1. Potential roles of gut microbiome and metabolites in modulating ALS in mice
- Author
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Yotam Cohen, Michal Zabari, Gunnar C. Hansson, Noam Bar, Adrian Israelson, Hagit Shapiro, Izhak Levi, Stavros Bashiardes, Alon Harmelin, Alexander Brandis, Niv Zmora, Yael Kuperman, Rotem Ben-Zeev Brik, Daphna Rothschild, Mally Dori-Bachash, Marc Gotkine, Nira Amar, Michael Tsoory, Yotam Harnik, Eran Blacher, Claudia Moresi, Michal Schwartz, Eran Elinav, Uria Mor, Denise Kviatcovsky, Tevie Mehlman, Malin E. V. Johansson, Inbal E. Biton, Liisa Arike, Eran Segal, Leenor Alfahel, Christian Kleimeyer, and Maya Zur
- Subjects
0301 basic medicine ,Male ,Niacinamide ,Transgene ,SOD1 ,Longevity ,Mice, Transgenic ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Superoxide Dismutase-1 ,Verrucomicrobia ,medicine ,Animals ,Germ-Free Life ,Humans ,Microbiome ,Amyotrophic lateral sclerosis ,Symbiosis ,Multidisciplinary ,biology ,Nicotinamide ,Amyotrophic Lateral Sclerosis ,Akkermansia ,biology.organism_classification ,medicine.disease ,3. Good health ,Anti-Bacterial Agents ,Gastrointestinal Microbiome ,Survival Rate ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immunology ,Dysbiosis ,Female ,030217 neurology & neurosurgery ,Akkermansia muciniphila - 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.
- Published
- 2019