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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    380—Early Life Stress: Molecular Mechanisms and Effects

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    380.13: Of vaginas and guts: The microbiome as a novel mechanism for maternal stress reprogramming of the offspring brain

    Location: Halls B-H

    ">C. L. HOWERTON, C. D. HOWARD, *T. L. BALE;
    Dept Animal Biol, Univ. Pennsylvania, PHILADELPHIA, PA

    Abstract Body: Prenatal stress is associated with an increased risk for neurodevelopmental diseases. In our established mouse model of early prenatal stress (EPS), the long-term programming effects on offspring stress pathway neurodevelopment have been demonstrated. The process through which this fetal antecedent contributes to reprogramming of the developing brain is not clear. Current evidence points to a likely influence of maternal stress experience on the maternal vaginal microbiome. The host-microbe interaction between the enteric microbial ecology and the developing neonate is a novel and innovative mechanism with the potential to significantly affect neurodevelopment through early postnatal nutrient availability and endogenous signaling pathways in the offspring gut. As the neonate’s gut is initially populated by the maternal vaginal microbiome following passage through the birth canal, changes in the vaginal microbiome produced by maternal stress experience would then alter this initial microbe population. Using targeted approaches in mice, we have determined that EPS affects both the maternal and offspring levels of Lactobacillus, and further that there is a significant positive relationship between the maternal vaginal levels and that of her offspring’s gut. From these findings we hypothesize that the vaginal microbiome is modulated by stress through changes in the mucosal immunity, and that these changes in the vaginal microbiome alter the initial population of the offspring’s gut microbiome impacting neurodevelopment. To test these hypotheses, we took a multi-dimensional approach using deep sequencing, mass spectrometry and whole transcriptome analyses. Specifically, we monitored the microbial ecology of both the maternal vagina and the offspring gut, evaluated metabolic consequences in the offspring by measuring circulating nutrients and key metabolites, observed changes in early offspring hypothalamic gene expression and determined key changes in the maternal vaginal mucosal immunity. Together, data from these experiments have identified a novel mechanism by which maternal stress contributes to reprogramming of the developing brain and may predispose individuals to neurodevelopmental disorders.

    Lay Language Summary: The bacterial ecology that comprises a substantial portion of our makeup outnumbers our own cells 10 to 1, and can impact brain development and function in profound ways. This bacterial contribution is critical for survival, as bacteria in the gastrointestinal tract allow us to digest foods for nutrient absorption that otherwise would be unavailable. Interestingly, at birth, our gut microbiome is initially populated from our mother’s vaginal microbiome as we pass through the birth canal.
    We have developed a mouse model of maternal early pregnancy stress in which male offspring show elevated stress dysregulation as adults, a key risk factor in neurodevelopmental disorders in humans. However, the mechanisms that contribute to these changes in the brain are not clear. Our current studies have examined the hypothesis that mom’s stress experience during pregnancy can significantly change her vaginal microbiome, thus altering the baby’s gut at birth and producing long-term consequences important for brain development.
    To test this hypothesis we exposed pregnant female mice to stress during early pregnancy, and measured the composition of the vaginal microbiome and mucosal immunity both during pregnancy and after giving birth. Concurrently, we evaluated the offspring’s gut microbiome, circulating nutrients by metabolomics analyses, and early brain development by microarray analyses.
    In support of our hypothesis, we found that moms who experienced stress during early pregnancy had dramatic changes in their vaginal microbiome. Further, when we looked at their pups’ gut microbiome a few days after birth, we saw the same changes there as well. As predicted, these differences within the offspring microbiome were associated with altered circulating nutrients and disrupted early brain development, specifically within the developing hypothalamus, the part of the brain critical in regulation of stress responsivity.
    Our findings suggest that alterations in the vaginal microbiome as a result of mom experiencing psychological stressors during her pregnancy can dramatically affect her offspring’s brain development, in part, through alterations in nutrient availability resulting from changes in the gut microbiome. These studies support a novel mechanism whereby maternal stress can reprogram the developing brain, changes that may be linked with an increased risk for neurodevelopmental disorders. Future studies will examine ways in which intervention at the level of the gut microbiome can rescue the stress dysregulation phenotype in the offspring.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    380—Early Life Stress: Molecular Mechanisms and Effects

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    380.13: Of vaginas and guts: The microbiome as a novel mechanism for maternal stress reprogramming of the offspring brain

    Location: Halls B-H

    ">C. L. HOWERTON, C. D. HOWARD, *T. L. BALE;
    Dept Animal Biol, Univ. Pennsylvania, PHILADELPHIA, PA

    Abstract Body: Prenatal stress is associated with an increased risk for neurodevelopmental diseases. In our established mouse model of early prenatal stress (EPS), the long-term programming effects on offspring stress pathway neurodevelopment have been demonstrated. The process through which this fetal antecedent contributes to reprogramming of the developing brain is not clear. Current evidence points to a likely influence of maternal stress experience on the maternal vaginal microbiome. The host-microbe interaction between the enteric microbial ecology and the developing neonate is a novel and innovative mechanism with the potential to significantly affect neurodevelopment through early postnatal nutrient availability and endogenous signaling pathways in the offspring gut. As the neonate’s gut is initially populated by the maternal vaginal microbiome following passage through the birth canal, changes in the vaginal microbiome produced by maternal stress experience would then alter this initial microbe population. Using targeted approaches in mice, we have determined that EPS affects both the maternal and offspring levels of Lactobacillus, and further that there is a significant positive relationship between the maternal vaginal levels and that of her offspring’s gut. From these findings we hypothesize that the vaginal microbiome is modulated by stress through changes in the mucosal immunity, and that these changes in the vaginal microbiome alter the initial population of the offspring’s gut microbiome impacting neurodevelopment. To test these hypotheses, we took a multi-dimensional approach using deep sequencing, mass spectrometry and whole transcriptome analyses. Specifically, we monitored the microbial ecology of both the maternal vagina and the offspring gut, evaluated metabolic consequences in the offspring by measuring circulating nutrients and key metabolites, observed changes in early offspring hypothalamic gene expression and determined key changes in the maternal vaginal mucosal immunity. Together, data from these experiments have identified a novel mechanism by which maternal stress contributes to reprogramming of the developing brain and may predispose individuals to neurodevelopmental disorders.

    Lay Language Summary: The bacterial ecology that comprises a substantial portion of our makeup outnumbers our own cells 10 to 1, and can impact brain development and function in profound ways. This bacterial contribution is critical for survival, as bacteria in the gastrointestinal tract allow us to digest foods for nutrient absorption that otherwise would be unavailable. Interestingly, at birth, our gut microbiome is initially populated from our mother’s vaginal microbiome as we pass through the birth canal.
    We have developed a mouse model of maternal early pregnancy stress in which male offspring show elevated stress dysregulation as adults, a key risk factor in neurodevelopmental disorders in humans. However, the mechanisms that contribute to these changes in the brain are not clear. Our current studies have examined the hypothesis that mom’s stress experience during pregnancy can significantly change her vaginal microbiome, thus altering the baby’s gut at birth and producing long-term consequences important for brain development.
    To test this hypothesis we exposed pregnant female mice to stress during early pregnancy, and measured the composition of the vaginal microbiome and mucosal immunity both during pregnancy and after giving birth. Concurrently, we evaluated the offspring’s gut microbiome, circulating nutrients by metabolomics analyses, and early brain development by microarray analyses.
    In support of our hypothesis, we found that moms who experienced stress during early pregnancy had dramatic changes in their vaginal microbiome. Further, when we looked at their pups’ gut microbiome a few days after birth, we saw the same changes there as well. As predicted, these differences within the offspring microbiome were associated with altered circulating nutrients and disrupted early brain development, specifically within the developing hypothalamus, the part of the brain critical in regulation of stress responsivity.
    Our findings suggest that alterations in the vaginal microbiome as a result of mom experiencing psychological stressors during her pregnancy can dramatically affect her offspring’s brain development, in part, through alterations in nutrient availability resulting from changes in the gut microbiome. These studies support a novel mechanism whereby maternal stress can reprogram the developing brain, changes that may be linked with an increased risk for neurodevelopmental disorders. Future studies will examine ways in which intervention at the level of the gut microbiome can rescue the stress dysregulation phenotype in the offspring.