Potential roles of gut microbiome and metabolites in modulating ALS in mice

Eran Blacher, Stavros Bashiardes, Hagit Shapiro, Daphna Rothschild, Uria Mor, Mally Dori-Bachash, Christian Kleimeyer, Claudia Moresi, Yotam Harnik, Maya Zur, Michal Zabari, Rotem Ben-Zeev Brik, Denise Kviatcovsky, Niv Zmora, Yotam Cohen, Noam Bar, Izhak Levi, Nira Amar, Tevie Mehlman, Alexander Brandis, Inbal Biton, Yael Kuperman, Michael Tsoory, Leenor Alfahel, Alon Harmelin, Michal Schwartz, Adrian Israelson, Liisa Arike, Malin E. V. Johansson, Gunnar C. Hansson, Marc Gotkine (), Eran Segal () and Eran Elinav ()
Additional contact information
Eran Blacher: Weizmann Institute of Science
Stavros Bashiardes: Weizmann Institute of Science
Hagit Shapiro: Weizmann Institute of Science
Daphna Rothschild: Weizmann Institute of Science
Uria Mor: Weizmann Institute of Science
Mally Dori-Bachash: Weizmann Institute of Science
Christian Kleimeyer: Weizmann Institute of Science
Claudia Moresi: Weizmann Institute of Science
Yotam Harnik: Weizmann Institute of Science
Maya Zur: Weizmann Institute of Science
Michal Zabari: Hadassah-Hebrew University Medical Center
Rotem Ben-Zeev Brik: Weizmann Institute of Science
Denise Kviatcovsky: Weizmann Institute of Science
Niv Zmora: Weizmann Institute of Science
Yotam Cohen: Weizmann Institute of Science
Noam Bar: Weizmann Institute of Science
Izhak Levi: Weizmann Institute of Science
Nira Amar: Weizmann Institute of Science
Tevie Mehlman: Weizmann Institute of Science
Alexander Brandis: Weizmann Institute of Science
Inbal Biton: Weizmann Institute of Science
Yael Kuperman: Weizmann Institute of Science
Michael Tsoory: Weizmann Institute of Science
Leenor Alfahel: Ben-Gurion University of the Negev
Alon Harmelin: Weizmann Institute of Science
Michal Schwartz: Weizmann Institute of Science
Adrian Israelson: Ben-Gurion University of the Negev
Liisa Arike: University of Gothenburg
Malin E. V. Johansson: University of Gothenburg
Gunnar C. Hansson: University of Gothenburg
Marc Gotkine: Hadassah-Hebrew University Medical Center
Eran Segal: Weizmann Institute of Science
Eran Elinav: Weizmann Institute of Science

Nature, 2019, vol. 572, issue 7770, 474-480

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1443-5

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