Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA; Department of Neurology, Faculty of Medicine and University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
Exp Neurol. 2024 Jun;376:114774. doi: 10.1016/j.expneurol.2024.114774. Epub 2024 Apr 9.
Peripheral nerve injury (PNI) resulting from trauma or neuropathies can cause significant disability, and its prognosis deteriorates with age. Emerging evidence suggests that gut dysbiosis and reduced fecal short-chain fatty acids (SCFAs) contribute to an age-related systemic hyperinflammation (inflammaging), which hinders nerve recovery after injury. This study thus aimed to evaluate the pro-regenerative effects of a rejuvenating fecal microbiota transplant (FMT) in a preclinical PNI model using aged mice. Aged C57BL/6 mice underwent bilateral crush injuries to their sciatic nerves. Subsequently, they either received FMT from young donors at three and four days after the injury or retained their aged gut microbiota. We analyzed gut microbiome composition and SCFA concentrations in fecal samples. The integrity of the ileac mucosal barrier was assessed by immunofluorescence staining of Claudin-1. Flow cytometry was utilized to examine immune cells and cytokine production in the ileum, spleen, and sciatic nerve. Various assessments, including behavioural tests, electrophysiological studies, and morphometrical analyses, were conducted to evaluate peripheral nerve function and repair following injury. Rejuvenating FMT reversed age-related gut dysbiosis by increasing Actinobacteria, especially Bifidobacteriales genera. This intervention also led to an elevation of gut SCFA levels and mitigated age-related ileac mucosal leakiness in aged recipients. Additionally, it augmented the number of T-helper 2 (Th2) and regulatory T (Treg) cells in the ileum and spleen, with the majority being positive for anti-inflammatory interleukin-10 (IL-10). In sciatic nerves, rejuvenating FMT resulted in increased M2 macrophage counts and a higher IL-10 production by IL-10TNF-α M2 macrophage subsets. Ultimately, restoring a youthful gut microbiome in aged mice led to improved nerve repair and enhanced functional recovery after PNI. Considering that FMT is already a clinically available technique, exploring novel translational strategies targeting the gut microbiome to enhance nerve repair in the elderly seems promising and warrants further evaluation.
周围神经损伤（PNI）由创伤或神经病变引起，会导致严重残疾，且其预后随年龄增长而恶化。新出现的证据表明，肠道菌群失调和粪便短链脂肪酸（SCFA）减少导致与年龄相关的全身性炎症反应（炎症衰老），这阻碍了损伤后的神经恢复。因此，本研究旨在使用老年小鼠评估一种促进再生的粪便微生物群移植（FMT）在临床前 PNI 模型中的促再生作用。老年 C57BL/6 小鼠接受双侧坐骨神经挤压伤。随后，它们在损伤后 3 天和 4 天接受来自年轻供体的 FMT，或保留其老年肠道微生物群。我们分析了粪便样本中的肠道微生物组组成和 SCFA 浓度。通过 Claudin-1 的免疫荧光染色评估回肠黏膜屏障的完整性。流式细胞术用于检测回肠、脾脏和坐骨神经中的免疫细胞和细胞因子产生。通过行为测试、电生理学研究和形态计量学分析等各种评估来评估损伤后周围神经功能和修复。促进再生的 FMT 通过增加放线菌，特别是双歧杆菌目属，逆转了与年龄相关的肠道菌群失调。这种干预还导致肠道 SCFA 水平升高，并减轻了老年受者与年龄相关的回肠黏膜通透性。此外，它增加了回肠和脾脏中辅助性 T 细胞 2（Th2）和调节性 T（Treg）细胞的数量，其中大多数为抗炎性白细胞介素 10（IL-10）阳性。在坐骨神经中，促进再生的 FMT 导致 M2 巨噬细胞计数增加，并且 IL-10TNF-α M2 巨噬细胞亚群产生的 IL-10 增加。最终，在老年小鼠中恢复年轻的肠道微生物组可改善 PNI 后的神经修复和功能恢复。考虑到 FMT 已经是一种临床可用的技术，探索针对肠道微生物组的新型转化策略以增强老年人的神经修复似乎很有前景，值得进一步评估。
