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

胃肠道问题在自闭症谱系障碍等神经发育障碍中非常常见 (ASD)，以及肠道微生物群和肠上皮屏障的改变在最近的研究中被报道。 生命早期的环境毒物暴露越来越多地与神经发育障碍有关，如 包括空气污染在内的自闭症。有强有力的证据表明，空气污染中的颗粒物(PM) 影响直接接触的人和啮齿动物的肠道微生物群和肠道功能。不太有特色的是如果 PM暴露在怀孕雌性体内会改变后代的肠道微生物群，尽管这可能提供了证据表明 母亲的肠道微生物群决定了新生儿微生物群的轨迹，特别是在阴道分娩时。 为了研究环境污染物对小鼠孤独症样行为的影响，我们开发了一个新的模型 孕期接触柴油废气颗粒物(DEP)与母亲应激(MS)的结合 在怀孕的最后三个月。最近的几项研究表明，母亲的压力与自闭症有关，这可能是 对于因其他因素而变得脆弱的人群来说，这是最有害的。我们已经证明了联合产前 副多发性硬化症在生命早期会产生显著的沟通和社交缺陷，并持续存在认知缺陷和 成年后焦虑增加，在男性后代中，但在女性后代中不是。我们的初步数据也显示出 孕期接触尘埃的雄性子代肠道细菌组成和肠道结构的变化 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变化在 联合环境暴露后怀孕的母鸡会传染给新生的后代和基础 持续的行为异常。总的来说，这些研究将：(1)充分描述产前的影响 环境毒物(DEP)暴露对母子微生物组发育的影响，(2)因果关系 在微生物区系变化中，肠道上皮结构/功能和炎症，以及行为异常 以及(3)建立关键窗口(S)，在该窗口中可以防止或 相反，在出生时和断奶后进行干预。如果成功，他们将极大地推进我们的 了解肠道生物失调和行为/脑功能障碍之间的出现和因果联系 自闭症等破坏性疾病，以及环境毒素在导致这些变化中的作用 AS提示了一种潜在的治疗选择和治疗窗口。

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.