Increased pathological severity of Familial Dysautonomia enriches murine gut microbial composition

Abstract

Familial dysautonomia (FD) is the most prevalent type of Hereditary Sensory and Autonomic Neuropathies, which are rare genetic neurological disorders that affect both the peripheral and central nervous systems. Previous studies have found significant alterations in the gut microbiome and metabolome in FD patients compared to healthy individuals. However, it is unclear how gut microbial composition differs with varying levels of FD severity. Here, we aim to investigate whether there are compositional differences among murine gut models with mild, moderate, and severe FD. First, we showed a significant increase in species richness as severity increases. Moreover, beta diversity analysis indicated increasing compositional differences as severity increases. Second, a differential abundance analysis revealed significant downregulation of core commensal microbes in mice with severe FD compared to healthy controls. Additionally, Indicator Species Analysis unveiled the presence of unique pathogenic species, such as select Clostridium spp., underlining the relationship between specific bacterial species and FD pathologies. Overall, our findings suggest that increases in gut microbial richness observed in murine models with severe FD is due to the downregulation of some commensal microbes and the introduction of unique pathogenic species. These results accentuate the gut-brain and gut-metabolism axes as promising therapeutic targets for FD.