Exposure to cyanobacteria and BMAA in ALS through the gut environment microbiome

ALS 患者通过肠道环境微生物组接触蓝藻和 BMAA

• 批准号: 8934118
• 负责人: Roel A Ophoff
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934118
• 关键词: Affect; Alanine; Amyotrophic Lateral Sclerosis; Bacteria; Biological Markers; Blood; Brain; Clinical; Consumption; Cyanobacterium; Cycad; Data; Disease; Disease Outbreaks; Disease Progression; Disease susceptibility; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; Family history of; Guam; Health; Human; In Vitro; Incidence; Individual; Island; Life Style; Motor Neurons; Neurotoxins; Nuts; Pacific Ocean; Paralysed; Participant; Patients; Play; Population; Predisposition; Production; Reporting; Role; Saliva; Sampling; Shotgun Sequencing; Spinal Cord; Symptoms; Therapeutic; Tissues; Transplantation; United States; brain tissue; excitotoxicity; expectation; gene environment interaction; in vivo; insight; metagenome; microbiome; motor neuron degeneration; nervous system disorder; neuron loss; novel

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is characterized by motor neuron-specific degeneration leading to a progressive and lethal paralysis. Up to 10% of all ALS cases are characterized by a family history of the disease with the remaining 90% of the patients suffering from sporadic ALS. For both patient groups, familial and sporadic ALS, a gene-environment interaction is hypothesized, but barely any environmental risk factors have been identified. It has been postulated in a specific population on the island Guam with high incidence of ALS that the disease is caused by neurotoxin accumulation through the consumption of the cycad nuts and biomagnification of such. This neurotoxin is �-N-Methylamino-L-alanine (BMAA) and is associated to ALS symptoms. Furthermore increased levels of BMAA are reported in post mortem brain tissue of ALS patients. However, these studies have been small and a more systematic approach is needed to decipher the role of BMAA in ALS susceptibility and disease progression. BMAA is produced by cyanobacteria and this bacteria has been associated to localized 'outbreaks' of ALS in the past, including in the USA. Cyanobacteria, also known as blue-green algae, have recently been found to also reside in the human gut microbiome. In this explorative study, we hypothesize that exposure to cyanobacteria in the gut of ALS patients in the United States is an environmental risk factor contributing to ALS by producing the neurotoxin BMAA. Alternatively, other species in the human gut microbiome may play a role in the disease. We will examine BMAA levels in post mortem spinal cord tissues of ALS patients and unaffected control subjects. Furthermore, we will collect biosamples of 30 ALS patients and 30 unrelated control subjects to assess BMAA levels in blood, saliva and fecal samples. We will perform whole metagenome shotgun sequencing of the gut microbiome to study the presence of (different strains of) cyanobacteria in patients and controls. The gut microbiome profiles will also be used in an unbiased analysis to explore differences that may be related to disease. This study will be one of the first to systematically examine the environmental exposure of cyanobacteria and its neurotoxins in human ALS.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）的特征是运动神经元特异性变性，导致进行性和致死性瘫痪。高达10%的所有ALS病例的特征在于该疾病的家族史，其余90%的患者患有散发性ALS。对于两个患者组，家族性和散发性ALS，假设基因-环境相互作用，但几乎没有任何环境风险因素已被确定。据推测，在ALS发病率高的关岛特定人群中，这种疾病是由食用苏铁坚果和生物放大引起的神经毒素积累引起的。这种神经毒素是β-N-甲基氨基-L-丙氨酸（BMAA），与ALS症状有关。此外，在ALS患者的死后脑组织中报告了BMAA水平的增加。然而，这些研究规模较小，需要更系统的方法来解释BMAA在ALS易感性和疾病进展中的作用。BMAA是由蓝细菌产生的，这种细菌在过去与ALS的局部“爆发”有关，包括在美国。蓝细菌，也被称为蓝绿藻，最近被发现也存在于人类肠道微生物组中。在这项探索性研究中，我们假设美国ALS患者肠道中的蓝细菌暴露是通过产生神经毒素BMAA导致ALS的环境风险因素。或者，人类肠道微生物组中的其他物种可能在疾病中发挥作用。我们将检查ALS患者和未受影响的对照受试者死后脊髓组织中的BMAA水平。此外，我们将收集30名ALS患者和30名无关对照受试者的生物样本，以评估血液、唾液和粪便样本中的BMAA水平。我们将对肠道微生物组进行全宏基因组鸟枪测序，以研究患者和对照组中（不同菌株）蓝细菌的存在。肠道微生物组特征也将用于无偏分析，以探索可能与疾病相关的差异。这项研究将是第一个系统地研究环境暴露的蓝藻及其神经毒素在人类ALS。