Potential roles of gut microbiome commensals & metabolites in modulation of murine ALS

Amyotrophic Lateral Sclerosis (ALS) is a genetically-driven neurodegenerative disorder, whose manifestations may be influenced by unknown environmental factors. We demonstrate that ALS-prone SOD1-Tg mice, featuring a vivarium-dependent pre-symptomatic dysbiosis and altered metabolite configuration, develop an exacerbated disease under germ-free or wide-spectrum antibiotic treatment conditions. We correlate 11 distinct commensals at our vivarium with mouse-ALS course, and exemplify by their individual supplementation into antibiotic-treated SOD1-Tg mice that Akkermansia muciniphila (AM) negatively modulates & Ruminococcus torques & Parabacteroides distasonis positively modulate mouse-ALS severity. AM-administered SOD1-Tg mice feature a CNS accumulation of AM-associated nicotinamide, while systemically-administered nicotinamide ameliorates motor symptoms and impacts the CNS transcriptome of SOD-1-Tg mice. In humans, we identify distinct microbiomes and metabolite configurations, including impaired systemic & cerebrospinal-fluid nicotinamide levels, in ALS patients compared to household-controls. Together, we suggest that environmentally-driven microbiome-brain interactions may modulate murine ALS, and call for similar investigations in other models and in human ALS.