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，在世界范围内具有主要的公共卫生问题。越来越多的研究 表明CD是一种神经毒性，CD暴露与学习和记忆定义有关，并且 人类的各种神经退行性疾病。我以前的研究发现与环境相关的CD 暴露会损害动物的学习和记忆。但是，当前有关机制的知识 CD神经毒性的含量仍然非常有限。人们越来越认识到肠道轴，通信 中枢神经系统与肠道微生物组之间的途径对于控制神经学很重要 功能。由于肠道微生物组是CD毒性的靶标，我假设肠脑轴 机械上有助于CD神经毒性。该项目旨在确定肠道微生物组是否贡献 在学习和记忆方面的CD神经毒性，并确定特定的微生物组和微生物代谢物 机械上有助于CD神经毒性。 K99修复了相位建议，以（1）检查变化 根据CD诱导的学习和记忆的开始，肠道微生物组和微生物代谢物 确定的，进一步（2）确定肠道微生物组是否既需要且足以容纳CD神经毒性 使用抗生素处理的小鼠来确定肠道微生物组的耗竭如何调节CD诱导的 学习和记忆在小鼠中定义，并在经过抗生素治疗的小鼠中进行粪便微生物群移植 接种与记忆受损的CD处理的小鼠收集的肠含量，以确定如何 “患病的微生物组”本身有助于认知缺陷。在此期间，候选人将完成 在微生物组，生物信息学，第二代测序和其他的培训和课程 专业发展培训为独立R00阶段做准备。在独立阶段，有 来自K99阶段的发现，该项目将进一步识别特定的微生物组和微生物中性活性 在学习和记忆中有助于CD毒性的代谢产物。关于预期的结果，这个项目 将首次确定肠道轴在CD诱导的神经毒性中的重要性，从而增强 了解CD和其他环境神经毒性的神经毒性的机制， 并为设计预防和干预策略的设计提供转化见解，以减轻CD 通过重新编程肠道微生物组来神经毒性。