Myelination in the peripheral and central nervous systems is critical in regulating motor, sensory, and cognitive functions. As myelination occurs rapidly during early life, neonatal gut dysbiosis during early colonization can potentially alter proper myelination by dysregulating immune responses and neuronal differentiation. Despite common usage of antibiotics (Abx) in children, the impact of neonatal Abx-induced dysbiosis on the development of microbiota, gut, brain (MGB) axis, including myelination and behavior, is unknown. We hypothesized that neonatal Abx-induced dysbiosis dysregulates host-microbe interactions, impairing myelination in the brain, and altering the MGB axis. Neonatal C57BL/6 mice were orally gavaged daily with an Abx cocktail (neomycin, vancomycin, ampicillin) or water (vehicle) from postnatal day 7 (P7) until weaning (P23) to induce gut dysbiosis. Behavior (cognition; anxiety-like behavior), microbiota sequencing, and qPCR (ileum, colon, hippocampus and pre-frontal cortex [PFC]) were performed in adult mice (6-8 weeks). Neonatal Abx administration led to intestinal dysbiosis in adulthood, impaired intestinal physiology, coupled with perturbations of bacterial metabolites and behavioral alterations (cognitive deficits and anxiolytic behavior). Expression of myelin-related genes (Mag, Mog, Mbp, Mobp, Plp) and transcription factors (Sox10, Myrf) important for oligodendrocytes were significantly increased in the PFC region of Abx-treated mice. Increased myelination was confirmed by immunofluorescence imaging and western blot analysis, demonstrating increased expression of MBP, SOX10 and MYRF in neonatally Abx-treated mice compared to sham controls in adulthood. Finally, administration of the short chain fatty acid butyrate following completion of the Abx treatment restored intestinal physiology, behavior, and myelination impairments, suggesting a critical role for the gut microbiota in mediating these effects. Taken together, we identified a long-lasting impact of neonatal Abx administration on the MGB axis, specifically on myelin regulation in the PFC region, potentially contributing to impaired cognitive function and bacterial metabolites are effective in reversing this altered phenotype.

中文翻译：

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髓磷脂作为微生物群-肠-脑轴发育的调节剂


周围和中枢神经系统的髓鞘形成对于调节运动、感觉和认知功能至关重要。由于髓鞘形成在生命早期迅速发生，早期定植期间的新生儿肠道菌群失调可能会通过免疫反应失调和神经元分化来改变正常的髓鞘形成。尽管儿童普遍使用抗生素 (Abx)，但新生儿 Abx 引起的菌群失调对微生物群、肠道、大脑 (MGB) 轴发育（包括髓鞘形成和行为）的影响尚不清楚。我们假设新生儿 Abx 引起的生态失调会失调宿主-微生物相互作用，损害大脑中的髓鞘形成并改变 MGB 轴。从出生后第 7 天 (P7) 直至断奶 (P23)，每天用 Abx 混合物（新霉素、万古霉素、氨苄青霉素）或水（媒介物）对新生 C57BL/6 小鼠进行口服灌胃，以诱导肠道菌群失调。对成年小鼠（6-8 周）进行行为（认知；焦虑样行为）、微生物群测序和 qPCR（回肠、结肠、海马和前额皮质 [PFC]）。新生儿 Abx 给药会导致成年期肠道菌群失调、肠道生理机能受损，以及细菌代谢物的扰动和行为改变（认知缺陷和抗焦虑行为）。 Abx 处理小鼠的 PFC 区域中，对少突胶质细胞重要的髓磷脂相关基因（Mag、Mog、Mbp、Mobp、Plp）和转录因子（Sox10、Myrf）的表达显着增加。免疫荧光成像和蛋白质印迹分析证实髓鞘形成增加，表明与成年假对照组相比，新生 Abx 治疗小鼠的 MBP、SOX10 和 MYRF 表达增加。 最后，完成 Abx 治疗后给予短链脂肪酸丁酸酯可恢复肠道生理、行为和髓鞘形成损伤，表明肠道微生物群在调节这些影响中发挥着关键作用。综上所述，我们确定了新生儿 Abx 给药对 MGB 轴的长期影响，特别是对 PFC 区域的髓磷脂调节，可能导致认知功能受损，而细菌代谢物可有效逆转这种改变的表型。