Gut-brain dysfunction following combined prenatal stressors: relevance for autism

工作概要 这是以下获奖项目的多样性补充申请：胃肠道问题 在自闭症谱系障碍（ASD）等神经发育障碍中非常常见， 最近已经报道了肠道微生物组和肠上皮屏障的改变 问题研究生命早期的环境毒物暴露越来越多地涉及到 神经发育障碍，如ASD，包括空气污染。有强有力的证据表明 空气污染中的颗粒物（PM）显著影响肠道微生物组和肠道功能， 直接接触的人类和啮齿动物。不太清楚的是，如果PM暴露于妊娠女性， 改变了后代的肠道微生物组，尽管这很可能证明母体肠道 微生物组设定了新生儿微生物组的轨迹，特别是阴道分娩。到 为了研究环境污染物对小鼠自闭症样行为的影响，我们开发了一种 一种新的模型结合产前柴油机排气颗粒（DEP）暴露在整个怀孕期间 在妊娠的最后三个月，母亲的压力（MS）。母亲压力与自闭症有关 在最近的几项研究中，这可能对因其他原因而易受伤害的人口最为有害。 因素我们已经证明，结合产前DEP + MS产生惊人的沟通 和社会缺陷，以及持续的认知缺陷和焦虑增加， 成年后，在男性而不是女性后代。我们的初步数据还显示， 出生前暴露于以下物质的雄性后代的肠道细菌组成和肠道结构变化 DEP/MS与未暴露对照品的比较。我们的目标是检验肠道微生物组 妊娠母鼠在综合环境暴露后的变化被传递到 新生儿的后代和基础的持续行为异常。这些研究 将：（1）充分表征产前环境毒物（DEP）暴露对 母体和后代微生物组发育，（2）归因于微生物组变化之间的因果关系， 肠道上皮结构/功能和炎症，以及后代的行为异常，以及 (3)建立可预防后代微生物组变化的关键窗口，或 在出生时和断奶后进行干预。如果成功的话， 我们对肠道生态失调和行为/大脑之间的因果关系的理解 自闭症等毁灭性疾病中的功能障碍，以及环境毒素在 诱导这些变化，以及提出一个潜在的治疗选择和窗口， 治疗

SUMMARY OF WORK This is a diversity supplement application for the following awarded project: Gastrointestinal issues are extremely common in neurodevelopmental disorders like autism spectrum disorder (ASD), and alterations of the gut microbiome and intestinal epithelial barrier have been reported in recent studies. Environmental toxicant exposures early in life are increasingly implicated in neurodevelopmental disorders such as ASD, including air pollution. There is strong evidence that particulate matter (PM) in air pollution significantly impacts the gut microbiome and gut function of directly-exposed humans and rodents. Less characterized is if PM exposure to pregnant females alters the gut microbiome of offspring, though this is likely given evidence that the maternal gut microbiome sets the trajectory of the newborn microbiome, especially with a vaginal delivery. To study the impact of environmental pollutants on autism-like behaviors in mice, we developed a novel model combining prenatal diesel exhaust particle (DEP) exposure throughout pregnancy with maternal stress (MS) during the last trimester of gestation. Maternal stress is linked to autism in several recent studies, which may be most harmful for populations made vulnerable by other factors. We have demonstrated that combined prenatal DEP + MS produce striking communication and social deficits early in life, and persistent cognitive deficits and increased anxiety into adulthood, in male but not female offspring. Our preliminary data also show significant changes in the composition of gut bacteria and gut structural changes in male offspring exposed prenatally to DEP/MS compared to unexposed controls. Our goal is to test the hypothesis that gut microbiome changes in pregnant dams following combined environmental exposures are transmitted to newborn offspring and underlie the persistent behavioral abnormalities. Together these studies will: (1) fully characterize the impact of prenatal environmental toxicant (DEP) exposure on maternal and offspring microbiome development, (2) ascribe causality among microbiota changes, gut epithelial structure/function and inflammation, and behavioral abnormalities in offspring, and (3) establish the critical window(s) in which microbiome changes in offspring can be prevented or reversed using interventions at birth vs. post-weaning. If successful they will significantly advance our understanding of the emergence and causal link between gut dysbiosis and behavioral/brain dysfunction in devastating disorders such as autism, and the role of environmental toxins in inducing these changes, as well as suggest a potential therapeutic option and window for treatment.