Investigating the Gut Microbiome for Novel Therapies and Diagnostics for Autism

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/刻板印象的行为以及沟通和社会互动的缺陷。最近的研究表明ASD患者存在显著的神经和外周免疫失调。此外，ASD儿童中有相当一部分出现胃肠道(GI)并发症，包括肠道通透性增加和肠道微生物区系组成改变。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与行为症状相关并导致行为症状的假设，我们采用了ASD风险因素--母体免疫激活(MIA)的小鼠模型。我们的结果表明，这些表现出ASD样行为和神经病理的小鼠也表现出胃肠道病理。这包括肠上皮紧密连接成分表达的变化和肠漏，或上皮屏障功能减弱，这在ASD儿童中有很大的报道。值得注意的是，这种渗漏的肠道与MIA小鼠血清中代谢产物的变化有关，这表明GI的通透性导致细菌产物转移到循环中。此外，我们还表明，给予这些小鼠一种益生菌--脆弱类杆菌，在恢复胃肠道屏障功能的同时，可以治愈一些行为异常。我们的中心假设是，使用益生菌纠正胃肠道异常可能是一种安全有效的治疗ASD某些异常行为的方法。检验这一假说的具体目的是：1)在机械实验中，确定与MIA相关的细胞因子是否会导致肠道渗漏；2)确定从肠道渗漏出来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，该项目旨在探索自闭症临床前模型中胃肠道屏障缺陷与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记物，并潜在地开发一种新的益生菌疗法，用于至少一部分有胃肠道问题的ASD儿童。

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.