Elevated phenylacetylglutamine caused by gut dysbiosis associated with type 2 diabetes increases neutrophil extracellular traps formation and exacerbates brain infarction.

Type 2 diabetes (T2D) aggravates ischemic stroke. The association between gut microbiota-derived metabolite phenylacetylglutamine (PAGln) and ischemic stroke patients with T2D remains unclear. Therefore, we aimed to explore the change of gut microbiota and its metabolite, PAGln in ischemic stroke patients with T2D, as well as investigate the role of PAGln in this disease. We performed two clinical cohort studies to investigate the changes of gut microbiota and PAGln in ischemic stroke patients with T2D. Then, we transplanted fecal microbiota from patients into rats and established a middle cerebral artery occlusion model. Finally, an intraperitoneal injection of PAGln was administered to rats to test whether it exacerbates brain infarction. Plasma PAGln levels were significantly higher in stroke patients with T2D compared to those without T2D. There was a positive correlation of Plasma PAGln with NETs. Enterobacteriaceae, Verrucomicrobiota, and Klebsiella were enriched in stroke patients with T2D and showed a significant positive correlation with PAGln levels. The rats transplanted with fecal microbes from stroke patients with T2D developed a more severe brain injury and had higher levels of plasma PAGln and NETs compared to the rats transplanted with fecal microbes from stroke patients without T2D. Additionally, rats treated with PAGln exhibited more severe brain injury accompanied by increased systemic inflammation, oxidative stress and NET formation. Our results suggest elevated circulating PAGln levels, resulting from gut dysbiosis in stroke patients with T2D, may exacerbate brain infarction through NETs formation, systemic inflammation, and oxidative stress.