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Nature. 2019 Aug;572(7770):474-480. doi: 10.1038/s41586-019-1443-5. Epub 2019 Jul 22.

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

Author information

1
Immunology Department, Weizmann Institute of Science, Rehovot, Israel.
2
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
3
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.
4
Neuromuscular/EMG service and ALS/Motor Neuron Disease Clinic, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
5
Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel.
6
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
7
Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel.
8
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
9
Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
10
Neuromuscular/EMG service and ALS/Motor Neuron Disease Clinic, Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. marc@gotkine.com.
11
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. eran.segal@weizmann.ac.il.
12
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. eran.segal@weizmann.ac.il.
13
Immunology Department, Weizmann Institute of Science, Rehovot, Israel. eran.elinav@weizmann.ac.il.
14
Division of Cancer-Microbiome Research, DKFZ, Heidelberg, Germany. eran.elinav@weizmann.ac.il.

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.

PMID:
31330533
DOI:
10.1038/s41586-019-1443-5

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