Geographical Distribution and Diversity of Gut Microbial NADH: Ubiquinone Oxidoreductase Sequence Associated with Alzheimer's Disease
Geographical Distribution and Diversity of Gut Microbial NADH: Ubiquinone Oxidoreductase Sequence Associated with Alzheimer's Disease
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DOI：
10.3233/jad-170764
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发表时间：
2018-01-01
影响因子：
4
通讯作者：
Aksenoff, Igor
中科院分区：
文献类型：
--
作者：
Paley, Elena L.;Merkulova-Rainon, Tatiana;Aksenoff, Igor
早些时候，我们报道了色氨酸代谢物诱导神经毒性和神经变性，将代谢改变与阿尔茨海默病（AD）联系起来。色氨酸是莽草酸途径（SP）的产物。人类细胞缺乏 SP，而人类肠道细菌专门利用 SP 来产生芳香族氨基酸 (AAA)。这项研究是对 AD 粪便样本中人类肠道微生物群进行基因靶向分析的首次尝试。为此工作新设计的寡核苷酸引物针对与人类活动相关的环境细菌中的 SP-AAA。使用聚合酶链反应 (PCR)，我们在大多数 AD 患者（20 名患者中的 18 名）中发现了独特的肠道细菌序列，尽管在对照组中很少见（13 名中的 1 名）。 AD 相关 PCR 产物 (ADPP) 的克隆和测序能够鉴定梭菌属中 Na(+) 转运 NADH：泛醌还原酶 (NQR)。无关的 AD 患者的 ADPP 具有几乎相同的序列。 NQR 底物泛醌是 SP 产品和人类神经保护剂。已确定许多神经肌肉和神经退行性疾病中存在泛醌缺乏。抗菌治疗促使 ADPP 阳性对照者的 ADPP 减少，该对照者后来被诊断患有 AD 痴呆。我们探索了肠道微生物组数据库，发现 ADPP 与来自不同地理位置的一些健康个体之间存在序列相似性（高达 97%）。重要的是，我们对 AD 人群和对照人群肠道微生物基因型显着差异的主要发现是一项突破。
Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer's disease (AD). Tryptophan is a product of Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough.