The gut brain axis: microbial impact on neural function

肠脑轴：微生物对神经功能的影响

• 批准号: 10115833
• 负责人: Mark Alkema
• 金额: $ 36.64万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115833
• 关键词: Acetylcholine; Address; Affect; Alzheimer' s Disease; Anxiety; Bacillus; Bacteria; Behavior; Brain; Caenorhabditis elegans; Calcium Channel; Cells; Choline; Clonic Seizure; Comamonas; Complex; Diet; Disease; Endocrine; Escherichia coli; Etiology; Familial Hemiplegic Migraine; Gastrointestinal Diseases; Genes; Genetic; Goals; Health; Human; Impairment; Intestines; Laboratories; Link; Mental Depression; Mental Health; Metabolic; Metabolic Pathway; Metabolism; Methionine; Migraine; Modeling; Molecular; Mutation; Nematoda; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Nutrient; Orthologous Gene; Pathway interactions; Phenotype; Physiology; Probiotics; Schizophrenia; Seizures; Surveys; Synapses; Synaptic Transmission; Testing; Tissues; Vitamin B 12; Vitamin B 12 Deficiency; autism spectrum disorder; behavior influence; brain health; cholinergic; experimental study; gain of function mutation; genetic analysis; gut bacteria; gut microbiome; gut microbiota; gut-brain axis; improved; insight; microbial; microbiome; microbiome research; microbiota; mutant; nervous system disorder; neural circuit; neurochemistry; neurophysiology; novel; novel strategies; presynaptic; relating to nervous system; success; symptomatic improvement; tool; transmission process; voltage

The discovery that gut microbiota can influence behavior is emerging as an exciting new concept in neurophysiology and disease. In humans, links have been drawn between the gut microbiome and neurological disorders such as depression, migraine, anxiety, autism, schizophrenia, and neurodegenerative disorders. However, the question of causality in microbiome studies remains unanswered and the molecular basis of the complex interaction of diet, microbiota, and the brain is still poorly understood. The goal of this proposal is to identify microbiome factors that contribute to neural function and to uncover an important mechanistic link between diet, gut microbiota, and neurological disorders. The nematode C. elegans is ideally suited for this approach because both its neural circuits and bacterial diets are simple, well-defined and genetically tractable. We have generated and characterized a C. elegans model for a channelopathy that provides a sensitized genetic background to study gut-brain interactions. Specifically, we have isolated a novel gain-of-function (gf) mutation in the neuronal voltage-gated calcium channel gene unc-2/CaV2α. Similar mutations in human ortholog, CACNA1A, cause Familial Hemiplegic Migraine-type I (FHM1) in humans. C. elegans unc-2/CaV2α(FHM1) mutants have increased synaptic transmission and display clonic seizures. We made the striking observation that a diet of bacteria that make vitamin B12 greatly reduces the seizure behavior of unc-2/CaV2α(FHM1) mutants. Vitamin B12 is an essential nutrient for brain health. Vitamin B12 deficiency has been associated with many neurological disorders, including depression, schizophrenia, Alzheimer's and migraine. However, how vitamin B12 impacts neural function is largely unclear. We will determine how vitamin B12 changes metabolic processes in the gut, and how such changes impair neural function in the brain. In addition, we will take advantage of our unique C. elegans migraine model to identify beneficial microbiota and other factors that improve neural health. These experiments will provide valuable understanding into elusive mechanisms of gut-brain communication and can ultimately inform the use of probiotics to improve symptoms of neurological disorders.

肠道微生物群可以影响行为的发现正在成为一个令人兴奋的新概念 在人类中，肠道微生物组与神经生理学和疾病之间存在联系。 神经系统疾病，如抑郁症、偏头痛、焦虑症、自闭症、精神分裂症和神经退行性疾病 然而，微生物组研究中的因果关系问题仍然没有得到解答，而且分子生物学也没有得到解答。 饮食、微生物群和大脑复杂相互作用的基础仍然知之甚少。 提议是确定有助于神经功能的微生物组因素并揭示一个重要的 饮食、肠道微生物群和神经系统疾病之间的机制联系线虫秀丽隐杆线虫是理想的。 适合这种方法，因为它的神经回路和细菌饮食都很简单、定义明确且 我们已经生成并表征了通道病的秀丽隐杆线虫模型。 为研究肠脑相互作用提供了敏感的遗传背景。具体来说，我们分离出了一种新的。 神经元电压门控钙通道基因 unc-2/CaV2α 的功能获得性 (gf) 突变。 人类直系同源物 CACNA1A 的突变会导致人类家族性偏瘫型偏头痛 (FHM1) C. 线虫 unc-2/CaV2α(FHM1) 突变体增加了突触传递并表现出阵挛性癫痫发作。 做出了惊人的观察：含有产生维生素 B12 的细菌饮食可大大减少癫痫发作 unc-2/CaV2α(FHM1) 突变体的行为 维生素 B12 是大脑健康的必需营养素。 缺乏症与许多神经系统疾病有关，包括抑郁症、精神分裂症、 然而，维生素 B12 如何影响神经功能尚不清楚。 确定维生素 B12 如何改变肠道代谢过程，以及这些变化如何损害神经 此外，我们将利用我们独特的秀丽隐杆线虫偏头痛模型来识别。 这些实验将提供有价值的有益微生物群和其他改善神经健康的因素。 了解肠脑通讯的难以捉摸的机制，并最终可以为使用提供信息 益生菌可改善神经系统疾病的症状。