Elevated circulating levels of phenylacetylglutamine in stroke patients with T2D are linked to specific gut microbiota

Abstract Objective Type 2 diabetes (T2D) aggravates the injury of ischemic stroke (IS). The alterations of gut microbiota and its metabolite phenylacetylglutamine (PAGln) levels in stroke patients with T2D remain unclear. Therefore, our study aimed to explore the differences in gut microbiota and its metabolite PAGln between IS patients with and without T2D. Methods In our study, 35 IS with T2D (IS-T2D group), 50 IS patients without T2D (IS-NT2D group), and 29 healthy controls (HC group) were recruited. Fecal samples were collected and analyzed using high-throughput sequencing of 16S rRNA genes, and plasma samples were subjected to targeted metabolomics to detect metabolite PAGln. Plasma PAGln levels of rats with transplantation of fecal microbes from patients were assessed. Results Our results showed that the plasma PAGln levels in IS-T2D patients were significantly higher than those in IS-NT2D patients. Correlation analysis showed that plasma PAGln levels were significantly correlated with the relative abundance of Enterobacteriaceae, Verrucomicrobiota, and Klebsiella, which were enriched in IS-T2D patients. Further studies demonstrated that plasma PAGln levels were positively correlated with the concentration of neutrophil extracellular traps (NETs), and NETs levels were increased in a dose-dependent manner according to PAGln levels. Moreover, the rats transplanted with fecal microbes from IS-T2D patients developed more severe brain injury and higher plasma PAGln levels compared to the rats transplanted with fecal microbes from IS-NT2D patients. Conclusions Our results suggest that T2D may contribute to aggravation in stroke patients via NETs, mediated in part by gut microbiota and its metabolite PAGln.