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

• 批准号: 8850491
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850491
• 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; gut microbiota; immune activation; innovation; interest; intestinal epithelium; maternal serum; metabolomics; microbiome; mouse model; neuropathology; novel; offspring; prevent; relating to nervous system; research study; sex; social

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.

自闭症谱系障碍 (ASD) 包括一系列复杂的神经发育障碍，其特征是重复/刻板行为以及沟通和社交互动缺陷。最近的研究强调了自闭症谱系障碍中显着的神经和外周免疫失调。此外，相当一部分 ASD 儿童表现出胃肠道 (GI) 并发症，包括肠道通透性增加和肠道微生物群组成改变。胃肠道异常、肠道细菌和行为缺陷之间的潜在联系尚未得到令人信服的研究。为了检验胃肠道病理学与行为症状相关并导致行为症状的假设，我们采用了自闭症谱系障碍危险因素——母体免疫激活（MIA）的小鼠模型。我们的结果表明，这些表现出主要自闭症谱系障碍样行为和神经病理学的小鼠也表现出胃肠道病理学。这包括肠上皮和“肠漏”中紧密连接成分表达的变化，或上皮屏障功能减弱，据报道，这种情况在 ASD 儿童的一个重要亚群中出现。值得注意的是，这种肠漏与 MIA 小鼠血清中代谢物谱的改变有关，表明胃肠道通透性导致细菌产物易位到循环中。此外，我们还发现，对这些小鼠施用益生菌脆弱拟杆菌可以治愈多种行为异常，同时恢复胃肠道屏障功能。我们的中心假设是，用益生菌纠正胃肠道异常可能是治疗自闭症谱系障碍的一些异常行为的安全有效的方法。检验这一假设的具体目标是：1) 在机制实验中，确定与 MIA 相关的细胞因子是否会诱发肠漏；2) 确定从肠道漏出的假定代谢物是否会导致或改变行为异常。基于令人信服的初步证据，该项目旨在探索胃肠道屏障缺陷与自闭症临床前模型行为改变之间的潜在联系。我们的长期目标是探索用于 ASD 诊断的可能的血清生物标志物，并有可能为至少一部分患有胃肠道问题的 ASD 儿童开发一种新型益生菌疗法。