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

胃肠问题在自闭症谱系障碍等神经发育障碍中非常常见 (ASD)以及肠道微生物组和肠上皮屏障的改变在最近的研究中已经报道。 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， ASD包括空气污染有强有力的证据表明，颗粒物（PM）在空气污染显着 影响直接接触的人类和啮齿动物的肠道微生物组和肠道功能。不太确定的是，如果 PM暴露于怀孕女性会改变后代的肠道微生物组，尽管这可能有证据表明， 母体肠道微生物组设定了新生儿微生物组的轨迹，特别是在阴道分娩时。 为了研究环境污染物对小鼠自闭症样行为的影响，我们开发了一种新的模型， 将整个妊娠期的产前柴油机排气颗粒（DEP）暴露与母体应激（MS）相结合 在怀孕的最后三个月在最近的几项研究中，母亲的压力与自闭症有关， 对因其他因素而易受伤害的人口最为有害。我们已经证明了产前联合检查 DEP + MS在生命早期会产生显着的沟通和社交缺陷，以及持续的认知缺陷， 成年后的焦虑增加，在男性而不是女性后代中。我们的初步数据还显示， 产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在肠道中发生变化的假设。 怀孕的母鼠在综合环境暴露后，会传染给新生的后代， 持续的行为异常这些研究将：（1）充分描述产前检查的影响 环境毒物（DEP）暴露对母体和后代微生物组发育的影响，（2）归因于因果关系 在微生物群变化、肠道上皮结构/功能和炎症以及行为异常中， （3）建立关键窗口，在该窗口中可以预防后代中的微生物组变化，或者 在出生时和断奶后进行干预。如果成功的话，将大大提高我们的 了解肠道生态失调和行为/脑功能障碍之间的出现和因果关系， 破坏性疾病，如自闭症，以及环境毒素在诱导这些变化中的作用， 提示了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.