The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis
Open accessAbstract
Background: The gut microbiota can affect neurologic disease by shaping microglia, the primary immune cell in the central nervous system (CNS). While antibiotics improve models of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and the C9orf72 model of amyotrophic lateral sclerosis (ALS), antibiotics worsen disease progression the in SOD1 G93A model of ALS. In ALS, microglia transition from a homeostatic to a neurodegenerative (MGnD) phenotype and contribute to disease pathogenesis, but whether this switch can be affected by the microbiota has not been investigated. Results: In this short report , we found that a low-dose antibiotic treatment worsened motor function and decreased survival in the SOD1 mice, which is consistent with studies using high-dose antibiotics. We also found that co-housing SOD1 mice with wildtype mice had no effect on disease progression. We investigated changes in the microbiome and found that antibiotics reduced Akkermansia and butyrate-producing bacteria, which may be beneficial in ALS, and cohousing had little effect on the microbiome. To investigate changes in CNS resident immune cells, we sorted spinal cord microglia and found that antibiotics downregulated homeostatic genes and increased neurodegenerative disease genes in SOD1 mice. Furthermore, antibiotic-induced changes in microglia preceded changes in motor function, suggesting that this may be contributing to disease progression. Conclusions: Our findings suggest that the microbiota play a protective role in the SOD1 model of ALS by restraining MGnD microglia, which is opposite to other neurologic disease models, and sheds new light on the importance of disease-specific interactions between microbiota and microglia.
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Antibiotic-induced dysbiosis worsens disease progression in SOD1G93A mice by downregulating homeostatic microglial genes and upregulating MGnD signatures in the spinal cord.
“In addition, antibiotic-induced dysbiosis markedly worsened disease progression in SOD1G93A mice by downregulating homeostatic microglial genes and upregulating MGnD signatures in the spinal cord.229”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [229]
After antibiotic treatment, homeostatic genes were downregulated and neurodegenerative genes increased in microglia, and the microglia signature change preceded changes in motor function.
“There was a downregulation of homeostatic genes and an increase in neurodegenerative genes in microglia after antibiotic treatment, and the microglia signature change preceded changes in motor function.359”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [359]
Antibiotic administration to SOD1 mice altered gut microbiota composition, weakened motor function, and caused death.
“Antibiotic administration to SOD1 mice altered gut microbiota composition, weakened motor function, and caused death in the SOD1 mice.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [359]
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- Authors
- Cox, L. M., Calcagno, N., Gauthier, C., Madore, C., Butovsky, O., & Weiner, H. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Weiner, Howard L.
- ORCID
- Venue
- Microbiome
- Published
- 2022-03-11
- Volume
- 10
- Issue
- 1
- Pages
- 47-47
- ISSN
- 2049-2618 (ISSN-L)
- PMC
- PMC8915543
- OpenAlex
- W4220793283
- Cited by
- 53
- References
- 65
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 14 · 2023: 10 · 2022: 5
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Microbiome (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS115951, R01NS088137)
- Brigham Research Institute (NextGen Award)
- National Institute on Aging (R01AG051812, R01AG054672)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- gut microbiota, amyotrophic lateral sclerosis, microglia, neurodegeneration, SOD1 G93A mice, antibiotic therapy, Akkermansia, butyrate-producing bacteria, cohousing, motor function, neuroinflammation, microbiota-gut-brain axis
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Anti-Bacterial Agents, Disease Models, Animal, Mice, Transgenic, Superoxide Dismutase, Microglia, Disease Progression, Neurodegenerative Diseases, Mice, Microbiota
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