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.