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: 10385767
• 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/10385767
• 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非常普遍 （ASD）和肠道微生物组和肠上皮屏障的改变已在最近的研究中报道。 生命早期的环境有毒物质暴露越来越涉及神经发育障碍 如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 影响直接暴露的人和啮齿动物的肠道微生物组和肠道功能。较少的特征是如果 PM暴露于怀孕的女性会改变后代的肠道微生物组，尽管这很可能有证据表明 母体肠道微生物组设定了新生微生物组的轨迹，尤其是阴道递送。 为了研究环境污染物对小鼠自闭症类行为的影响，我们开发了一种新型模型 将产前柴油排气颗粒（DEP）与孕妇应力（MS）结合在一起 在妊娠的最后三个月中。在最近的几项研究中，孕产妇的压力与自闭症有关，这可能是 对其他因素造成的人口最有害。我们已经证明了结合产前 DEP + MS在生命的早期产生引人注目的沟通和社会缺陷，并持续的认知缺陷和 在男性后代，焦虑到成年后的焦虑。我们的初步数据也显示出重要的 肠道细菌组成和男性后代的肠道结构变化的变化在产前暴露于 DEP/MS与未暴露的对照相比。我们的目标是检验肠道微生物组改变的假设 结合环境暴露后的怀孕大坝被传播给新生儿后代和基础 持续的行为异常。这些研究将共同​​：（1）完全表征产前的影响 孕产妇和后代微生物组发展的环境有毒物质（DEP）暴露，（2）系索因果关系 在微生物群的变化中，肠道上皮结构/功能和炎症以及行为异常 后代和（3）建立关键窗口，其中可以防止微生物组变化或 使用干预措施与出生后与断奶后相反。如果成功的话，他们将大大提高我们的 了解肠道营养不良与行为/脑功能障碍之间的出现和因果关系 自闭症等毁灭性疾病，以及环境毒素在诱导这些变化中的作用 这表明了潜在的治疗选择和治疗窗口。