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

工作总结 这是以下获奖项目的多样性补充申请：胃肠道问题 在神经发育障碍中非常常见，如自闭症谱系障碍(ASD)，以及 肠道微生物群和肠道上皮屏障的改变在最近几年有报道。 学习。生命早期的环境毒物暴露越来越多地与 神经发育障碍，如自闭症，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群和肠道功能 直接接触的人类和啮齿动物。不太典型的是PM是否接触怀孕的女性 改变后代的肠道微生物群，尽管这很可能是因为有证据表明，母亲的肠道 微生物组决定了新生儿微生物组的轨迹，特别是在阴道分娩时。至 为了研究环境污染物对小鼠孤独症样行为的影响，我们开发了一种 结合孕期柴油废气颗粒物(DEP)暴露的新模型 妊娠最后三个月的母体应激(MS)。母亲的压力与自闭症有关 在最近的几项研究中，这可能是对易受其他疾病影响的人群最有害的 各种因素。我们已经证明，产前DEP+MS的组合产生了显著的沟通 和早期的社交缺陷，以及持续的认知缺陷和增加的焦虑 成年，雄性后代，但不是雌性后代。我们的初步数据还显示， 孕期接触尘埃的雄性子代肠道细菌组成及肠道结构变化 DEP/MS与未暴露的对照组进行比较。我们的目标是测试肠道微生物群的假设 联合环境暴露后怀孕大坝的变化会传播到 新生后代是持续性行为异常的基础。把这些研究放在一起 将：(1)充分描述产前环境毒物(DEP)暴露对以下方面的影响 母子微生物组发育，(2)确定微生物区系变化之间的因果关系， 子代肠道上皮结构/功能和炎症，以及行为异常，以及 (3)建立预防子代微生物群变化的关键窗口(S)或 相反，在出生时和断奶后进行干预。如果成功，他们将大幅进步 我们对肠道生物失调和行为/大脑之间的出现和因果联系的理解 自闭症等破坏性疾病中的功能障碍，以及环境毒素在 诱导这些变化，以及建议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.