TY - JOUR
T1 - Potential roles of gut microbiome and metabolites in modulating ALS in mice
AU - Blacher, Eran
AU - Bashiardes, Stavros
AU - Shapiro, Hagit
AU - Rothschild, Daphna
AU - Mor, Uria
AU - Dori-Bachash, Mally
AU - Kleimeyer, Christian
AU - Moresi, Claudia
AU - Harnik, Yotam
AU - Zur, Maya
AU - Zabari, Michal
AU - Brik, Rotem Ben Zeev
AU - Kviatcovsky, Denise
AU - Zmora, Niv
AU - Cohen, Yotam
AU - Bar, Noam
AU - Levi, Izhak
AU - Amar, Nira
AU - Mehlman, Tevie
AU - Brandis, Alexander
AU - Biton, Inbal
AU - Kuperman, Yael
AU - Tsoory, Michael
AU - Alfahel, Leenor
AU - Harmelin, Alon
AU - Schwartz, Michal
AU - Israelson, Adrian
AU - Arike, Liisa
AU - Johansson, Malin E.V.
AU - Hansson, Gunnar C.
AU - Gotkine, Marc
AU - Segal, Eran
AU - Elinav, Eran
N1 - Funding Information:
Acknowledgements We thank the members of the Elinav and Segal laboratories, and members of the DKFZ cancer-microbiome division for discussions, and apologize to authors whose work was not included owing to space constraints. We thank R. Straussman, D. Nejman and E. Hornstein for suggestions and help with experimental methodologies; C. Bar-Nathan for assistance with animal work; S. Belkin for providing reagents and A. Godneva for computational assistance. We thank J. Suez and N. Zmora for extensive editing during production. E.B. is supported by the Weizmann Institute Dean of Faculty fellowship. D.R. received a Levi Eshkol PhD Scholarship for Personalized Medicine by the Israeli Ministry of Science. N.Z. is supported by the Gilead Sciences International Research Scholars Program in Liver Disease. C.K. is supported by an MD fellowship of the Boehringer Ingelheim Fonds. Y.K. is the incumbent of the Sarah and Rolando Uziel Research Associate Chair. H.S. is the Incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. E.S. is supported by the Crown Human Genome Center; the Else Kroener Fresenius Foundation; Donald L. Schwarz, Sherman Oaks, CA; Jack N. Halpern, NeNY; Leesa Steinberg, Canada; and grants funded by the European Research Council and the Israel Science Foundation. E.E. is supported by Y. and R. Ungar; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the Else Kroener Fresenius Foundation; the estate of J. Gitlitz; the estate of L. Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; the Adelis Foundation; J. L. and V. Schwartz; A. and G. Markovitz; A. and C. Adelson; the French National Center for Scientific Research (CNRS); D. L. Schwarz; The V. R. Schwartz Research Fellow Chair; L. Steinberg; J. N. Halpern; A. Edelheit; and by grants funded by the European Research Council, the Israel Science Foundation and the Helmholtz Foundation. E.E. is the Sir Marc and Lady Tania Feldmann Professorial Chair in Immunology, Weizmann Institute of Science, Israel; is the Director of the Microbiome Research Division, DKFZ, Heidelberg, Germany; is a senior fellow of the Canadian Institute of Advanced Research (CIFAR) and is an international scholar of The Bill and Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/8/22
Y1 - 2019/8/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070805768&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1443-5
DO - 10.1038/s41586-019-1443-5
M3 - Article
AN - SCOPUS:85070805768
SN - 0028-0836
VL - 572
SP - 474
EP - 480
JO - Nature
JF - Nature
IS - 7770
ER -