The interplay between mutant huntingtin, gut microbiota and gut physiology in a Drosophila melanogaster model

Huntington’s disease (HD) is a fatal neurodegenerative condition caused by expansion of a CAG trinucleotide repeat in the HTT gene. Several studies suggest that the gut microbiota (GM) modulates host metabolism, inflammation, and immune responses, and may thereby influence pathogenesis of neurodegenerative disorders such as HD. A Drosophila model of HD was employed to investigate the effects of pan-neuronal mutant HTT (mHTT) expression on the GM as well as gut physiology and histology.

GM composition was analysed via bacterial culture and metagenomics analysis. Colony viability assays found higher levels of culturable bacteria, particularly Lactobacillus spp. and Acetobacter spp., in mHTT Drosophila gut homogenates, indicating gut dysbiosis. This dysbiosis was modulated via a faecal microbiota transplantation (FMT) assay, based on a cohabitation method where the bacterial environment was shared. FMT increased the lifespan and median survival of mHTT flies, potentially due to the observed shift in the Lactobacillus/Acetobacter ratio, two species previously linked to the maintenance of gut homeostasis through the modulation of TOR signalling, intestinal stem cell (ISc) homeostasis, and insulin signalling pathways.

Gut physiology and histology studies demonstrated that mHTT flies have a higher gut permeability to blue dye, suggesting an intestinal barrier dysfunction and loss of normal gut architecture, further highlighted by the enteroendocrine and ISc percentages recorded in the anterior midgut. Significant changes in food intake and defecation rates paralleled gastrointestinal symptoms observed in HD patients. Transcriptomic analysis identified differentially expressed genes in the gut and head tissues of mHTT flies, highlighting alterations in cell proliferation/differentiation processes, lipid, carbohydrate, protein and chitin metabolism as well as immune response and inflammation. This study supports the influence of HD on GM content and epithelial physiology, suggesting a possible causative relationship between mHTT expression and altered gut bacteria homeostasis, dysregulation of cell gut proliferation/differentiation processes and disruption of gut metabolism.