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

剖析微生物群-肠道-大脑的相互作用以实现生酮饮食的抗癫痫作用

• 批准号: 10160978
• 负责人: Elaine Hsiao
• 金额: $ 38.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10160978
• 关键词: Acute; Aftercare; Amino Acids; Antiepileptic Agents; Bacteria; Behavior; Biological Process; Brain; Brain Diseases; Calcium; Carbohydrates; Child; Clinical; Complex; Data; Development; Diet; Diet therapy; Dietary Intervention; Disease; Electroencephalography; Electrophysiology (science); Epilepsy; Fatty acid glycerol esters; Glutamate Metabolism Pathway; Gnotobiotic; Health; Hippocampus (Brain); Homeostasis; Human; Human Microbiome; Image; Immune; Immunity; Incidence; Individual; Intractable Epilepsy; Ketone Bodies; Laboratories; Lead; Link; Mammals; Measures; Mediating; Medical History; Metabolic; Metabolism; Metagenomics; Methodology; Microbe; Modeling; Modification; Molecular; Molecular Biology; Multivariate Analysis; Mus; Nerve; Nervous system structure; Neurobiology; Neuronal Dysfunction; Neurons; Neurosciences; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiology; Play; Predisposition; Publications; Reporting; Research; Role; Seizures; Sensory; Severities; Signal Transduction; Symptoms; Testing; Therapeutic; Tonic - clonic seizures; Transplantation; Work; base; brain research; childhood epilepsy; clinical effect; clinical investigation; clinical practice; dietary; effective therapy; frontier; functional genomics; gamma-Aminobutyric Acid; gut microbes; gut microbiome; gut microbiota; gut-brain axis; host microbiome; insight; ketogenic diet; metabolomics; microbial; microbiome; microbiota; microbiota-gut-brain axis; microorganism; mouse model; multiple omics; nervous system disorder; neuroregulation; novel; novel strategies; nutrition; protective effect; response; side effect; stool sample; translational approach

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.

项目概要/摘要 哺乳动物栖息着大量多样的微生物群落，统称为微生物群落。 微生物群，影响广泛的生物过程。最近的研究表明，除了 肠道菌群在营养、免疫和代谢方面发挥着重要作用，在 神经系统的发育和活动，影响多种复杂的宿主行为。拟议的 研究计划旨在揭示特定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学的影响。 该研究计划将调查微生物组-肠-脑之间的相互作用，以介导微生物的抗癫痫作用 生酮饮食（KD）。 KD 是治疗难治性癫痫和越来越多的其他疾病的有效方法 脑部疾病。然而，由于实施、合规性和有效性方面的困难，KD 的使用率仍然很低。 不良副作用，以及在药物失败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 介导的癫痫发作保护的分子基础将揭示 对从肠道微生物到神经系统的信号传导机制的新见解以及新的途径 治疗神经系统疾病。值得注意的是，我们实验室之前的一份出版物报道称 KD 结果 肠道微生物群发生显着变化，而这些变化是饮食的抗癫痫作用所必需的 在两种癫痫发作模型中。我们现在建议 i) 确定临床 KD 如何影响人类肠道 难治性癫痫儿童的微生物群，ii) 评估 KD 相关的人类肠道微生物群是否 调节癫痫小鼠模型的癫痫易感性，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的能力 潜在的代谢组学特征、感觉神经元活动、酮体水平和/或免疫稳态 任何依赖微生物群的宿主表型的途径。 这项工作将推动微生物群-肠-脑研究的前沿，以发现新的分子途径 用于治疗神经系统疾病。拟议的研究测试了变革性假设，即改变 人类肠道微生物组有助于生酮饮食的抗癫痫作用，并可能激发新的研究 增强 KD 保护作用同时克服严格饮食的主要障碍的策略 治疗。它在方法论上整合了神经生物学的研究，借鉴了功能学的进步 基因组学、代谢组学、生殖学、成像、分子生物学和神经科学。