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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要癫痫是一种常见的神经系统疾病，全球患病率超过 6500 万。一致认为癫痫是由神经网络过度兴奋引起的，并且大多数治疗策略都已即使使用现有的抗癫痫药，也专注于通过靶向神经元突触蛋白来减少兴奋。癫痫病目前还没有治愈药物，30%的患者对治疗有抵抗力。然而，这种以大脑为中心的观点仅仅由大脑过程的缺陷驱动；目前的研究认识到，神经系统的功能受到身体代谢状态的影响。微生物通过改变肠道（“肠脑轴”）中的代谢因素来影响大脑。迄今为止的相关证据表明，肠道微生物群的变化会影响癫痫发作的结果。然而，对于肠道微生物导致癫痫发作的具体机制的了解还存在差距。可能为治疗病毒感染引起的癫痫提供新方法的开发是最重要的。全世界癫痫的常见原因，由于死亡率高，通常很难在啮齿类动物中建立模型。然而，泰勒氏鼠脑脊髓炎病毒 (TMEV) 是一种低死亡率的病毒诱导模型颅内 TMEV 注射导致海马神经元功能障碍，广泛的皮质。大约 50% 的成年 C57BL/6 小鼠中，星形胶质细胞增生和癫痫发作在感染后 6 天达到峰值。神经系统炎症已被认为是癫痫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。大多数分类学在具有癫痫表型的 TMEV 感染小鼠中代表性不足，其中包含属与细菌代谢物 S-牛尿酚的产生有关。这些细菌将膳食中的黄豆苷元转化为大豆黄酮。 S-牛尿酚，已被证明可以激活大电导 Ca2+- 和电压激活的 K+ (BK) 通道。 BK 通道的激活在控制神经兴奋性方面发挥着重要作用，因此代表了该提案将确定是否消除微生物来源的新靶标。代谢物 S-牛尿酚会增加注射 TMEV 的小鼠癫痫发作的发生率，这进一步验证了 S- 的假设。产生雌马酚的微生物物种赋予神经保护作用，防止癫痫易感性和神经元通过激活 BK 通道注射 TMEV 后的过度兴奋性将使用结合脑电图和电生理学记录、质谱分析和 16S RNA 测序。为了确定这些发现是否广泛适用于其他类型的癫痫，我们将检查三种模型这项工作在因果关系上迈出了关键的一步。特定微生物对神经元兴奋性、癫痫发作和癫痫的转变，并将识别微生物代谢物可以作为治疗干预的目标。