‘Dysbiosis’ of the maternal gut microbiome, in response to challenges such as infection 1 , altered diet 2 and stress 3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring 4 . However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain. Small molecules that arise from the maternal gut microbiome in pregnant dams promote fetal thalamocortical axonogenesis in their offspring.

中文翻译：

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母体微生物组调节小鼠胎儿神经发育

为应对感染 1 、饮食改变 2 和孕期压力 3 等挑战，母体肠道微生物群的“生态失调”越来越多地与后代脑功能和行为异常相关 4 。然而，尚不清楚母体肠道微生物组是否会在关键的产前时期和没有环境挑战的情况下影响神经发育。在这里，我们研究了母体肠道微生物组的耗竭和选择性重建如何影响小鼠的胎儿神经发育。来自抗生素处理和无菌水坝的胚胎表现出与轴突发生相关的基因表达减少，丘脑皮质轴突缺陷和丘脑轴突对细胞外在因素的反应受损。用有限的细菌群对微生物组耗尽的水坝进行定生菌定植，可防止胎儿大脑基因表达和丘脑皮质轴突发生异常。代谢组学分析表明，母体微生物组调节母体血清和胎儿后代大脑中的许多小分子。选择微生物群依赖性代谢物促进胎儿丘脑外植体的轴突生长。此外，母体补充这些代谢物消除了胎儿丘脑皮质轴突的缺陷。在怀孕期间对母体微生物组和微生物代谢物的操纵产生了在两个令人厌恶的体感行为任务中具有改变的触觉敏感性的成年后代，但在许多其他感觉运动行为中没有明显差异。一起，我们的研究结果表明，母体肠道微生物群促进胎儿丘脑皮质轴突发生，可能是通过微生物调节的代谢物向发育中的大脑神经元发出信号。孕母体内肠道微生物群产生的小分子促进其后代的胎儿丘脑皮层轴突发生。