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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

基本信息

批准号：
10343846
负责人：
Elaine Hsiao
金额：
$ 33.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10343846
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

项目摘要

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.

项目总结/文摘