Wei Minping, Huang Qin, Yu Fang, Luo Yun-Fang, Feng Xianjing, Liao Di, Li Jiaxin, Zhang Boxin, Liu Ze-Yu, Xia Jian
Xiangya Hospital Central South University, Changsha, China, 410008.
Xiangya Hospital Central South University, Hunan, China, 410008.
Clin Sci (Lond). 2025 Jun 5. doi: 10.1042/CS20242943.
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.
2型糖尿病（T2D）会加重缺血性中风。肠道微生物群衍生代谢物苯乙酰谷氨酰胺（PAGln）与T2D缺血性中风患者之间的关联尚不清楚。因此，我们旨在探讨T2D缺血性中风患者肠道微生物群及其代谢物PAGln的变化，并研究PAGln在该疾病中的作用。我们进行了两项临床队列研究，以调查T2D缺血性中风患者肠道微生物群和PAGln的变化。然后，我们将患者的粪便微生物群移植到大鼠体内，并建立了大脑中动脉闭塞模型。最后，对大鼠进行腹腔注射PAGln，以测试其是否会加重脑梗死。与无T2D的中风患者相比，T2D中风患者的血浆PAGln水平显著更高。血浆PAGln与中性粒细胞胞外陷阱（NETs）呈正相关。肠杆菌科、疣微菌门和克雷伯菌在T2D中风患者中富集，且与PAGln水平呈显著正相关。与移植无T2D中风患者粪便微生物的大鼠相比，移植T2D中风患者粪便微生物的大鼠发生了更严重的脑损伤，血浆PAGln和NETs水平更高。此外，接受PAGln治疗的大鼠表现出更严重的脑损伤，伴有全身炎症、氧化应激和NET形成增加。我们的结果表明，T2D中风患者肠道微生物群失调导致循环PAGln水平升高，可能通过NETs形成、全身炎症和氧化应激加重脑梗死。
