PCB-mediated dysbiosis of the gut microbiome: A missing link in PCB-mediated neurodevelopmental disorders?

PCB 介导的肠道微生物群失调：PCB 介导的神经发育障碍中缺失的一环？

• 批准号: 10093046
• 负责人: Yue Cui
• 金额: $ 62.11万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093046
• 关键词: Address; Adolescent; Adult; Affect; Behavior; Brain; Cytochrome P450; Data; Development; Diagnosis; Diet; Dose; Environmental Impact; Enzymes; Etiology; Evaluation; Exposure to; Family; Fetus; Future; Germ-Free; Goals; Health; Hepatic; Individual; Intervention; Knowledge; Lactation; Life; Link; Liver; Maternal Exposure; Measures; Mediating; Metabolic Biotransformation; Metabolism; Microbe; Mission; Mus; Neonatal; Neurodevelopmental Disorder; Neurotoxins; Organism; Outcome; Outcome Study; Oxidative Stress; Polychlorinated Biphenyls; Positioning Attribute; Predisposition; Pregnancy; Public Health; Research; Rodent; Role; Societies; Synapses; Systems Biology; Testing; Toxic Environmental Substances; Transplantation; United States National Institutes of Health; adverse outcome; base; developmental neurotoxicity; dysbiosis; experimental study; fecal transplantation; gut dysbiosis; gut microbiome; human disease; innovation; insight; microbial; microbiome; microbiome alteration; microbiome composition; mother nutrition; mouse model; multidisciplinary; neurodevelopment; neuroinflammation; neurotoxic; neurotoxicity; novel; pup

PROJECT SUMMARY/ABSTRACT Exposure of the developing brain to polychlorinated biphenyls (PCBs) and disruption of the gut microbiome have independently been implicated in the etiology of neurodevelopmental disorders (NDDs). Both phenomena likely interact by two mechanisms to cause adverse neurodevelopmental outcomes: PCB-mediated changes in the gut microbiome (1) alter the profile of neuroactive microbial metabolites distributed to the developing brain and (2) affect PCB disposition in the developing brain by modifying host and microbial PCB metabolism. A mechanistic understanding of these interactions is required to address the critical need for interventional strategies that effec- tively reduce the impact of PCB-induced NDDs on individuals, families, and society. The long-term goal is to de- termine the role of the gut microbiome–liver–brain axis in modulating susceptibility to PCB effects on the develop- ing brain, with the objective of characterizing how dose-dependent interactions between maternal exposure to an environmentally relevant PCB mixture and the gut microbiome influence neurotoxic outcomes in conventional (CV) vs. germ-free (GF) juvenile mice. We will test the central hypothesis that dysbiosis of the gut microbiome as- sociated with developmental exposure to varying doses of PCBs contributes to adverse neurodevelopmental out- comes later in life. This hypothesis is based on preliminary studies showing that: (1) PCB exposure causes dysbiosis of the gut microbiome; (2) PCBs and their metabolites are present in the rodent brain; (3) the expression of PCB-metabolizing enzymes differs between CV vs. GF mice; (4) PCB disposition differs between CV and GF mice; and (5) PCBs are developmental neurotoxicants in mice. Guided by these preliminary data, the novel hy- pothesis will be tested by (a) characterizing gut microbiome composition and function and neuroactive microbial metabolites; (b) determining how differences in host vs. microbial biotransformation affect disposition of PCBs and their metabolites; and (c) examining neuroinflammation, oxidative stress, synaptic connectivity, and behavior in dams and fetuses/pups derived from (i) CV vs.GF dams exposed to PCBs in the diet and (ii) GF dams who re- ceived a fecal transplant from PCB-exposed or vehicle control CV dams. The proposed research is innovative because it uses a systems biology approach in a state-of-the-art mouse model to assess the role of the gut mi- crobiome–liver–brain axis in modulating neurotoxic outcomes following exposure to an environmental PCB mix- ture. The anticipated outcome of these studies is a new research paradigm demonstrating that developmental exposures to PCBs mediate (1) longitudinal changes in gut microbiome composition and function and (2) alter PCB disposition in the developing brain that influence neurodevelopmental outcomes later in life. This outcome will have a significant impact on public health by informing future studies of cellular mechanisms of the devel- opmental origin of PCB neurotoxicity and, ultimately, provide critical insights regarding the plausibility of micro- biome-based approaches to diagnose and treat NDDs induced by exposure to neurotoxicants.

项目概要/摘要 发育中的大脑接触多氯联苯 (PCB) 并破坏肠道微生物组 已独立地涉及神经发育障碍（NDD）的病因学。两种现象 可能通过两种机制相互作用，导致不良的神经发育结果： PCB 介导的变化 肠道微生物群 (1) 改变分布到发育中大脑的神经活性微生物代谢物的分布， (2)通过改变宿主和微生物的PCB代谢来影响发育中大脑中的PCB处置。机械论 需要了解这些相互作用才能解决有效干预策略的迫切需求 积极减少PCB引起的NDD对个人、家庭和社会的影响。长期目标是去 确定肠道微生物群-肝-脑轴在调节 PCB 对发育的影响的敏感性中的作用 大脑，目的是描述母亲暴露于某种物质之间的剂量依赖性相互作用 环境相关的 PCB 混合物和肠道微生物组影响传统方法中的神经毒性结果 (CV) 与无菌 (GF) 幼年小鼠。我们将测试肠道微生物群失调的中心假设： 与发育过程中接触不同剂量的 PCB 相关，会导致神经发育不良 会在以后的生活中出现。该假设基于初步研究表明： (1) PCB 暴露原因 肠道微生物群失调； (2) PCBs及其代谢物存在于啮齿类动物的大脑中； (3) 表达式 CV 小鼠与 GF 小鼠的 PCB 代谢酶不同； (4) CV和GF的PCB配置不同 老鼠； (5) PCB 是小鼠发育神经毒物。在这些初步数据的指导下，新颖的hy- 假设将通过以下方式进行测试：（a）表征肠道微生物组的组成和功能以及神经活性微生物 代谢物； (b) 确定宿主与微生物生物转化的差异如何影响多氯联苯的处置和 他们的代谢物； (c) 检查神经炎症、氧化应激、突触连接和行为 母鼠和胎儿/幼崽源自 (i) CV 与 GF 母鼠暴露于饮食中的多氯联苯 (PCB) 和 (ii) GF 母鼠 接受了来自 PCB 暴露或车辆对照 CV 水坝的粪便移植。所提出的研究具有创新性 因为它在最先进的小鼠模型中使用系统生物学方法来评估肠道微生物的作用 微生物群-肝-脑轴在暴露于环境 PCB 混合物后调节神经毒性结果 确实。这些研究的预期结果是一个新的研究范式，表明发育 接触多氯联苯会介导 (1) 肠道微生物组组成和功能的纵向变化，以及 (2) 改变 发育中大脑中的 PCB 分布会影响以后的神经发育结果。这个结果 通过为未来的细胞发育机制研究提供信息，将对公共健康产生重大影响 PCB 神经毒性的基本起源，并最终提供关于微量的合理性的重要见解 基于生物群落的方法来诊断和治疗因暴露于神经毒物而引起的 NDD。