Investigating the Gut Microbiome for Novel Therapies and Diagnostics for Autism

描述（由申请人提供）：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会互动方面的缺陷。最近的研究强调了ASD中显著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调查。为了检验胃肠道病理与行为症状相关并有助于行为症状的假设，我们采用了一个ASD危险因素的小鼠模型，母体免疫激活（MIA）。我们的研究结果表明，这些小鼠表现出主要的asd样行为和神经病理，也表现出GI病理。这包括肠上皮紧密连接成分的表达变化和“漏肠”，或上皮屏障功能减弱，这在ASD儿童的一个重要亚群中有报道。值得注意的是，这种渗漏的肠道与MIA小鼠血清中代谢物的改变有关，这表明胃肠道的通透性导致细菌产物易位进入循环。此外，我们发现给这些小鼠注射一种益生菌，脆弱拟杆菌，可以治愈几种行为异常，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一种安全有效的治疗ASD中一些异常行为的方法。验证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诱导肠漏；2)确定从肠道泄漏的推定代谢物是否有助于或改变行为异常；3)将我们的结果扩展到环境ASD风险因素的小鼠模型，测试这种益生菌治疗是否可以纠正遗传模型中的GI和行为异常

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.