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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

基本信息

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
项目类别：
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

项目摘要

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