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

联合产前应激源后的肠脑功能障碍：与自闭症的相关性

• 批准号: 10227509
• 负责人: Staci D Bilbo
• 金额: $ 34.04万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10227509
• 关键词: Ablation; Address; Adult; Age; Air Pollution; Anxiety; Atopobium vaginae; Attention; Bacteria; Behavior; Behavioral; Birth; Brain; Brain region; Characteristics; Cognitive deficits; Communication; Data; Deglutition; Development; Diesel Exhaust; Disease; Environmental Exposure; Environmental Impact; Environmental Pollutants; Etiology; Excitatory Synapse; Exposure to; Female; Fostering; Functional disorder; Goals; Housing; Immune response; Impairment; Inflammation; Inhalation; Intervention; Intestinal permeability; Life; Link; Metagenomics; Microglia; Modeling; Morphology; Mus; Neurodevelopmental Disorder; Newborn Infant; Outcome; Particulate Matter; Patients; Phagocytes; Phagocytosis; Phenocopy; Phenotype; Population; Pregnancy; Reporting; Rodent; Role; Stimulus; Structure; Supplementation; Synapses; Testing; Therapeutic; Third Pregnancy Trimester; Time; Toxic Environmental Substances; Toxicant exposure; Vaginal delivery procedure; Virus Diseases; Volatile Fatty Acids; Weaning; autism spectrum disorder; behavioral outcome; brain dysfunction; comorbidity; disorder risk; environmental stressor; exposed human population; gastrointestinal; gastrointestinal epithelium; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; immune activation; in vivo; intestinal epithelium; male; maternal microbiome; maternal stress; microbial; microbiome; microbiome composition; microbiota; novel; offspring; particle; particle exposure; pregnant; prenatal; prenatal exposure; prevent; pup; receptor; sex; single cell sequencing; social deficits; stressor; virtual

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.

胃肠道问题在自闭症谱系障碍等神经发育障碍中极为常见 最近的研究报道了自闭症谱系障碍（ASD）以及肠道微生物组和肠上皮屏障的改变。 生命早期接触环境毒物越来越多地与神经发育障碍有关，例如 自闭症谱系障碍（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）显着 影响直接暴露的人类和啮齿动物的肠道微生物组和肠道功能。不太有特点的是如果 怀孕女性接触 PM 会改变后代的肠道微生物组，尽管有证据表明这很可能 母体肠道微生物组决定了新生儿微生物组的轨迹，尤其是在阴道分娩时。 为了研究环境污染物对小鼠自闭症样行为的影响，我们开发了一种新模型 将整个怀孕期间的产前柴油机尾气颗粒 (DEP) 暴露与孕产妇压力 (MS) 相结合 在妊娠的最后三个月。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危害最大。我们已经证明，结合产前 DEP + MS 在生命早期产生显着的沟通和社交缺陷，以及持续的认知缺陷和 成年后的焦虑增加，男性后代的焦虑感增加，而女性后代则不然。我们的初步数据也显示出显着 产前接触过的雄性后代肠道细菌组成的变化和肠道结构的变化 DEP/MS 与未暴露的对照进行比较。我们的目标是检验肠道微生物组变化的假设 综合环境暴露后怀孕的母鼠会传染给新生后代并形成后代 持续的行为异常。这些研究将：（1）充分描述产前妊娠的影响 环境毒物 (DEP) 暴露对母体和后代微生物组发育的影响，(2) 归因因果关系 微生物群变化、肠道上皮结构/功能和炎症以及行为异常之间的关系 (3) 建立关键窗口，在该窗口中可以预防或 使用出生时干预与断奶后干预来逆转。如果成功的话，他们将显着推进我们的 了解肠道菌群失调与行为/大脑功能障碍之间的出现和因果关系 自闭症等毁灭性疾病，以及环境毒素在诱发这些变化中的作用 这表明了潜在的治疗选择和治疗窗口。