International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, 7F., No. 250, Wuxing St., Xinyi Dist., Taipei city 110, Taiwan.
Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong St., Taipei 11221, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University. 12F., Education and Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., New Taipei City 23564, Taiwan.
Neuroimage. 2024 Nov 15;302:120899. doi: 10.1016/j.neuroimage.2024.120899. Epub 2024 Oct 24.
Autism spectrum disorder (ASD) is characterized by social interaction deficits and repetitive behaviors. Recent research has linked that gut dysbiosis may contribute to ASD-like behaviors. However, the exact developmental time point at which gut microbiota alterations affect brain function and behavior in patients with ASD remains unclear. We hypothesized that ASD-related brain microstructural changes and gut dysbiosis induce metabolic dysregulation and proinflammatory responses, which collectively contribute to the social behavioral deficits observed in early childhood. We used an autistic-like rat model that was generated via prenatal valproic acid exposure. We analyzed brain microstructural changes using diffusion tensor imaging (DTI) and examined microbiota, blood, and fecal samples for inflammation biomarkers. The ASD model rats exhibited significant brain microstructural changes in the anterior cingulate cortex, hippocampus, striatum, and thalamus; reduced microbiota diversity (Prevotellaceae and Peptostreptococcaceae); and altered metabolic signatures. The shift in microbiota diversity and density observed at postnatal day (PND) 35, which is a critical developmental period, underscored the importance of early ASD interventions. We identified a unique metabolic signature in the ASD model, with elevated formate and reduced acetate and butyrate levels, indicating a dysregulation in short-chain fatty acid (SCFA) metabolism. Furthermore, increased astrocytic and microglial activation and elevated proinflammatory cytokines-interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)-were observed, indicating immune dysregulation. This study provided insights into the complex interplay between the brain and the gut, and indicated DTI metrics as potential imaging-based biomarkers in ASD, thus emphasizing the need for early childhood interventions.
自闭症谱系障碍（ASD）的特征是社交互动缺陷和重复行为。最近的研究将肠道菌群失调与 ASD 样行为联系起来。然而，确切的发育时间点，即肠道微生物群的改变如何影响 ASD 患者的大脑功能和行为，仍不清楚。我们假设 ASD 相关的大脑微观结构变化和肠道菌群失调会导致代谢失调和促炎反应，这些共同导致了儿童早期观察到的社交行为缺陷。我们使用了一种通过产前丙戊酸暴露产生的类似自闭症的大鼠模型。我们使用弥散张量成像（DTI）分析大脑微观结构变化，并检查微生物群、血液和粪便样本中的炎症生物标志物。ASD 模型大鼠在前扣带回皮质、海马体、纹状体和丘脑表现出明显的大脑微观结构变化；微生物多样性减少（普雷沃氏菌科和消化链球菌科）；代谢特征改变。在出生后第 35 天（PND）观察到的微生物多样性和密度的变化是一个关键的发育时期，这突显了早期 ASD 干预的重要性。我们在 ASD 模型中确定了一个独特的代谢特征，其中甲酸盐水平升高，乙酸盐和丁酸盐水平降低，表明短链脂肪酸（SCFA）代谢失调。此外，还观察到星形胶质细胞和小胶质细胞的激活增加以及促炎细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）水平升高，表明免疫失调。这项研究深入了解了大脑和肠道之间的复杂相互作用，并表明 DTI 指标可能是 ASD 的潜在成像生物标志物，因此强调了需要进行儿童早期干预。
