Understanding the role of the gut-brain axis in modulating Cadmium neurotoxicity

了解肠脑轴在调节镉神经毒性中的作用

• 批准号: 10697303
• 负责人: Hao Wang
• 金额: $ 10.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697303
• 关键词: Affect; Alzheimer' s Disease; Animals; Antibiotics; Bacteria; Bacteroides; Bacteroides thetaiotaomicron; Bile Acids; Bioinformatics; Cadmium; Central Nervous System; Cognitive deficits; Communication; Data; Development; Disease; Dose; Female; Food; General Population; Generations; Heavy Metals; Hippocampus; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Intervention; Intestinal Content; Intestinal permeability; Knowledge; Lead; Learning; Memory; Memory impairment; Mentors; Microbe; Mus; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurotoxins; Outcome; Parkinson Disease; Pathway interactions; Phase; Play; Poison; Preparation; Prevention strategy; Public Health; Research; Role; Smoking; Source; Statistical Models; Testing; Time; Toxic Environmental Substances; Toxic effect; Training; Volatile Fatty Acids; autism spectrum disorder; cytokine; data integration; design; disease registry; dysbiosis; fecal transplantation; gut dysbiosis; gut microbiome; gut-brain axis; insight; male; microbial; microbiome; microbiome composition; nervous system disorder; neuroprotection; neurotoxic; neurotoxicity; novel; remediation; remote sensing; response

PROJECT SUMMARY Cadmium (Cd) is a heavy metal with major public health concern around the world. Increasing studies suggest that Cd is a neurotoxicant, and the Cd exposure is associated with learning and memory deficits, and various neurodegenerative diseases in humans. My previous study has found that environmental relevant Cd exposure can impair learning and memory in animals. However, the current knowledge about the mechanisms of Cd neurotoxicity is still very limited. There is an increasing recognition that the gut-brain axis, a communication pathway between the central nervous system and the gut microbiome, is important for regulating neurological functions. Since the gut microbiome is a target of Cd toxicity, I hypothesized that the gut-brain axis mechanistically contributes to Cd neurotoxicity. This project aims to determine if the gut microbiome contributes to Cd neurotoxicity on learning and memory and identify specific microbiomes and microbial metabolites that mechanistically contribute to Cd neurotoxicity. The K99 mentored phase proposes to (1) examine the changes of the gut microbiome and microbial metabolites according to the onset of Cd-induced learning and memory deficits, and further (2) determine if the gut microbiome is both necessary and sufficient for Cd neurotoxicity by using antibiotics-treated mice to determine how depletion of the gut microbiome modulates the Cd-induced learning and memory deficits in mice, and conducting fecal microbiota transplant in antibiotics-treated mice inoculated with intestinal content collected from Cd-treated mice with impaired memory to determine how a “diseased microbiome” itself contributes to cognitive deficits. During this time, the candidate will complete mentored training and courses in the microbiome, bioinformatics, second-generation sequencing, and other professional development training in preparation for the independent R00 phase. In the independent phase, with the findings from the K99 phase, this project will further identify specific microbiomes and microbial neuroactive metabolites that contribute to Cd toxicity in learning and memory. Regarding the expected outcomes, this project will determine for the first time the importance of the gut-brain axis in Cd-induced neurotoxicity, enhance the understanding of the mechanisms concerning the neurotoxicity of Cd and other environmental neurotoxicants, and provide translational insights for the design of prevention and intervention strategies to mitigate Cd neurotoxicity by reprogramming the gut microbiome.

项目摘要 镉（Cd）是一种重金属，在世界范围内引起了重大的公共健康问题。增加研究 提示镉是一种神经毒性物质，镉暴露与学习记忆障碍有关， 各种神经退行性疾病。我以前的研究发现，环境相关的镉 暴露在空气中会损害动物的学习和记忆能力。然而，目前关于这些机制的知识 镉的神经毒性仍然是非常有限的。越来越多的人认识到，肠-脑轴，一种沟通， 中枢神经系统和肠道微生物组之间的通路，对于调节神经系统 功能协调发展的由于肠道微生物组是镉毒性的目标，我假设肠-脑轴 机制上有助于镉的神经毒性。该项目旨在确定肠道微生物组是否有助于 镉对学习和记忆的神经毒性，并确定特定的微生物组和微生物代谢物， 机制上有助于镉的神经毒性。K99指导阶段建议（1）检查变更 根据镉诱导的学习和记忆的发作， 缺陷，并进一步（2）确定肠道微生物组是否是镉神经毒性的必要和充分条件， 使用抗生素治疗的小鼠来确定肠道微生物组的消耗如何调节镉诱导的 小鼠的学习和记忆缺陷，并在驱虫剂处理的小鼠中进行粪便微生物群移植 接种从镉处理的记忆受损小鼠收集的肠内容物，以确定 “患病的微生物组”本身也会导致认知缺陷。在此期间，候选人将完成 微生物组、生物信息学、第二代测序等方面的辅导培训和课程 为独立R 00阶段做准备的专业发展培训。在独立阶段，随着 K99阶段的研究结果，该项目将进一步确定特定的微生物组和微生物神经活性 在学习和记忆过程中，镉的代谢产物会导致镉的毒性。关于预期成果，该项目 将首次确定肠-脑轴在镉诱导的神经毒性中的重要性，增强 了解镉和其他环境神经毒物的神经毒性机制， 并为预防和干预策略的设计提供翻译见解，以减轻镉 神经毒性通过重新编程肠道微生物组。