来自以色列魏茨曼科学研究所、德国癌症研究中心等机构的国际合作团队，发布一项最新研究成果，揭示了肠道微生物组和代谢物在调节小鼠肌萎缩侧索硬化（ALS，俗称渐冻症）中的潜在作用。 相关论文于发表在2019年8月22日出版的《自然》上。

编码SOD1（超氧化物歧化酶1）蛋白的基因发生突变是一种家族性ALS的主要致病原因，在此基础上，科学家们创造了第一个ALS小鼠模型(Sod1-Tg)，用来模拟人类患者的病理特征来研究疾病机理。发现在出现运动神经元功能障碍症状之前，小鼠的肠道菌群构成就已经发生了改变。研究人员鉴定出有11种肠道细菌似乎会影响到小鼠的ALS严重程度，其中有些细菌种类的浓度升高会加剧疾病进展。有一种细菌引起了研究人员的注意，它被称为嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila，简称AM菌），这种细菌在肠道菌群中的相对数量明显下降。而如果给ALS小鼠补充这种细菌，它们的症状可以得到改善，并且还会显著提高存活率。与补充AM菌类似，小鼠补充烟酰胺后，症状同样得到了减轻。并且，补充AM菌和补充烟酰胺时，有多个相同的基因改变表达。目前这项人体研究的规模还很小，而人类肠道中的微生物非常复杂，还不足以构成治疗推荐。研究者也因此呼吁，需要开展队列研究加以验证。有些正在开展的临床研究或许应该把肠道菌群变化的分析包括进去。

据介绍，肌萎缩侧索硬化症（ALS）是一种复杂的神经退行性疾病，其临床表现可能受遗传和未知环境因素的影响。

附：英文原文

Title: Potential roles of gut microbiome and metabolites in modulating ALS in mice

Author: Eran Blacher, Stavros Bashiardes, Hagit Shapiro, Daphna Rothschild, Uria Mor, Mally Dori-Bachash, Christian Kleimeyer, Claudia Moresi, Yotam Harnik, Maya Zur, Michal Zabari, Rotem Ben-Zeev Brik, Denise Kviatcovsky, Niv Zmora, Yotam Cohen, Noam Bar, Izhak Levi, Nira Amar, Tevie Mehlman, Alexander Brandis, Inbal Biton, Yael Kuperman, Michael Tsoory, Leenor Alfahel, Alon Harmelin, Michal Schwartz, Adrian Israelson, Liisa Arike, Malin E. V. Johansson, Gunnar C. Hansson, Marc Gotkine, Eran Segal, Eran Elinav

Issue&Volume: Volume 572 Issue 7770

Abstract: 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 configurationsincluding reduced levels of nicotinamide systemically and in the cerebrospinal fluidin a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiomebrain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.

DOI: 10.1038/s41586-019-1443-5

Source:https://www.nature.com/articles/s41586-019-1443-5