Department of Critical Care Medicine, Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310006, China.
Department of Critical Care Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
Nutrients. 2022 Aug 24;14(17):3467. doi: 10.3390/nu14173467.
Traumatic brain injury (TBI) is a common cause of disability and mortality, affecting millions of people every year. The neuroinflammation and immune response post-TBI initially have neuroprotective and reparative effects, but prolonged neuroinflammation leads to secondary injury and increases the risk of chronic neurodegenerative diseases. Persistent microglial activation plays a critical role in chronic neuroinflammation post-TBI. Given the bidirectional communication along the brain-gut axis, it is plausible to suppose that gut microbiota dysbiosis post-TBI influences microglial activation. In the present study, hippocampal microglial activation was observed at 7 days and 28 days post-TBI. However, in TBI mice with a depletion of gut microbiota, microglia were activated at 7 days post-TBI, but not at 28 days post-TBI, indicating that gut microbiota contributes to the long-term activation of microglia post-TBI. In addition, in conventional mice colonized by the gut microbiota of TBI mice using fecal microbiota transplant (FMT), microglial activation was observed at 28 days post-TBI, but not at 7 days post-TBI, supporting the role of gut microbiota dysbiosis in persistent microglial activation post-TBI. The RNA sequencing of the hippocampus identified a microglial activation gene, Lyz2, which kept upregulation post-TBI. This persistent upregulation was inhibited by oral antibiotics and partly induced by FMT. 16s rRNA gene sequencing showed that the composition and function of gut microbiota shifted over time post-TBI with progressive dysbiosis, and untargeted metabolomics profiling revealed that the tryptophan metabolic phenotype was differently reshaped at 7 days and 28 days post-TBI, which may play a role in the persistent upregulation of Lyz2 and the activation of microglia. This study implicates that gut microbiota and Lyz2 are potential targets for the development of novel strategies to address persistent microglial activation and chronic neuroinflammation post-TBI, and further investigations are warranted to elucidate the specific mechanism.
创伤性脑损伤（TBI）是一种常见的残疾和死亡原因，每年影响数百万人。TBI 后神经炎症和免疫反应最初具有神经保护和修复作用，但长期的神经炎症会导致继发性损伤，并增加慢性神经退行性疾病的风险。持续的小胶质细胞激活在 TBI 后慢性神经炎症中起着关键作用。鉴于沿脑-肠轴的双向通讯，有理由假设 TBI 后肠道微生物组失调会影响小胶质细胞激活。在本研究中，在 TBI 后 7 天和 28 天观察到海马小胶质细胞激活。然而，在 TBI 小鼠的肠道微生物群耗竭中，小胶质细胞在 TBI 后 7 天被激活，但在 28 天不被激活，表明肠道微生物群有助于 TBI 后小胶质细胞的长期激活。此外，在使用粪便微生物群移植（FMT）使 TBI 小鼠的肠道微生物群定植的常规小鼠中，在 TBI 后 28 天观察到小胶质细胞激活，但在 7 天不被激活，支持肠道微生物群失调在 TBI 后持续小胶质细胞激活中的作用。海马的 RNA 测序鉴定了一个小胶质细胞激活基因 Lyz2，该基因在 TBI 后持续上调。这种持续上调被口服抗生素抑制，部分被 FMT 诱导。16s rRNA 基因测序显示，TBI 后肠道微生物群的组成和功能随时间推移发生变化，出现进行性失调，非靶向代谢组学分析显示色氨酸代谢表型在 TBI 后 7 天和 28 天发生不同重塑，这可能在 Lyz2 的持续上调和小胶质细胞的激活中发挥作用。这项研究表明，肠道微生物群和 Lyz2 是开发针对 TBI 后持续小胶质细胞激活和慢性神经炎症的新策略的潜在靶点，需要进一步研究以阐明具体机制。
