Sex Influences Gut Microbial Composition in Mice with Familial Dysautonomia but is not the Primary Determinant of Microbial Functional Diversity

Abstract

Familial dysautonomia is a genetic neurological disease characterized by impaired nervous system functions due to a mutation of Elongator acetyltransferase Complex subunit 1. Previous studies have demonstrated that the severity of familial dysautonomia is associated with variations in the gut microbiota and metabolite profiles in both human patients and mice. However, the mouse model for familial dysautonomia has yet to be characterized in terms of demographic factors (i.e. sex and age) associated with their gut microbial dysbiosis and metabolic composition. Hence, we aim to investigate the variables associated with gut microbial dysbiosis and how they impact gut microbial dynamics and metabolic functions in mice with familial dysautonomia. First, through univariate regression analysis with Bray-Curtis distance and principle coordinate analysis, we determined that sex was the strongest indicator correlated with compositional variations. Next, our taxonomic composition analysis revealed a decrease in the abundance of Bacteroidota and increased Firmicutes in male familial dysautonomia mice compared to females. Furthermore, indicator species analysis identified signature genera of class Clostridia, that were representative in male familial dysautonomia mice. Despite no significant sex differences across metabolic pathways from a predictive functional analysis, correlation analysis identified a strong association between genera Romboutsia and creatinine degradation II pathways that were shown to be upregulated in males compared to female FD mice. Ultimately, our findings presented that microbial dysbiosis is intricately linked with sex in the familial dysautonomia mouse model. Further characterization of the mouse model allowed insight into its representation of FD and applicability to human patients.