A042 Pan-neuronal mutant HTT expression affects the gut microbiota and physiology in Drosophila melanogaster model

<h3></h3> Huntington’s disease (HD) is a fatal neurodegenerative condition caused by the expansion of a CAG trinucleotide repeat in the HTT gene. Evidence suggests the gut microbiota (GM) modulates host metabolism, inflammation, and immune responses, possibly influencing neurodegenerative disorders such as HD. We have used a Drosophila model of HD to investigate the effects of pan-neuronal mutant HTT (mHTT) expression on the GM and gut physiology. GM were analysed via bacterial culture and metagenomics analysis. A faecal microbiota transplantation assay (FMT) was performed as an approach to modulate the observed gut dysbiosis. Gut physiology was studied through gut permeability and immunochemistry assays, and RNAseq analysis. Colony viability assays indicated higher levels of culturable bacteria in mHTT Drosophila gut homogenates, in particular Lactobacillus ssp. and Acetobacter ssp. FMT approach increased the lifespan and median survival of mHTT flies and altered the Lactobacillus ssp./Acetobacter ssp. ratio. mHTT flies also exhibited an increased permeability to blue dye, suggesting an intestinal barrier dysfunction and loss of the normal gut architecture, further highlighted by the altered enteroendocrine and intestinal stem cell numbers. Differentially expressed genes in the gut of mHTT flies highlight alterations in cell proliferation/differentiation processes (chinmo, D, Notum), as well as lipid (FASN3, Fad2), carbohydrate (LMan, Mal-B1) and chitin metabolism (Cht5, Cht9). Our 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.