The Gut Microbiota Regulates Motor Deficits via Butyrate in a Gnal<sup>+/-</sup> Mouse Model of DYT25 Dystonia.

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Dystonia is the third most common movement disorder, following essential tremor and Parkinson's disease. The underlying mechanisms behind dystonia are still one of the crucial unsolved research topics. Gnal haploinsufficient (Gnal+/-) mice are used as a model of DTY25 dystonia to investigate the mechanistic relationship between gut microbiota and dystonia. The present study unveiled Gnal+/- mice exhibit significant motor deficits of dystonia, along with a marked gut microbiota dysbiosis. Analysis of the gut microbiota composition and function reveals that Gnal+/- mice have decreased butyrate-producing bacteria abundance (such as Lachnospiraceae_NK4A136, Blautia, and Butyricicoccus) and disrupted butanoate metabolism. The targeted metabolomics analysis indicates that the Gnal+/- mice exhibit decreased butyrate levels in feces and serum. The colonization of antibiotic-treated wild-type mice with fecal microbiota from Gnal+/- mice is sufficient to induce motor deficit symptoms. Oral administration of sodium butyrate ameliorated motor deficits in the Gnal+/- mouse model of DYT25 dystonia. Striatal single-nucleus RNA sequencing reveals cell-type-specific gene expression changes, suggesting that butyrate modulates neurotransmitter pathways, particularly GABA signaling. This is confirmed by restored striatal GABA levels after butyrate supplementation. In sum, gut microbiome contributes to dystonia pathogenesis, and butyrate supplementation alleviates the motor deficits of dystonia in Gnal+/- mice.

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