Authors: 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
Summary: Amyotrophic Lateral Sclerosis (ALS) is a genetically-driven neurodegenerative disorder, whose clinical manifestations may be influenced by unknown environmental factors. We demonstrate that ALS-prone SOD1-Tg mice feature a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease in germ-free or wide-spectrum antibiotic treatment conditions. We correlate 11 distinct commensals at our vivarium with mouse-ALS severity, and exemplify by their individual supplementation into antibiotic-treated SOD1-Tg mice that Akkermansia muciniphila (AM) ameliorates & Ruminococcus torques & Parabacteroides distasonis exacerbate mouse-ALS symptoms. Furthermore, AM-administered SOD1-Tg mice feature a CNS accumulation of AM-associated nicotinamide, which improves, upon systemic supplementation, motor symptoms and spinal-cord gene expression patterns in SOD-1-Tg mice. In humans, we identify distinct microbiome/metabolite configurations, including impaired systemic & cerebrospinal-fluid nicotinamide levels, in a small preliminary study assessing ALS patients versus household-controls. Together, we suggest that environmentally-driven microbiome-brain interactions may modulate murine ALS, and call for similar investigations in human ALS.
Source: Nature, 2019