Fecal Microbiota Transfer Attenuates Gut Dysbiosis and Functional Deficits After Traumatic Brain Injury.
Fecal Microbiota Transfer Attenuates Gut Dysbiosis and Functional Deficits After Traumatic Brain Injury.
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DOI：
10.1097/shk.0000000000001934
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发表时间：
2022-06-01
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创伤性脑损伤(TBI)是一种未被充分认识的公共健康威胁。脑外伤的幸存者经常遭受长期的神经认知缺陷，导致神经退行性疾病的进行性发作。最近的数据表明，肠道-脑轴在这一过程中是同谋的。然而，还没有专门研究粪便微生物区系转移(FMT)是否能减轻脑外伤后的神经功能障碍。我们假设粪便微生物区系转移可以减轻脑外伤后的神经认知、解剖和病理缺陷。C57BL/6小鼠采用头部控制性皮质撞击，造成重型颅脑损伤(n=20)或假损伤(n=20)。损伤后，这组小鼠在脑损伤后1h开始每周用健康小鼠粪便或交通工具浆液灌胃，随后进行行为测试和神经病理学分析。用16S核糖体RNA测序的方法分析损伤前后肠道微生物群落结构。用零迷宫和开场测试评估创伤后焦虑、探索行为和一般活动。3D增强磁共振成像用于确定皮质体积丢失和脑白质连通性的差异。在安乐死之前，大脑被采集用于神经病理分析。粪便微生物组分析显示，接受赋形剂治疗的TBI组和假手术组动物之间存在很大差异，而FMT治疗的TBI组小鼠的肠道生态失调恢复到了对照组小鼠的水平。神经认知测试显示，在接受FMT治疗的脑损伤小鼠中，正常的焦虑样和探索行为得到了挽救。与车辆组的小鼠(13%)相比，经fmt处理的脑外伤小鼠在开阔场地中心区域花费的时间百分比(22%，P=0.0001)更大。车祸组小鼠在零迷宫开放区域的时间(19%)也比短程组小鼠(30%，P=0.0001)少。与接受软组织移植治疗的脑损伤小鼠相比，核磁共振显示脑室增大显著减轻(P<；0.002)，各向异性分数显著改变(即白质连接性丧失)(P<；0.0001)。脑切片组织学分析显示，小胶质细胞/巨噬细胞特异性离子钙结合蛋白Iba1存在FMT损伤依赖的相互作用(P=0.002)。这些数据表明，恢复损伤前肠道微生物群落结构可能是一种有希望的脑外伤后治疗干预措施。
Traumatic brain injury (TBI) is an underrecognized public health threat. Survivors of TBI often suffer long-term neurocognitive deficits leading to the progressive onset of neurodegenerative disease. Recent data suggests that the gut-brain axis is complicit in this process. However, no study has specificallyaddressed whether fecal microbiota transfer (FMT) attenuates neurologic deficits after TBI. We hypothesized that fecal microbiota transfer would attenuate neurocognitive, anatomic, and pathologic deficits after TBI. C57Bl/6 mice were subjected to severe TBI (n = 20) or sham-injury (n = 20) via an open-head controlled cortical impact. Post-injury, this cohort of mice underwent weekly oral gavage with a slurry of healthy mouse stool or vehicle alone beginning 1 h post-TBI followed by behavioral testing and neuropathologic analysis. 16S ribosomal RNA sequencing of fecal samples was performed to characterize gut microbial community structure pre- and post-injury. Zero maze and open field testing were used to evaluate post-traumatic anxiety, exploratory behavior, and generalized activity. 3D, contrast enhanced, magnetic resonance imaging was used to determine differences in cortical volume loss and white matter connectivity. Prior to euthanasia, brains were harvested for neuropathologic analysis. Fecal microbiome analysis revealed a large variance between TBI, and sham animals treated with vehicle, while FMT treated TBI mice had restoration of gut dysbiosis back to levels of control mice. Neurocognitive testing demonstrated a rescue of normal anxiety-like and exploratory behavior in TBI mice treated with FMT. FMT treated TBI mice spent a greater percentage of time (22%, P = 0.0001) in the center regions of the Open Field as compared to vehicle treated TBI mice (13%). Vehicle-treated TBI animals also spent less time (19%) in the open areas of zero maze than FMT treated TBI mice (30%, P = 0.0001). Comparing in TBI mice treated with FMT, MRI demonstrated a marked attenuation in ventriculomegaly (P < 0.002) and a significant change in fractional anisotropy (i.e., loss of white matter connectivity) (P < 0.0001). Histologic analysis of brain sections revealed a FMT-injury dependent interaction in the microglia/macrophage-specific ionized calcium-binding protein, Iba1 (P = 0.002). These data suggest that restoring a pre-injury gut microbial community structure may be a promising therapeutic intervention after TBI.