The gut brain axis: microbial impact on neural function

肠道微生物区系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，肠道微生物群和 神经性疾病，如抑郁、偏头痛、焦虑、自闭症、精神分裂症和神经退行性变 精神错乱。然而，微生物组研究中的因果关系问题仍然没有答案，分子 饮食、微生物区系和大脑之间复杂的相互作用的基础仍然知之甚少。这样做的目的是 建议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、肠道微生物区系和神经紊乱之间的机械联系。线虫线虫是理想的 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， 基因上很容易驯服。我们已经生成并表征了一种线虫的经络病模型 为研究肠道与大脑的相互作用提供了敏化的遗传背景。具体地说，我们分离出了一部小说 神经元电压门控钙通道基因UNC-2/CaV2α功能增强突变。类似 人类同源基因CACNA1A的突变导致人类家族性偏瘫I型(FHM1)。C。 线虫UNC-2/CaV2α(FHM1)突变体增加了突触传递并表现出克隆性癫痫。我们 令人惊讶的是，饮食中含有制造维生素B12的细菌，大大减少了癫痫的发作 UNC-2/CaV2α(FHM1)突变体的行为。维生素B12是大脑健康所必需的营养物质。维生素B12 缺乏与许多神经疾病有关，包括抑郁症、精神分裂症、 阿尔茨海默氏症和偏头痛。然而，维生素B12对神经功能的影响在很大程度上还不清楚。我们会 确定维生素B12如何改变肠道的新陈代谢过程，以及这种改变如何损害神经 大脑的功能。此外，我们将利用我们独特的线虫偏头痛模型来识别 有益的微生物区系和其他改善神经健康的因素。这些实验将提供有价值的 对难以捉摸的肠脑沟通机制的理解，并最终可以帮助使用 益生菌用于改善神经疾病的症状。

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.