Abstract
Background: 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.Methods: 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.Results: 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; p < 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).Conclusions: 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.
Highlights
Stroke is a great threat to public health globally, especially in developing countries
We found that levels of PAGln, another microbiota-derived metabolite associated with cardiovascular disease (CVD) [7], were elevated in patients with ischemic strokes (IS)
Representative Liquid Chromatography-Mass Spectrometry (LC-MS) total ion current (TIC) chromatograms of the quality control (QC) plasma samples were shown in Supplementary Figure S1
Summary
Stroke is a great threat to public health globally, especially in developing countries. Despite decades of substantial basic and clinical studies, the etiology of IS has not been fully elucidated, and only a few effective treatments are available. It is essential to discover new circulating biomarkers to help understand the pathogenesis of IS. Unlike well-studied genomics and proteomics, metabolomics technologies have only made a major shift in the last two decades. Metabolomics profiling can provide high-throughput data and can identify small metabolites (
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