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: 10533404
• 负责人: Staci D Bilbo
• 金额: $ 10.49万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533404
• 关键词: 16S ribosomal RNA sequencing; Adult; Air Pollution; Alveolar Macrophages; Amniotic Fluid; Anxiety; Area; Atopobium vaginae; Award; B-Lymphocytes; Behavior; Behavioral; Birth; Blood; Blood Circulation; Brain; CCL2 gene; CD46 Antigen; CD8B1 gene; CSF3 gene; CXCL1 gene; CXCL2 gene; CXCL6 gene; Cardiac; Cells; Cognitive deficits; Communication; Complement; Complement 1q; Complement Factor H; Data; Development; Diesel Exhaust; Disease; Environment; Environmental Exposure; Environmental Impact; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Exposure to; Female; Fetal Development; Flow Cytometry; Goals; Health; Human; Immune; Immunohistochemistry; In Situ Hybridization; Infiltration; Inflammation; Inflammatory; Interleukin-10; Interleukin-17; Interleukin-6; Intervention; Intestinal permeability; Life; Link; Lung; Lymphoid Cell; Measures; Microglia; Modeling; Mus; Myeloid Cells; Natural Killer Cells; Neurodevelopmental Disorder; Newborn Infant; Parents; Particulate Matter; Placenta; Population; Pregnancy; Proteins; Protocols documentation; Puncture procedure; Reporting; Rodent; Role; Stress; Structure; Synapses; Syringes; T-Lymphocyte; Testing; Therapeutic; Third Pregnancy Trimester; Tissues; Toxic Environmental Substances; Toxicant exposure; Vaginal delivery procedure; Weaning; Western Blotting; Work; autism spectrum disorder; autistic behaviour; brain dysfunction; chemokine; comorbidity; complement pathway; cytokine; exposed human population; fetal; gastrointestinal; gastrointestinal epithelium; gene complementation; gut bacteria; gut dysbiosis; gut homeostasis; gut microbiome; immune activation; in utero; inhibitor; interleukin-22; interstitial; intestinal epithelium; lung microbiome; mRNA Expression; male; maternal microbiome; maternal stress; member; microbiome; microbiome alteration; microbiome composition; microbiota; milk microbiome; novel; offspring; particle; particle exposure; pregnant; prenatal; prenatal exposure; prevent; response; social deficits; stressor; vaginal microbiome; virtual

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.

工作总结 这是以下获奖项目的多样性补充申请：胃肠问题 在自闭症谱系障碍 (ASD) 等神经发育障碍中极为常见，并且 最近报道了肠道微生物组和肠上皮屏障的改变 研究。生命早期接触环境毒物越来越多地涉及 神经发育障碍，如自闭症谱系障碍，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）显着影响肠道微生物群和肠道功能 直接暴露的人类和啮齿动物。较少被表征的是，如果PM暴露于怀孕女性 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 微生物组决定了新生儿微生物组的轨迹，尤其是阴道分娩时。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 结合整个孕期产前柴油机尾气颗粒 (DEP) 暴露的新型模型 妊娠最后三个月期间的母亲压力（MS）。母亲的压力与自闭症有关 在最近的几项研究中，这可能对因其他原因而变得脆弱的人群危害最大 因素。我们已经证明，产前 DEP + MS 相结合可以产生惊人的沟通效果 生命早期的社交缺陷，以及持续的认知缺陷和增加的焦虑 成年期，在男性后代中，但在女性后代中则不然。我们的初步数据也显示出显着变化 产前接触过的雄性后代的肠道细菌组成和肠道结构变化 DEP/MS 与未暴露的对照进行比较。我们的目标是检验肠道微生物组的假设 综合环境暴露后怀孕母鼠的变化会传播到 新生后代，是持续行为异常的基础。这些研究一起 将：（1）充分描述产前环境毒物（DEP）暴露对 母体和后代微生物群的发育，(2) 归因微生物群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) 建立可以预防后代微生物组变化的关键窗口，或 使用出生时干预与断奶后干预来逆转。如果成功，他们将取得显着进步 我们对肠道菌群失调与行为/大脑之间的出现和因果关系的理解 自闭症等破坏性疾病的功能障碍，以及环境毒素在 诱导这些变化，并提出潜在的治疗选择和窗口 治疗。