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Nature ; 572(7770): 474-480, 2019 08.
Article in English | MEDLINE | ID: mdl-31330533

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 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.


Subject(s)
Amyotrophic Lateral Sclerosis/microbiology , Amyotrophic Lateral Sclerosis/physiopathology , Gastrointestinal Microbiome/physiology , Niacinamide/metabolism , Akkermansia , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Anti-Bacterial Agents/pharmacology , Disease Models, Animal , Dysbiosis , Female , Gastrointestinal Microbiome/drug effects , Germ-Free Life , Humans , Longevity , Male , Mice , Mice, Transgenic , Niacinamide/biosynthesis , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Survival Rate , Symbiosis/drug effects , Verrucomicrobia/metabolism , Verrucomicrobia/physiology
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