Potential roles of gut microbiome and metabolites in modulating ALS in mice
- PMID:31330533
- DOI: 10.1038/s41586-019-1443-5
Potential roles of gut microbiome and metabolites in modulating ALS in mice
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.
References
- Turner, M. R. et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 12, 310–322 (2013). - DOI
- Bensimon, G., Lacomblez, L. & Meininger, V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N. Engl. J. Med. 330, 585–591 (1994). - DOI
- The Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 16, 505–512 (2017). - DOI
- Su, F. C. et al. Association of environmental toxins with amyotrophic lateral sclerosis. JAMA Neurol. 73, 803–811 (2016). - DOI
- Kundu, P., Blacher, E., Elinav, E. & Pettersson, S. Our gut microbiome: the evolving inner self. Cell 171, 1481–1493 (2017). - DOI
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