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: 8484091
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484091
• 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

DESCRIPTION (provided by applicant): 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; 2) determine whether putative metabolites that leak from the gut contribute to or modify behavioral abnormalities; 3) extending our results from the mouse model of an environmental ASD risk factor, test if this probiotic treatment corrects GI and behavioral abnormalities in genetic models of ASD; 4) determine if human ASD subjects with GI complications display altered serum metabolites. 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, and extend these findings to humans. 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.

描述（由申请人提供）：自闭症谱系障碍（ASD）包括一组复杂的神经发育障碍，其特征是重复/刻板印象行为和交流和社交互动中的缺陷。最近的研究强调了ASD中引人注目的神经和周围免疫失调。此外，ASD儿童的显着子集表现出胃肠道（GI）并发症，包括肠道通透性的增加和肠道菌群的组成改变。 GI异常，肠道细菌和行为缺陷之间的潜在联系尚未令人信服地研究。为了检验胃肠道病理与行为症状相关的假设，我们采用了ASD危险因素的小鼠模型，母体免疫激活（MIA）。我们的结果表明，这些小鼠表现出类似ASD的行为和神经病理学，也表现出GI病理学。这包括肠上皮上紧密连接成分表达的变化和“渗漏肠”或上皮屏障功能降低的变化，这在ASD儿童的显着子集中报道。值得注意的是，这种泄漏的肠道与MIA小鼠血清中代谢物的改变有关，这表明GI渗透性导致细菌产物转移到循环中。此外，我们表明给予这些小鼠的益生菌细菌，细菌性脆弱的脆弱性，在恢复GI屏障功能的同时治愈了几种行为异常。我们的中心假设是，用益生菌纠正胃肠道异常可能是ASD中某些异常行为的安全有效治疗。检验该假设的具体目的是：1）在机械实验中，确定与MIA相关的细胞因子是否诱导肠道渗漏； 2）确定从肠道泄漏的推定代谢产物是否有助于或改变行为异常； 3）从环境ASD风险因素的小鼠模型中扩展结果 ASD； 4）确定患有胃肠道并发症的人ASD受试者是否显示出改变的血清代谢产物。基于引人注目的初步证据，该项目旨在探索自闭症临床前模型中GI屏障缺陷和行为改变之间的潜在联系，并将这些发现扩展到人类。我们的长期目标是探索可能的血清生物标志物来进行ASD诊断，并可能为至少一部分患有GI问题的儿童开发一种新型的益生菌疗法。