Dissecting the role of gut microbial-derived metabolites on epilepsy

剖析肠道微生物代谢物对癫痫的作用

• 批准号: 10502915
• 负责人: Susan Latoya Campbell
• 金额: $ 39.07万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10502915
• 关键词: Action Potentials; Acute; Adult; Affect; Agreement; Antiepileptic Agents; Bacteria; Blood - brain barrier anatomy; Brain; C57BL/6 Mouse; Cells; Cellular Membrane; Chronic; Data; Defect; Development; Drug resistance; Electroencephalography; Electrophysiology (science); Epilepsy; Frequencies; Genetic; Hippocampus (Brain); Homeostasis; Infection; Inflammation; Injections; Kainic Acid; Knowledge; Link; Liquid Chromatography; Mass Spectrum Analysis; Metabolic; Modeling; Molecular; Mus; Nervous System Physiology; Neuraxis; Neuronal Dysfunction; Neurons; Outcome; Patients; Phase; Phenotype; Physiological; Physiology; Plasma; Play; Predisposition; Prevalence; Process; Production; Proteins; Publishing; Research; Resistance; Resource-limited setting; Risk Factors; Rodent; Role; Sampling; Seizures; Signal Pathway; Supplementation; Synapses; Synaptic Transmission; TMEV; Taxonomy; Temporal Lobe; Temporal Lobe Epilepsy; Test Result; Testing; Therapeutic; Therapeutic Intervention; Time; Viral; Virus Diseases; Work; acquired epilepsy; astrogliosis; daidzein; design; dietary; equol; gut bacteria; gut microbes; gut microbiome; gut microbiota; gut-brain axis; innovation; large-conductance calcium-activated potassium channels; microbial; microbiome; microbiome analysis; microorganism; mortality; neglect; nervous system disorder; neuronal excitability; neuroprotection; novel; novel strategies; patch clamp; synaptic function; tandem mass spectrometry; targeted treatment; therapeutic target; transcriptome sequencing; voltage

Project Summary Epilepsy is a common neurological disorder, with a worldwide prevalence of over 65 million. There is general agreement that epilepsy is caused by hyperexcitable neuronal networks and most therapeutic strategies have focused on decreasing excitation by targeting neuronal synaptic proteins. Even with the available antiepileptic drugs, there is still no cure and 30% of patients are resistant to treatment. Historically, epilepsy has been viewed as driven solely by defects in brain processes; however, this brain-centric perspective neglects the fact that the function of the nervous system is affected by the metabolic state of the body. Current research recognizes that microorganisms influence the brain by modifying metabolic factors in the gut, the “gut-brain axis.” Most of the evidence thus far is correlative showing that changes in the gut microbiota can affect seizure outcomes. However, there is a gap in knowledge regarding specific mechanisms by which gut microbes contribute to seizure development that may offer novel approaches to treat epilepsy. Viral infection-induced epilepsy is the most common cause of epilepsy worldwide and is often difficult to model in rodents due to high mortality rates. However, the Theiler's murine encephalomyelitis virus (TMEV) is a low-mortality viral-induced model of temporal lobe epilepsy. Intracranial TMEV injection leads to hippocampal neuronal dysfunction, widespread cortical astrogliosis, and seizure-genesis peaking at 6 days post infection in ~50% of adult C57BL/6 mice. While central nervous system inflammation has been posited as a potential modulator of seizure phenotype development in TMEV infection, the molecular mechanism is unclear. Data obtained from this model surprisingly indicated that the majority of taxonomies underrepresented in TMEV-infected mice with seizure phenotypes contained genera associated with the production of the bacterial metabolite S-equol. These bacteria convert dietary daidzein into S-equol, which has been shown to activate large conductance Ca2+- and voltage-activated K+ (BK) channels. Activation of BK channels play an important role in controlling neuronal excitability and therefore represents a novel target for the treatment of epilepsy. This proposal will determine if depletion of the microbial-derived metabolite, S-equol, increase seizure occurrence in TMEV-injected mice. It further tests the hypothesis that S- equol-producing microbial species confer neuroprotection against seizure susceptibility and neuronal hyperexcitability following TMEV injection via activation of BK channels. This hypothesis will be tested using a combination of EEG and electrophysiology recordings, mass spectrometry and 16S RNA sequencing. To determine whether these findings are broadly applicable to other types of epilepsy we will examine three models of epilepsy, TMEV, kainic acid and a genetic epilepsy model. This work takes a critical step causally linking specific microbial shifts to neuronal excitability, seizures and epilepsy and will identify microbial metabolites that can be targeted for therapeutic intervention.

项目摘要 癫痫病是一种常见的神经系统疾病，全球患病率超过6500万。有一般 达成共识，癫痫是由过度兴奋的神经元网络和大多数治疗策略引起的 专注于通过靶向神经元突触蛋白来减少兴奋。即使有可用的抗癫痫药 药物，仍然无法治愈，30％的患者对治疗有抵抗力。从历史上看，癫痫已被观察到 正如脑过程中的缺陷所驱动的那样；但是，这种以脑为中心的观点忽略了 神经系统的功能受身体代谢状态的影响。当前的研究认识到 微生物通过修饰肠道中的代谢因子“肠脑轴”来影响大脑。大多数 迄今为止，相关的证据表明，肠道微生物群的变化会影响癫痫发作的结果。 但是，关于特定机制的知识存在差距，肠道微生物有助于癫痫发作 可能提供新颖的方法来治疗情节的发展。病毒感染引起的发作最多 全球癫痫的常见原因，由于高死亡率高，通常很难在啮齿动物中建模。 但是，Theiler的鼠脑脊髓炎病毒（TMEV）是一种低病毒诱导的临时模型 叶癫痫。颅内TMEV注射会导致海马神经元功能障碍，宽度皮质 大约50％的成年C57BL/6小鼠在感染后6天后，星形胶质细胞增多症和癫痫发作峰值。中心 神经系统注射作为癫痫发作表型发育的潜在调节剂是积极的 TMEV感染，分子机制尚不清楚。从该模型获得的数据令人惊讶地表明 在TMEV感染的小鼠中，大多数分类法含有属于属的TMEV的小鼠 与细菌代谢物S- Equol的产生有关。这些细菌将饮食大约泽林转化为 S-Equol，已证明可以激活大型电导Ca2+ - 和电压激活的K+（BK）通道。 BK通道的激活在控制神经元令人兴奋中起重要作用，因此代表 治疗癫痫的新目标。该提案将确定微生物衍生的耗尽 代谢产物，S-Equol，增加了TMEV注射小鼠的癫痫发作。它进一步检验了S-的假设 产生e夫微生物种类会议的神经保护症，针对癫痫发作易感性和神经元 通过激活BK通道，TMEV注射后过度兴奋。该假设将使用 脑电图和电生理记录，质谱和16S RNA测序的组合。到 确定这些发现是否广泛适用于其他类型的癫痫，我们将检查三个模型 癫痫，TMEV，海藻酸和遗传癫痫模型。这项工作偶尔会链接到关键的一步 特定的微生物转移到神经元令人兴奋，癫痫发作和癫痫病，将确定微生物代谢物 可以针对治疗干预。