The gut microbiota is a determinant of sexual dimorphism in ALS-linked TDP43 mice

The mechanisms underlying the earlier onset and male predominance of amyotrophic lateral sclerosis (ALS), the most common form of human motoneuron disease, are poorly understood. Here we show that the gut microbiota protects against TDP43 toxicity and contributes to the sexual dimorphism in mice expressing a mutant form of TDP43 (A315T) linked to ALS. TDP43 mice raised under germ-free conditions, or treated with antibiotics to deplete the gut microbiota, develop motoneuron disease earlier and show no sex differences in onset and lifespan. Behavioral and histopathological analyses confirm the exacerbation in neurodegeneration caused by the absence of gut microbiota. Castration did not alter disease course of male TDP43 mice, suggesting that male sex hormones do not interact with the gut microbiota to confer disease phenotype. Future identification of gut bacteria species and their mechanisms of action offers a unique opportunity to understand sexual dimorphism in ALS, with the ultimate goal to develop non-invasive and sex-specific treatments for ALS.