DYT1 mutation alters gut microbiome composition and gut-brain axis dynamics in a mouse model

Abstract

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+/{Delta}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 Tor1a+/{Delta}GAG mouse model using 16S rRNA gene sequencing and uncovered early emerging, persistent disruptions in microbial diversity and community composition that track with progressive motor impairment. Mutant mice exhibited an alteration of key commensal taxa, and molecular signatures indicative of compromised gut-barrier integrity. Parallel transcriptomic profiling of colonic epithelium reveals coordinated dysregulation of pathways governing epithelial stress responses, endoplasmic reticulum homeostasis, lipid signaling, autophagy, and DNA damage and repair, pointing to a previously unrecognized epithelial stress state in Tor1a+/{Delta}GAG mouse model. Integrative microbial-host interaction correlation analyses uncovered robust associations between specific dysbiotic taxa and host signaling pathways. These peripheral perturbations coincide with longitudinal motor deficits, suggesting a mechanistic gut-brain axis linking intestinal dysfunction to central neuronal vulnerability. Together, our findings provide the first experimental framework connecting microbiome perturbations, gut-barrier disruption, and neuronal vulnerability in a genetic model of dystonia. This work positions the gut microbiome and its regulation of epithelial and neuronal homeostasis as a novel entry point for disease modification in individuals carrying deleterious dystonia-associated variants.