POSTINJURY FECAL MICROBIOME TRANSPLANT DECREASES LESION SIZE AND NEUROINFLAMMATION IN TRAUMATIC BRAIN INJURY.
POSTINJURY FECAL MICROBIOME TRANSPLANT DECREASES LESION SIZE AND NEUROINFLAMMATION IN TRAUMATIC BRAIN INJURY.
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DOI：
10.1097/shk.0000000000001979
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发表时间：
2022-10-01
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创伤性脑损伤（TBI）是一种被低估的公共卫生威胁。TBI后小胶质细胞的组成性激活与长期神经认知缺陷和神经退行性疾病的进展有关。不断发展的证据表明，肠-脑轴在这一过程中起着关键作用。具体而言，TBI已被证明诱导肠道细菌的消耗。由此产生的肠道生态失调与神经炎症和疾病有关。我们假设粪便微生物群移植会减弱TBI后小胶质细胞活化并改善神经病理学。C57 B1/6小鼠通过开放头控制的皮质撞击经受严重TBI（n=10）或假损伤（n=10）。损伤后，小鼠每周一次通过口服管饲法接受粪便微生物群移植（FMT）或单独媒介物，持续四周。在TBI后59天，小鼠接受3D对比增强磁共振成像。成像后，处死小鼠，在60 DPI收获脑，并通过荧光激活细胞分选分离CD 45+细胞。使用IOx Genomics Chromium Single Cell 3'试剂盒制备cDNA文库，然后在HiSeq 4000仪器上测序，并进行计算分析。在TBI后59天，粪便微生物群移植导致脑室扩大的显著减少（p<0.002）和白色物质连通性的保留（p<0.0001）。此外，与仅用载体处理的小鼠相比，来自FMT处理的小鼠的小胶质细胞显著降低了炎症基因表达并丰富了涉及热休克反应的途径。我们假设通过粪便微生物群移植恢复肠道微生物群落结构将减弱小胶质细胞活化并减少TBI后的神经病理学。我们的数据表明，与单独使用溶剂治疗的小鼠相比，受伤后皮质体积和白色物质连接性显着保留。TBI后神经解剖结构的保存与FMT治疗小鼠小胶质细胞内炎症基因表达的显着减少有关。来自FMT处理的小鼠的小胶质细胞丰富了热休克反应中的通路，已知热休克反应在TBI和其他神经退行性疾病过程中发挥神经保护作用。
Traumatic brain injury (TBI) is an underrecognized public health threat. The constitutive activation of microglia after TBI has been linked to long-term neurocognitive deficits and the progression of neurodegenerative disease. Evolving evidence indicates a critical role for the gut-brain axis in this process. Specifically, TBI has been shown to induce the depletion of commensal gut bacteria. The resulting gut dysbiosis is associated with neuroinflammation and disease. We hypothesized that fecal microbiota transplantation would attenuate microglial activation and improve neuropathology after TBI. C57Bl/6 mice were subjected to severe TBI (n=10) or sham-injury (n=10) via an open-head controlled cortical impact. The mice underwent fecal microbiota transplantation (FMT) or vehicle alone via oral gavage once weekly for four weeks post-injury. At 59 days post-TBI, mice underwent 3D, contrast-enhanced magnetic resonance imaging. Following imaging, mice were sacrificed, brains harvested at 60 DPI, and CD45+ cells isolated via florescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3’ Reagent kit followed by sequencing on a HiSeq4000 instrument, and computational analysis was performed. Fecal microbiota transplantation resulted in a marked reduction of ventriculomegaly (p<0.002) and preservation of white matter connectivity at 59 days post-TBI (p<0.0001). Additionally, microglia from FMT-treated mice significantly reduced inflammatory gene expression and enriched pathways involving the heat shock response compared to mice treated with vehicle alone. We hypothesized that restoring gut microbial community structure via fecal microbiota transplantation would attenuate microglial activation and reduce neuropathology after TBI. Our data demonstrated significant preservation of cortical volume and white matter connectivity after an injury compared to mice treated with vehicle alone. This preservation of neuroanatomy after TBI was associated with a marked reduction in inflammatory gene expression within the microglia of FMT-treated mice. Microglia from FMT-treated mice enriched pathways in the heat shock response, which is known to play a neuroprotective role in TBI and other neurodegenerative disease processes.