Chen Zhili, Xin Ling, Yang Liu, Xu Meijie, Li Fei, Zhou Min, Yan Tao
Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China; Department of Neurology, Tangshan Gongren Hospital, Tangshan 063000, China.
Exp Neurol. 2023 May;363:114351. doi: 10.1016/j.expneurol.2023.114351. Epub 2023 Feb 17.
Aging increases the risk of stroke, may exacerbate neuroinflammatory responses, reduce angiogenesis, and promote white matter damage post-stroke, all of which contribute to long-term functional recovery. Butyric acid, an important gut microbial metabolite, showed the highest correlation with the outcomes of ischemic stroke, and butyrate was selected as an effective treatment for aged stroke mice. Here, we tested the neurorestorative effect and potential therapeutic mechanisms of butyrate in aged mice with stroke. Aged male C57BL/6 J mice (17-19 months) were subjected to photothrombotic stroke. We performed butyrate supplementation in the drinking water for 3 weeks before surgery until 14 days after the stroke. At 14 days after ischemic stroke, white matter damage, leukocyte infiltration, and blood-brain barrier permeability were all decreased in the aged stroke mice that received the butyrate treatment, which also improved neurological outcomes by stimulating angiogenesis. Stroke reduces the level of interleukin-22 (IL-22) and butyrate treatment significantly enhanced IL-22 expression in the brain. To further validate the mechanisms of butyrate promoting neurological function after stroke, monoclonal antibodies were used to block IL-22 in aged stroke mice when butyrate treatment was provided. Blocking IL-22 in butyrate-treated aged stroke fails to improve functional outcomes and attenuated butyrate-induced angiogenesis, increased axon/white matter density and blood-brain barrier (BBB) integrity, but has no effect on inflammatory cells infiltration. In conclusion, butyrate improves outcomes in aged mice after stroke by promoting angiogenesis and BBB integrity and reducing leukocyte infiltration. To some extent, IL-22 may contribute to butyrate treatment induced vascular remodeling and increased BBB integrity responses in aged stroke mice.
衰老会增加中风风险，可能加剧神经炎症反应，减少血管生成，并促进中风后的白质损伤，所有这些都会影响长期功能恢复。丁酸是一种重要的肠道微生物代谢产物，与缺血性中风的预后相关性最高，因此被选为老年中风小鼠的有效治疗方法。在此，我们测试了丁酸对老年中风小鼠的神经修复作用及其潜在治疗机制。选用17 - 19月龄的雄性C57BL/6 J老年小鼠进行光血栓性中风造模。在手术前3周开始通过饮用水补充丁酸，持续至中风后14天。缺血性中风后14天，接受丁酸治疗的老年中风小鼠的白质损伤、白细胞浸润和血脑屏障通透性均降低，同时通过刺激血管生成改善了神经功能结局。中风会降低白细胞介素-22（IL-22）水平，而丁酸治疗可显著增强大脑中IL-22的表达。为进一步验证丁酸促进中风后神经功能的机制，在给予丁酸治疗时，使用单克隆抗体阻断老年中风小鼠体内的IL-22。在接受丁酸治疗的老年中风小鼠中阻断IL-22并不能改善功能结局，且会减弱丁酸诱导的血管生成、增加轴突/白质密度和血脑屏障（BBB）完整性，但对炎症细胞浸润没有影响。总之，丁酸通过促进血管生成和血脑屏障完整性以及减少白细胞浸润来改善老年小鼠中风后的结局。在一定程度上，IL-22可能有助于丁酸治疗诱导老年中风小鼠的血管重塑和血脑屏障完整性增加反应。
