Genetic risk for dystonia reprograms host-microbiome interactions and gut-brain communication

Dystonia is a neurological movement disorder characterized by involuntary, sustained, or intermittent muscle contractions that result in twisting movements, repetitive motor patterns, or abnormal postures. While genetic mutations such as TOR1A+/∆GAG are known contributors, the environmental and peripheral factors influencing disease onset and progression remain poorly understood. Emerging evidence implicates the gut microbiome in shaping neurodevelopment and host behavioral function, yet its contribution to dystonia pathobiology is largely unexplored. Here, we longitudinally profiled the gut microbiome of a Tor1a+/∆GAG mouse model using 16S rRNA gene sequencing and uncovered early emerging, persistent disruptions in microbial diversity and community composition that coincided with progressive motor impairment. Mutant mice exhibited alterations in key commensal taxa, and molecular signatures indicative of compromised gut-barrier integrity. Parallel transcriptomic profiling of colonic tissues revealed coordinated dysregulation of pathways governing epithelial stress responses, endoplasmic reticulum homeostasis, lipid signaling, autophagy, and DNA damage and repair, suggesting a previously unrecognized epithelial stress state in Tor1a+/∆GAG mouse model. Integrative microbial-host interaction correlation analyses uncovered associations between specific dysbiotic taxa and host signaling pathways. These peripheral perturbations coincided with longitudinal motor deficits, identifying an age-dependent association between gut dysbiosis and neurobehavioral dysfunction. Together, our findings provide an experimental framework for investigating the relationship among microbiome perturbations, gut-barrier disruption, and neuronal vulnerability in a genetic model of dystonia. These findings reveal a previously underexplored peripheral dimension of DYT1 dystonia and provide a foundation for future studies to determine whether microbiome and intestinal alterations functionally contribute to disease pathobiology.