The gut brain axis: microbial impact on neural function

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， 神经生理学和疾病。在人类中，肠道微生物组与 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 紊乱然而，微生物组研究中的因果关系问题仍然没有答案， 饮食、微生物群和大脑之间复杂相互作用的基础仍然知之甚少。这个目标 一项新的建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械联系。线虫C. elegans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， 遗传上容易控制我们已经生成并表征了C。elegans模型的通道病， 为研究肠-脑相互作用提供了敏感的遗传背景。具体来说，我们分离出了一部小说 神经元电压门控钙通道基因unc-2/CaV 2 α的功能获得性（gf）突变。类似 人类直系同源物CACNA 1A的突变导致人类家族性偏瘫性偏头痛I型（FHM 1）。C. elegans unc-2/CaV 2 α（FHM 1）突变体具有增加的突触传递并显示阵挛性癫痫发作。我们 他做了一个惊人的观察，饮食中含有能产生维生素B12的细菌， unc 2/CaV 2 α（FHM 1）突变体的行为。维生素B12是大脑健康的必需营养素。维生素B12 缺乏与许多神经系统疾病有关，包括抑郁症，精神分裂症， 老年痴呆症和偏头痛然而，维生素B12如何影响神经功能在很大程度上尚不清楚。我们将 确定维生素B12如何改变肠道的代谢过程，以及这些变化如何损害神经 在大脑中的功能。此外，我们将利用我们独特的C。elegans偏头痛模型来识别 有益的微生物群和其他改善神经健康的因素。这些实验将提供有价值的 了解肠道-大脑沟通的难以捉摸的机制，并最终可以告知使用 益生菌改善神经系统疾病的症状。

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.