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 癫痫是一种常见的神经系统疾病，全球患病率超过6500万。人们普遍 一致认为癫痫是由过度兴奋的神经网络引起的，大多数治疗策略 专注于通过靶向神经元突触蛋白来降低兴奋。即使有抗癫痫药 然而，目前仍无法治愈，30%的患者对治疗产生抗药性。从历史上看， 仅仅是由大脑过程中的缺陷驱动的;然而，这种以大脑为中心的观点忽略了一个事实，即 神经系统的功能受身体代谢状态的影响。目前的研究认为， 微生物通过改变肠道中的代谢因子（“肠-脑轴”）来影响大脑。大部分 迄今为止的证据是相关的，表明肠道微生物群的变化可以影响癫痫发作的结果。 然而，关于肠道微生物导致癫痫发作的具体机制， 这可能为治疗癫痫提供新的方法。病毒感染引起的癫痫是最 癫痫是世界范围内常见的癫痫原因，由于死亡率高，通常难以在啮齿动物中建模。 然而，Theiler小鼠脑脊髓炎病毒（TMEV）是一种低死亡率的病毒诱导的暂时性脑脊髓炎模型， 脑叶癫痫颅内TMEV注射导致海马神经元功能障碍，广泛的皮质 星形胶质细胞增生，以及在约50%的成年C57 BL/6小鼠中在感染后6天达到高峰的神经纤维生成。而中心 神经系统炎症被认为是癫痫发作表型发展的潜在调节剂， TMEV感染的分子机制尚不清楚。从该模型获得的数据令人惊讶地表明， 在TMEV感染的小鼠癫痫发作表型中，大多数分类学表现不足， 与细菌代谢物S-雌马酚的产生有关。这些细菌将膳食大豆苷元转化为 S-雌马酚，已显示其激活大电导Ca 2+和电压激活的K+（BK）通道。 BK通道的激活在控制神经元兴奋性中起重要作用，因此代表了神经元兴奋性的一个重要方面。 治疗癫痫的新靶点。该提案将确定是否消耗微生物来源的 代谢物S-雌马酚增加TMEV注射小鼠中癫痫发作的发生。它进一步检验了S- 产生雌马酚的微生物物种赋予神经保护以对抗癫痫易感性和神经元 TMEV注射后通过激活BK通道的过度兴奋。这个假设将使用一个 EEG和电生理记录、质谱和16 S RNA测序的组合。到 为了确定这些发现是否广泛适用于其他类型的癫痫，我们将研究三种模型 癫痫，TMEV，海人酸和遗传性癫痫模型。这项工作迈出了关键的一步， 特异性微生物转移到神经元兴奋性，癫痫发作和癫痫，并将鉴定微生物代谢物， 可以作为治疗干预的目标。