Jašarević Eldin, Howerton Christopher L, Howard Christopher D, Bale Tracy L
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6046.
Endocrinology. 2015 Sep;156(9):3265-76. doi: 10.1210/en.2015-1177. Epub 2015 Jun 16.
The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. Because perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could be a contributing factor in significant and long-term consequences for the offspring. Therefore, to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain, we used genomic, proteomic and metabolomic technologies to examine outcomes in our mouse model of early prenatal stress. Multivariate modeling identified broad proteomic changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus, the prominent taxa in the maternal vagina. Loss of maternal vaginal Lactobacillus resulted in decreased transmission of this bacterium to offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Taken together, these results identify the vaginal microbiota as a novel factor by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.
新生儿在分娩过程中接触母体阴道微生物群，这为正常的肠道定植、宿主免疫成熟和新陈代谢提供了主要来源。宿主与微生物群之间的这些早期相互作用发生在神经发育的关键窗口期，这表明生命早期是发育中的肠道与大脑之间进行重要交流的时期。由于产前环境中的干扰因素，如母体压力，会增加神经发育疾病的风险，因此阴道生态系统的破坏可能是导致后代出现重大长期后果的一个因素。因此，为了检验阴道微生物组的变化与对后代肠道微生物群和发育中的大脑的影响相关这一假设，我们使用基因组学、蛋白质组学和代谢组学技术来研究我们的早期产前应激小鼠模型的结果。多变量建模确定了母体阴道环境中广泛的蛋白质组变化，这些变化会影响后代微生物群的组成以及正常神经发育所必需的代谢过程。母体压力改变了与阴道免疫相关的蛋白质以及母体阴道中主要菌群乳酸杆菌的丰度。母体阴道乳酸杆菌的缺失导致该细菌向后代的传播减少。此外，新生儿肠道中微生物群组成的改变与能量平衡中涉及的代谢物谱变化以及发育中大脑中氨基酸谱的区域和性别特异性破坏相对应。综上所述，这些结果确定阴道微生物群是一个新的因素，母体压力可能通过这个因素导致发育中的大脑重新编程，从而使个体易患神经发育障碍。
