Th181 - Selective Depletion of the Microbiota by Antibiotics Effects Survival in the SOD-1 Mouse Model of Amyotrophic Lateral Sclerosis

Abstract Text: While several genetic risk factors have been identified in the etiology of amyotrophic lateral sclerosis (ALS), the majority of cases present with no known underlying cause, suggesting environmental factors play a role. The gut microbiota is an important environmental factor that shapes disease onset and progression in ALS. We previously found that treating SOD-1 ALS mice with broad spectrum antibiotics worsened the disease and increased microglial inflammation, suggesting that the microbiome as a whole plays a protective role. To investigate the effect of specific microbes, we administered low dose, limited-spectrum antibiotics to female and male SOD mice, including vancomycin targeting Gram-positive bacteria and metronidazole targeting Gram-negative anaerobes. We found that vancomycin an improved survival in female mice, with a median survival benefit of 10 days (p=0.02), suggesting that vancomycin-sensitive bacteria worsen SOD disease progression.

Detailed analysis of bacterial populations revealed that vancomycin altered the gut microbiota composition compared to metronidazole and water-treated controls. These microbiota shifts were associated with improved survival and neurological function in female SOD1 mice. In contrast, metronidazole showed no significant impact on disease outcomes. Principal Coordinate Analysis (PCoA) further confirmed distinct gut microbiota profiles across treatment groups, highlighting the potential of microbiota-targeted therapies in ALS management.

These findings suggest that specific gut microbiota alterations, particularly those induced by vancomycin, may delay disease progression in SOD1 ALS, likely through mechanisms involving neuroinflammation and immune modulation. Future research will focus on identifying key microbial taxa and metabolites to develop novel therapeutic strategies for ALS.