Phenylacetylglutamine, a Novel Biomarker in Acute Ischemic Stroke

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.

Increased circulating phenylacetylglutamine concentration elevates the predictive value of cardiovascular event risk in heart failure patients

“…In recent years, the link between gut microbiota and circulating PAGln has been elucidated in several studies [35,36], especially by Nemet et al, which validates a major role for gut microbiota in PAGln generation in humans [20]. Notably, some literature regarding CVD seems to uncover the destructive role of circulating PAGln [18,19,23,25,[37][38][39]. For instance, PAGln is reportedly associated with the degree of coronary atherosclerotic severity in patients with coronary artery disease, and similar results were obtained in patients with carotid atherosclerosis [18,39].…”

Dengzhanshengmai capsule alleviates heart failure and concomitantly decreases phenylacetylglutamine level, interacting with the intestinal microflora in rats

“…PAGln, also a microbial-derived metabolite, has been reported to be associated with CVD and major adverse cardiovascular events, including myocardial infarction, stroke or death (Nemet et al, 2020;Ottosson et al, 2020;Poesen et al, 2016;Yu et al, 2021).…”

PAGln, an Atrial Fibrillation-Linked Gut Microbial Metabolite, Acts as a Promoter of Atrial Myocyte Injury

“…Altered gut microbial composition and metabolic patterns are involved in AF development and recurrence [ 18 , 26 , 27 , 28 ]. GM-derived metabolite PAGln has been found to be substantially elevated in end-stage renal disease, acute ischemic stroke and coronary artery disease (CAD) with stent stenosis and related to CVD and incident major adverse cardiovascular events including myocardial infarction, stroke and death [ 9 , 29 , 30 ]. Likewise, our data also confirmed the association between AF and PAGln.…”