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.

项目摘要 GI问题发生在30-80％的加速度中，可能会导致剧烈的疼痛和困扰。那是 迫切需要了解为什么在ASD中出现GI症状并制定更有效的干预措施。 最近的研究表明，肠道微生物组可能会导致ASD中的GI问题。自闭症患者与众不同 它们所携带的微生物中的对照，可能与自闭症相关饮食偏好相关的模式和 ASD连接基因和ASD连接环境暴露对肠道发展和功能的不利影响。 另外，从ASD患者中转移微生物在无菌小鼠中诱导ASD类似ASD的行为表明 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 粪便移植和结合和隔离的药物已显示出芳族代谢物 加速的人有希望的结果。尽管这些发现令人兴奋，但仍有很多事情要做 映射将肠道微生物群连接到gi和CNS功能的生物学机制。主要的objec- 这项研究是为了评估人源化肠道微生物组对GI和CNS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。在AIM 1中，我们将确定 如果肠道微生物组组成可以通过创建三个来调节产前VPA暴露对GI功能的影响 具有分化微生物组的动物组：特定的无病原体（SPF）小鼠，具有人类肠道微型的小鼠 由双歧杆菌（BIF）和人类肠道微生物组主导的生物组（BIF）主导 （BAC）。一半的动物将在妊娠第13天暴露于VPA（500 mg/kg），一半将接受 假治疗。我们将评估成人后代的结肠过渡和肠道通透性，辨别神经 - 使用免疫染色和RT-PCR的肠道组织，进行离体菌落运动分析，测量INTS- tinal炎症，并使用电生理方法记录肠神经和肌肉细胞的分离 肠的制剂研究突触和圆形肌肉神经传递。在AIM 2中，我们将确定 肠道微生物组组成是否会调节产前VPA暴露对中枢神经系统结构和 功能。使用与AIM 1相同的组，我们将使用良好的成年人行为评估少年和成人行为 范式与ASD直接相关。为了调查潜在机制，我们将评估神经炎症， 海马，杏仁核和前额叶皮层（PFC）中的树突形态和髓鞘形成。提议 研究在结合ASD的公认临床前模型（妊娠VPA暴露）中具有创新性 在婴儿期收集的人类微生物群落的移植，这是ASD病因的关键时期。这 拟议的研究很重要，因为它将增强我们对肠道微生物组在GI和CNS中的作用的理解 与ASD相关的功能。该项目将产生积极的影响，因为它将提供信息和 新型建模方法将有助于开发新型微生物组相关的干预措施 着装核心ASD符号和合并症，包括智力残疾，动画和GI问题。