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Colonic Function and the Gut Microbiome in Transgenic Mice with Machado-Joseph Disease
Machado-Joseph disease (MJD) is a fatal neurodegenerative condition denoted by progressive loss of muscle control and movement. MJD is caused by inheritance of a CAG repeat expansion within the ATXN3 gene, resulting in abnormal formation of ataxin-3 protein aggregates within the brain. A pre-clinical study identified gut microbiome changes in MJD mice before the onset of neurological impairment. While changes in the brain-gut-microbiome axis may contribute to MJD development, this remains largely unexplored.
We investigated whether colonic function changes in MJD and whether it occurs with or before gut microbiome and motor changes. Male and female transgenic MJD mice and wild-type controls were examined at pre-symptomatic (4, 5 and 7 weeks) and early-onset (9, 11 and 13 weeks) disease stages. Colonic and motor function was examined alongside neurological and behavioural health. The faecal microbiome was profiled using amplicon sequencing. Male MJD mice demonstrated significantly different microbiome communities by 5 weeks, faster gut transit by 9 weeks, impaired motor function by 11 weeks, and increased faecal output at 13 weeks compared to male WT controls. Our work suggests colonic dysfunction occurs after microbiome changes but before motor changes in MJD, which could serve as a MJD prognostic marker and treatment target.
