Investigating the Gut Microbiome for Novel Therapies and Diagnostics for Autism

研究肠道微生物组以寻找自闭症的新疗法和诊断

基本信息

批准号：
8701411
负责人：
Sarkis K Mazmanian
金额：
$ 55.81万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701411
关键词：
Adult Affect Age Animals Appearance Area Autistic Disorder Bacteria Bacterial Translocation Bacteroides fragilis Behavior Behavioral Behavioral Symptoms Biological Assay Biological Markers Blood Circulation Brain Centers for Disease Control and Prevention (U.S.)Child Colon Communication Complex Data Defect Development Diagnosis Diagnostic Disease Early Diagnosis Employee Strikes Environmental Risk Factor Epithelial Etiology Exhibits Functional disorder Genetic Risk Goals Human Immune Immune system Interleukin-6 Intervention Intestines Language Lead Mediating Medical Microglia Modeling Molecular Molecular Profiling Mus Neurodevelopmental Disability Pathology Patients Peripheral Permeability Pre-Clinical Model Probiotics Process Proteins Reporting Research Risk Factors Serum Social Interaction Stereotyping Symptoms Testing Therapeutic Tight Junctions Time United States Up-Regulation autism spectrum disorder autistic children base commensal microbes cytokine disorder risk effective therapy feeding gastrointestinal gastrointestinal bacteria gastrointestinal symptom immune activation innovation interest intestinal epithelium maternal serum metabolomics microbiome mouse model neuropathology novel offspring prevent relating to nervous system research study sex social

项目摘要

Autism spectrum disorder (ASD) comprises a set of complex neurodevelopmental disabilities characterized by repetitive/stereotypic behaviors and deficits in communication and social interaction. Recent studies highlight striking neural and peripheral immune dysregulation in ASD. Moreover, a significant subset of ASD children exhibit gastrointestinal (GI) complications, including increased intestinal permeability and altered composition of intestinal microbiota. The potential connections between GI abnormalities, intestinal bacteria, and behavioral deficits have not yet been convincingly investigated. To examine the hypothesis that GI pathology is associated with, and contributes to behavioral symptoms, we employ a mouse model of an ASD risk factor, maternal immune activation (MIA). Our results show that these mice, which display cardinal ASD-like behaviors and neuropathology, also exhibit GI pathology. This includes changes in expression of tight junction components in the intestinal epithelium and a ¿leaky gut¿, or diminished epithelial barrier function, which is reported in a significant subset of ASD children. Remarkably, this leaky gut is associated with an altered metabolite profile in the serum of the MIA mice, suggesting that GI permeability results in translocation of bacterial products into the circulation. Furthermore, we show that administration of a probiotic bacterium, Bacteroides fragilis, to these mice cures several behavioral abnormalities while restoring GI barrier function. Our central hypothesis is that correcting GI abnormalities with probiotic bacteria may be a safe and effective treatment for some of the abnormal behaviors in ASD. The specific aims that will test this hypothesis are: 1) in mechanistic experiments, determine if a cytokine relevant to MIA induces leaky gut and 2) determine whether putative metabolites that leak from the gut contribute to or modify behavioral abnormalities. Based on compelling preliminary evidence, this project aims to explore the potential connection between GI barrier defects and altered behavior in preclinical models of autism. Our long-term goal is to explore possible serum biomarkers for ASD diagnosis, and potentially develop a novel probiotic therapy for at least a subset of children with ASD with GI issues.

自闭症光谱障碍（ASD）以重复性为特征的一组复杂的神经发育症状，突出了ASD的神经和外周免疫失调。肠道肠和行为上的行为有令人信服的Y，并且有助于行为症状，我们采用了ASD风险因素的小鼠模型，我们的结果表明这些小鼠也表现出类似于Cardinal ASD的小鼠。诱使的胃肠道病理学包括肠上皮中紧密连接组件的表达变化漏水，或在ASD儿童的显着子集中报告的上皮屏障功能。细菌脆弱的小鼠在恢复GI屏障功能的同时对ASD的某些异常行为进行治疗。在自闭症的临床模型中，GI屏障缺陷和行为改变了至少一部分患有GI ISSEES的儿童。