Potential roles of gut microbiome and metabolites in modulating ALS in mice
Potential roles of gut microbiome and metabolites in modulating ALS in mice
复制标题
DOI：
10.1038/s41586-019-1443-5
复制
发表时间：
2019-08-22
期刊：
影响因子：
64.8
通讯作者：
Elinav, Eran
中科院分区：
文献类型：
--
作者：
Blacher, Eran;Bashiardes, Stavros;Elinav, Eran
肌萎缩侧索硬化症(ALS)是一种复杂的神经退行性疾病，其临床表现受遗传和未知环境因素的影响。在这里，我们显示了倾向于ALS的SOD1转基因(SOD1-TG)小鼠有症状前的、依赖于的生物失调和代谢产物结构改变，再加上在无菌条件下或在使用广谱抗生素治疗后病情加重。我们将11种不同的共生细菌与小鼠的肌萎缩侧索硬化症的严重程度相关联，并通过将它们单独补充到经抗生素治疗的SOD1-TG小鼠中，我们证明了粘液阿克曼杆菌(AM)可以改善ALS的症状，而扭矩瘤胃球菌和稻瘟副杆菌则会加重ALS的症状。此外，服用AM的SOD1-TG小鼠被发现在中枢神经系统中积累了AM相关的烟酰胺，全身补充烟酰胺改善了SOD1-TG小鼠的运动症状和脊髓中的基因表达模式。在人类身上，我们在一项比较ALS患者和家庭对照组的小型初步研究中确定了不同的微生物组和代谢物配置--包括系统性和脑脊液中烟酰胺水平的降低。我们认为，环境驱动的微生物-大脑相互作用可能调节小鼠的ALS，我们呼吁对人类形式的ALS进行类似的研究。
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.