Fagan Madison M, Welch Christina B, Scheulin Kelly M, Sneed Sydney E, Jeon Julie H, Golan Morgane E, Cheek Savannah R, Barany Deborah A, Oeltzschner Georg, Callaway Todd R, Zhao Qun, Park Hea Jin, Lourenco Jeferson M, Duberstein Kylee J, West Franklin D
Regenerative Bioscience Center, University of Georgia, Athens, GA, United States.
Biomedical and Health Sciences Institute, University of Georgia, Athens, GA, United States.
Front Neurosci. 2023 Sep 28;17:1249539. doi: 10.3389/fnins.2023.1249539. eCollection 2023.
Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to bidirectional communication between the brain and gut microbial population, introduction of key gut bacteria may mitigate critical TBI-induced secondary injury cascades, thus lessening neural damage and improving functional outcomes. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric piglet model. Male piglets at 4-weeks of age were randomly assigned to Sham + saline, TBI + saline, or TBI + FMT treatment groups. A moderate/severe TBI was induced by controlled cortical impact and Sham pigs underwent craniectomy surgery only. FMT or saline were administered by oral gavage daily for 7 days. MRI was performed 1 day (1D) and 7 days (7D) post TBI. Fecal and cecal samples were collected for 16S rRNA gene sequencing. Ipsilateral brain and ileum tissue samples were collected for histological assessment. Gait and behavior testing were conducted at multiple timepoints. MRI showed that FMT treated animals demonstrated decreased lesion volume and hemorrhage volume at 7D post TBI as compared to 1D post TBI. Histological analysis revealed improved neuron and oligodendrocyte survival and restored ileum tissue morphology at 7D post TBI in FMT treated animals. Microbiome analysis indicated decreased dysbiosis in FMT treated animals with an increase in multiple probiotic species, associated with anti-inflammatory therapeutic effects, in the cecum of the FMT treated animals, while non-treated TBI animals showed an increase in pathogenic bacteria, associated with inflammation and disease such in feces. FMT mediated enhanced cellular and tissue recovery resulted in improved motor function including stride and step length and voluntary motor activity in FMT treated animals. Here we report for the first time in a highly translatable pediatric piglet TBI model, the potential of FMT treatment to significantly limit cellular and tissue damage leading to improved functional outcomes following a TBI.
小儿创伤性脑损伤（TBI）是儿童死亡和残疾的主要原因。由于大脑与肠道微生物群之间存在双向交流，引入关键肠道细菌可能减轻严重TBI诱导的继发性损伤级联反应，从而减少神经损伤并改善功能结局。本研究的目的是在一个转化性仔猪模型中确定每日粪便微生物移植（FMT）减轻神经损伤严重程度、预防肠道菌群失调以及改善TBI后功能恢复的效果。4周龄的雄性仔猪被随机分配到假手术+生理盐水组、TBI+生理盐水组或TBI+FMT治疗组。通过控制性皮质撞击诱导中度/重度TBI，假手术组仔猪仅接受开颅手术。FMT或生理盐水每天经口灌胃给药，持续7天。在TBI后1天（1D）和7天（7D）进行MRI检查。收集粪便和盲肠样本进行16S rRNA基因测序。收集同侧脑和回肠组织样本进行组织学评估。在多个时间点进行步态和行为测试。MRI显示，与TBI后1D相比，FMT治疗的动物在TBI后7D时病变体积和出血量减少。组织学分析显示，FMT治疗的动物在TBI后7D时神经元和少突胶质细胞存活率提高，回肠组织形态恢复。微生物组分析表明，FMT治疗的动物肠道菌群失调减少，FMT治疗动物的盲肠中多种益生菌种类增加，与抗炎治疗效果相关，而未治疗的TBI动物粪便中的致病菌增加，与炎症和疾病相关。FMT介导的细胞和组织恢复增强导致FMT治疗的动物运动功能改善，包括步幅和步长以及自主运动活动。在此，我们首次在一个具有高度可转化性的仔猪TBI模型中报告，FMT治疗有可能显著限制细胞和组织损伤，从而改善TBI后的功能结局。
