An Investigation of the Gut Microbiota, Microglia, and Peripheral Immunity in the Sod1 Animal Model of ALS

Abstract

Amyotrophic lateral sclerosis is a devastating and debilitating disease as patients maintain cognitive abilities while losing motor function before dying, often from respiratory muscle paralysis within three to five years of symptomatic onset. With 10% of cases acquired from genetic mutations (familial), an environmental cause is implicated in 90% of cases of ALS. The gut microbiome is an environmental factor that has been associated with processes in neurologic diseases and is a prime target to investigate sporadic causes of ALS because of how it may affect protein aggregates and inflammatory responses contributing to upper and lower motor neuron death. The gut microbiome can communicate to the brain by several pathways including immune activation and neuroactive metabolite secretion. Microglia, the innate immune cell of the central nervous system, has been implicated in ALS and other neurodegenerative diseases and can be affected by the microbiome. This research demonstrates that the gut microbiome of the Sod1 ALS animal model, upregulates microglia genes associated with RNA processing, lysosomal function, and protein degradation in naïve mice, which is linked with decreased Akkermansia. Furthermore, treatment of Sod1 mice with Akkermansia muciniphila or butyrate producers, Agathobacter rectale and Roseburia intestinalis, delayed disease progression and reversed Sod1-related effects in expression of genes involved with the unfolded protein response and microglial activation. These findings provide evidence that specific microbes can ameliorate and delay disease progression in the Sod1 murine model of ALS and this demonstration of protection is linked with modulating genes implicated in ALS.