Does microbiome composition moderate GI and CNS function in a VPA-induced mouse model of autism?

在 VPA 诱导的自闭症小鼠模型中，微生物组组成是否会调节胃肠道和中枢神经系统功能？

• 批准号: 10753699
• 负责人: Rebecca Knickmeyer
• 金额: $ 43.04万
• 依托单位: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753699
• 关键词: Address; Adolescent; Adult; Adult Children; Adverse effects; Age; Amygdaloid structure; Animals; Anxiety; Autopsy; Bacteroides; Behavior; Behavioral; Behavioral Symptoms; Bifidobacterium; Binding; Biological; Biological Assay; Brain; Chemical Exposure; Child; Cognition; Colon; Communities; Development; Distress; Electrophysiology (science); Emotional; Encephalitis; Enteral; Environmental Exposure; Etiology; Exposure to; Eye; Face; Family; Functional disorder; Future; Gastrointestinal Diseases; General Population; Genes; Genetic Models; Germ-Free; Grooming; Hippocampus; Human; Impairment; Infant; Intellectual functioning disability; Intervention; Intestinal permeability; Intestines; Link; Maps; Marble; Measures; Meta-Analysis; Methods; Microbe; Modeling; Morphology; Mus; Muscle; Muscle Cells; National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Neurons; Odors; Pain; Pattern; Persons; Pharmaceutical Preparations; Placebos; Pre-Clinical Model; Prefrontal Cortex; Pregnancy; Preparation; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Self-Injurious Behavior; Social Conditions; Social Interaction; Structure; Symptoms; Synapses; Techniques; Testing; Transplantation; Valproic Acid; Variant; Vertebral column; Work; autism spectrum disorder; autistic; autistic children; behavior test; cell motility; chemical association; cognitive ability; comorbidity; comparison control; conditioned place preference; density; dietary; early childhood; effective intervention; gastrointestinal; gastrointestinal function; gastrointestinal symptom; germ free condition; gut inflammation; gut microbiome; gut microbiota; gut-brain axis; habituation; human microbiota; improved; in utero; individuals with autism spectrum disorder; infancy; infant gut microbiome; innovation; interest; microbial community; microbiome; microbiome composition; mouse model; myelination; neurodevelopment; neuroinflammation; neuropsychiatry; neurotransmission; novel; object recognition; offspring; open label; preference; prenatal; pup; repetitive behavior; response; social; therapeutic target

Project Summary GI issues occur in 30-80% of autistic individuals and may result in significant pain and distress. Thus, there is an urgent need to understand why GI symptoms occur in ASD and to develop more effective interventions. Recent research suggests the gut microbiome may contribute to GI issues in ASD. Autistic people differ from controls in the microbes they carry, patterns that may be linked to autism-related dietary preferences and the adverse effects of ASD linked genes and ASD linked environmental exposures on gut development and function. In addition, transfer of microbes from people with ASD induces ASD-like behaviors in germ-free mice suggesting these differences, regardless of their causes, contribute to behavioral issues. Further, recent open label trials of fecal matter transplant and of a drug that binds and sequesters aromatic metabolites in the gut have shown promising results in autistic people. While these findings are exciting, there is still much to be done in terms of mapping the biological mechanisms connecting gut microbiota to GI and CNS function in ASD. The main objec- tive of this study is to evaluate the effect of humanized gut microbiomes on GI and CNS function in a valproic acid (VPA)-induced mouse model of ASD. We will achieve this objective via 2 aims. In Aim 1, we will determine if gut microbiome composition moderates the impact of prenatal VPA exposure on GI function by creating three groups of animals with differing microbiomes: specific pathogen-free (SPF) mice, mice with a human gut micro- biome dominated by Bifidobacterium (BIF), and mice with a human gut microbiome dominated by Bacteroides (BAC). Half of the animals will be exposed to VPA (500 mg/kg) on day 13 of gestation and half will receive a sham treatment. We will assess colonic transit and intestinal permeability in live adult offspring, discern neuro- enteric organization using immunostaining and RT-PCR, conduct ex vivo colonic motility assays, measure intes- tinal inflammation, and use electrophysiological methods to record from enteric nerve and muscle cells in isolated preparations of intestine to study synaptic and circular muscle neurotransmission. In Aim 2, we will determine whether gut microbiome composition moderates the impact of prenatal VPA exposure on CNS structure and function. Using the same groups as in Aim 1, we will evaluate juvenile and adult behavior using well established paradigms directly relevant to ASD. To investigate underlying mechanisms, we will assess neuroinflammation, dendritic morphology, and myelination in hippocampus, amygdala, and prefrontal cortex (PFC). The proposed study is innovative in combining a well-established preclinical model for ASD – gestational VPA exposure – with transplant of human microbial communities collected during infancy, a key period in the etiology of ASD. The proposed study is significant as it will enhance our understanding of the gut microbiome’s role in GI and CNS functions relevant to ASD. The project will have a positive impact because it will provide information and a novel modelling approach that will facilitate the development of novel microbiome-related interventions to ad- dress core ASD symptoms and comorbidities including intellectual disability, anxiety and GI issues.

项目概要 30-80% 的自闭症患者会出现胃肠道问题，并可能导致严重的疼痛和困扰。 迫切需要了解自闭症谱系障碍中出现胃肠道症状的原因并制定更有效的干预措施。 最近的研究表明，自闭症患者的肠道微生物群可能与自闭症患者不同。 控制它们携带的微生物，可能与自闭症相关的饮食偏好和模式有关 ASD 相关基因和 ASD 相关环境暴露对肠道发育和功能的不利影响。 此外，从 ASD 患者身上转移微生物会在无菌小鼠中诱导类似 ASD 的行为，这表明 这些差异，无论其原因如何，都会导致行为问题。此外，最近的开放标签试验。 粪便物质移植和一种在肠道中结合和隔离芳香代谢物的药物的研究表明 尽管这些发现令人兴奋，但在自闭症患者方面仍有许多工作要做。 绘制自闭症谱系障碍 (ASD) 中肠道微生物群与胃肠道和中枢神经系统功能之间的生物学机制。 本研究的目的是评估人源化肠道微生物组对丙戊酸患者胃肠道和中枢神经系统功能的影响 酸（VPA）诱导的 ASD 小鼠模型 我们将通过 2 个目标来实现这一目标。 如果肠道微生物组组成通过创建三个因素来调节产前 VPA 暴露对胃肠道功能的影响 具有不同微生物群的动物组：无特定病原体（SPF）小鼠、具有人类肠道微生物的小鼠 以双歧杆菌（BIF）为主的生物群落，以及以拟杆菌为主的人类肠道微生物群落的小鼠 (BAC)。一半的动物将在妊娠第 13 天接触 VPA（500 毫克/千克），一半的动物将接受 VPA（500 毫克/千克）。 我们将评估活体成年后代的结肠运输和肠道通透性，辨别神经- 使用免疫染色和 RT-PCR 检测肠组织，进行离体结肠运动测定，测量肠组织 肠炎症，并使用电生理学方法记录分离的肠神经和肌肉细胞 在目标 2 中，我们将确定研究突触和环肌神经传递的肠道准备工作。 肠道微生物组成是否会调节产前 VPA 暴露对中枢神经系统结构的影响以及 使用与目标 1 中相同的组，我们将使用成熟的方法来评估青少年和成人的行为。 与自闭症谱系障碍直接相关的范式为了研究潜在的机制，我们将评估神经炎症， 海马体、杏仁核和前额皮质 (PFC) 的树突形态和髓鞘形成。 该研究的创新之处在于将成熟的 ASD 临床前模型（妊娠 VPA 暴露）与 移植婴儿期收集的人类微生物群落，婴儿期是自闭症谱系障碍病因学的关键时期。 拟议的研究意义重大，因为它将增强我们对肠道微生物组在胃肠道和中枢神经系统中作用的理解 与 ASD 相关的功能 该项目将产生积极影响，因为它将提供信息和 新颖的建模方法将促进新型微生物组相关干预措施的开发 治疗自闭症谱系障碍 (ASD) 的核心症状和合并症，包括智力障碍、焦虑和胃肠道问题。