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

项目总结 镉(Cd)是一种重金属，在世界各地都有重大的公共卫生问题。不断增加的研究 提示镉是一种神经毒物，接触镉与学习和记忆障碍有关，以及 人类的各种神经退行性疾病。我之前的研究发现，与环境有关的Cd 暴露在空气中会损害动物的学习和记忆。然而，目前对这种机制的了解 对镉的神经毒性的研究仍然非常有限。越来越多的人认识到，肠道-脑轴是一种交流 中枢神经系统和肠道微生物群之间的通路，对调节神经系统很重要 功能。由于肠道微生物群是镉中毒的目标，我假设肠道-脑轴 机械性地导致镉的神经毒性。该项目旨在确定肠道微生物群是否对 镉对学习和记忆的神经毒性，并鉴定特定的微生物群和微生物代谢物 机械性地导致镉的神经毒性。K99指导阶段建议(1)检查更改 肠道微生物组和微生物代谢物与镉诱导的学习和记忆的关系 缺陷，并进一步(2)确定肠道微生物群对于镉的神经毒性是否既必要又充分 用抗生素处理的小鼠来确定肠道微生物群的枯竭是如何调节镉诱导的 小鼠的学习和记忆障碍，以及抗生素处理的小鼠进行粪便微生物区系移植 用从镉处理的记忆受损的小鼠收集的肠道内容物接种，以确定 “病态微生物群”本身就会导致认知缺陷。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指导培训和课程 为独立R00阶段做准备的专业发展培训。在独立阶段， K99阶段的发现，该项目将进一步确定特定的微生物群和微生物神经活性 导致学习和记忆中镉毒性的代谢物。关于预期结果，这个项目 将首次确定肠道-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， 并为设计预防和干预策略提供翻译见解，以减轻CD 通过对肠道微生物群进行重新编程而产生的神经毒性。

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.