Dissecting Microbiota-Gut-Brain Interactions for the Anti-Seizure Effects of the Ketogenic Diet

项目摘要/摘要 哺乳动物与一个巨大而多样的微生物联盟在一起定居，统称为 微生物区系，影响一系列广泛的生物过程。最近的研究表明，除了 肠道微生物区系在营养、免疫和新陈代谢中起着基础性作用。 神经系统的发育和活动，影响几种复杂的寄主行为。建议数 研究计划旨在揭示特定基因之间相互作用的分子和细胞机制 肠道微生物和大脑，并阐明这些关系对宿主生理的影响。 这项研究计划将研究微生物群-肠道-脑的相互作用，以中介的抗癫痫作用的 生酮饮食(KD)。KD是治疗难治性癫痫和越来越多的其他癫痫的有效方法 大脑紊乱。然而，由于执行、遵守和执行方面的困难，KD的使用率仍然很低。 副作用，以及在药物无效的情况下，饮食到底是如何成功治疗神经功能障碍的 仍然不为人知。了解KD介导的抗癫痫发作的分子基础将揭示 从肠道微生物到神经系统的信号机制的新见解和新的信号通路 治疗神经系统疾病。值得注意的是，我们实验室之前发表的一篇论文报告称，KD结果 肠道微生物区系的显著变化，而这些变化是饮食抗癫痫效果所必需的 在两个癫痫模型中。我们现在建议：1)确定临床KD如何影响人类肠道 难治性癫痫儿童的微生物区系，II)评估KD相关的人类肠道微生物区系 调节癫痫小鼠模型的癫痫敏感性，III)揭示分子和细胞机制 微生物对神经元活动的影响。在这样做的过程中，我们将考虑微生物调节 代谢谱、感觉神经元活性、酮体水平和/或免疫稳态是潜在的 任何依赖微生物区系的寄主表型的途径。 这项工作将推动微生物区系-肠道-脑研究的前沿，以揭示新的分子途径 用来治疗神经系统疾病。这项拟议的研究测试了变革性假说，即 人体肠道微生物群有助于生酮饮食的抗癫痫作用，并可能启发新的 在克服严格饮食的主要障碍的同时增强KD的保护作用的策略 心理治疗。它的神经生物学研究在方法上是综合的，借鉴了功能生物学的进展 基因组学、代谢组学、生理学、成像学、分子生物学和神经科学。

PROJECT SUMMARY/ABSTRACT Mammals are colonized with a vast and diverse consortium of microorganisms, collectively called the microbiota, that influence a wide array of biological processes. Recent studies demonstrate that in addition to their roles in nutrition, immunity and metabolism, the intestinal microbiota plays a fundamental role in the development and activity of the nervous system, influencing several complex host behaviors. The proposed research plan aims to uncover molecular and cellular mechanisms underlying the interaction between specific gut microbes and the brain, and to elucidate the impact of these relationships on host physiology. This research plan will investigate microbiome-gut-brain interactions that mediate the antiseizure effects of the ketogenic diet (KD). The KD is an effective treatment for refractory epilepsy and an increasing number of other brain disorders. However, use of the KD remains low due to difficulties with implementation, compliance and adverse side effects, and exactly how the diet succeeds in treating neural dysfunction in cases when drugs fail remains unknown. Understanding the molecular bases for KD-mediated protection against seizures will reveal new insights into signaling mechanisms from gut microbes to the nervous system and novel pathways for treating neurological disease. Notably, a previous publication from our laboratory reported that the KD results in striking changes in the gut microbiota, and these changes are required for the anti-seizure effects of the diet in two seizure models. We now propose to i) determine how the clinical KD influences the human gut microbiota in children with refractory epilepsy, ii) evaluate whether the KD-associated human gut microbiota regulates seizure susceptibility in mouse models for epilepsy, iii) uncover molecular and cellular mechanisms for microbial influences on neuronal activity. In doing so, we will consider the ability of microbes to modulate metabolomic profiles, sensory neuronal activity, ketone body levels and/or immune homeostasis as potential pathways for any microbiota-dependent host phenotypes. This work will push the frontiers of microbiota-gut-brain research toward uncovering new molecular pathways for treating neurological disease. The proposed research tests the transformative hypothesis that alterations in the human gut microbiome contribute to the anti-seizure effects of the ketogenic diet and could inspire novel strategies for enhancing the protective effects of the KD while overcoming major obstacles of strict dietary therapy. It is methodologically integrative in its study of neurobiology, drawing from advancements in functional genomics, metabolomics, gnotobiotics, imaging, molecular biology and neuroscience.