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Updated: Sep 30, 2025
Primary Cultures of Rat Astrocytes and Microglia and Their Use in the Study of Amyotrophic Lateral Sclerosis
Published on: June 23, 2022
The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis
Laura M Cox1, Narghes Calcagno1, Christian Gauthier1
1Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA.
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 SOD1G93A 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. Video abstract.
Insights
Gut microbiota protect against ALS progression in the SOD1 mouse model by preventing microglia from adopting a neurodegenerative phenotype. Antibiotic treatment worsens disease, highlighting disease-specific microbiota-microglia interactions.
Area of Science:
- Neuroimmunology
- Microbiome Research
- Amyotrophic Lateral Sclerosis (ALS) Pathogenesis
Background:
- Gut microbiota influence central nervous system (CNS) immune cells like microglia.
- Antibiotics generally benefit neurologic disease models but worsen SOD1-ALS progression.
- Microglia transition to a neurodegenerative (MGnD) phenotype in ALS, contributing to pathogenesis.
Purpose of the Study:
- Investigate the impact of microbiota on microglia phenotype in the SOD1-ALS model.
- Determine if microbiota modulation affects ALS disease progression.
Main Methods:
- Administered low-dose antibiotics to SOD1-G93A mice.
- Performed co-housing experiments with SOD1-G93A and wildtype mice.
- Analyzed microbiome composition and spinal cord microglia gene expression.
Main Results:
- Antibiotic treatment worsened motor function and decreased survival in SOD1 mice.
- Antibiotics reduced beneficial bacteria (Akkermansia, butyrate-producers) and shifted microglia to a neurodegenerative phenotype.
- Microglial changes preceded motor deficits, suggesting a causal role.
Conclusions:
- Microbiota play a protective role in the SOD1-ALS model by inhibiting MGnD microglia.
- This contrasts with other neurologic disease models, emphasizing disease-specific microbiota-microglia interactions.
- Findings offer new insights into microbiota-targeted therapeutic strategies for ALS.
