅酶A生物合成。在非靶向LC-MS分析中观察到IS患者血浆PAGln水平高于健康对照，并通过靶向定量得到证实（中位数2.0 vs. 1.0 μmol/L；<0.001）。在发现和验证阶段，具有中度至重度中风症状和不良短期结局的患者PAGln水平也较高。在调整潜在混杂因素后，高PAGln水平与IS独立相关（与最低三分位数相比，中间三分位数的OR = 3.183，95%CI 1.671 - 6.066；最高三分位数的OR = 9.362，95%CI 3.797 - 23.083）以及不良短期结局的风险（最高三分位数的OR = 2.286，95%CI 1.188 - 4.401）。IS患者的血浆PAGln水平高于健康对照。PAGln可能是IS以及IS患者不良功能结局的潜在生物标志物。
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