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

项目总结/摘要 哺乳动物被一个庞大而多样的微生物群落所定殖，这些微生物统称为 微生物群，影响广泛的生物过程。最近的研究表明，除了 它们在营养、免疫和代谢中的作用，肠道微生物群在营养、免疫和代谢中起着重要作用。 神经系统的发育和活动，影响几种复杂的宿主行为。拟议 该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。 这项研究计划将调查微生物群-肠道-大脑相互作用，介导的抗癫痫作用， 生酮饮食（KD）。KD是治疗难治性癫痫的有效方法， 大脑紊乱然而，由于在执行、遵守和执行方面的困难， 不良副作用，以及在药物无效的情况下，饮食如何成功治疗神经功能障碍 仍然未知。了解KD介导的抗癫痫保护作用的分子基础将揭示 对从肠道微生物到神经系统的信号传导机制以及 治疗神经系统疾病值得注意的是，我们实验室以前的一份出版物报告说，KD结果 在肠道微生物群的显着变化，这些变化是所需的抗癫痫效果的饮食 在两个癫痫模型中。我们现在提出i）确定临床KD如何影响人类肠道 ii）评估KD相关的人类肠道微生物群是否与难治性癫痫儿童的肠道微生物群有关， 调节癫痫小鼠模型的癫痫发作易感性，iii）揭示分子和细胞机制 微生物对神经元活动的影响在此过程中，我们将考虑微生物调节 代谢组学特征、感觉神经元活动、酮体水平和/或免疫稳态作为潜在的 任何微生物群依赖的宿主表型的途径。 这项工作将推动微生物群-肠道-大脑研究的前沿，以揭示新的分子途径。 用于治疗神经系统疾病。这项拟议的研究测试了一个变革性的假设， 人类肠道微生物组有助于生酮饮食的抗癫痫作用， 提高KD的保护作用，同时克服严格的饮食限制的主要障碍的策略 疗法它在神经生物学的研究中是方法上综合的，借鉴了功能性神经生物学的进展。 基因组学、代谢组学、营养生物学、成像、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.