698. PREBIOTICS IMPROVE MOTOR FUNCTION, COGNITION AND GUT HEALTH IN A PRECLINICAL MODEL OF HUNTINGTON’S DISEASE

Abstract Background Huntington's disease (HD) is a currently incurable neurodegenerative disorder characterised by psychiatric symptoms (notably depression), cognitive deficits and motor abnormalities, as well as peripheral manifestations, including gastrointestinal impairments. Evidence of gut dysbiosis has been discovered by our group in preclinical HD, and subsequently in clinical studies, and is strongly associated with disease symptoms, including affective, cognitive and behavioural outcomes. Aims & Objectives We aimed to evaluate the therapeutic potential of gut microbial modulation by prebiotics in treating HD. Given the well-documented role of prebiotics (PREB) as substrates of beneficial microbes, we hypothesised that chronic supplementation (PREB intervention) would ameliorate the gut dysbiosis associated with HD and consequently attenuate affective and other deficits in a preclinical model. Method Here, R6/1 HD mice and wild-type (WT) littermate controls were randomised to receive PREB or vehicle (drinking water) from 6-20 weeks of age. We assessed the onset and progression of motor, cognitive and affective deficits, as well as gastrointestinal parameters and gut macroscopy. Additionally, we profiled the gut microbiota and assessed their derivatised short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs). Results Compared to vehicle controls, PREB improved the motor performance of female HD mice and enhanced the cognitive performance of female HD and WT mice, but did not modulate behavioural despair. Furthermore, PREB increased stool softness (females) and faecal levels of SCFAs, including butyrate (males), acetate (both sexes)and propionate in both HD and WT males, but female HD mice only. The prebiotics intervention also decreased gut transit time in females at late onset and faecal output in both HD and WT males at early onset. Furthermore, PREB decreased alpha diversity and increased beta diversity in both sexes, including a remarkable increase in SCFA-producing microbes such as Bifidobacterium animalis in PREB-treated animals. Discussion & Conclusions Taken together, PREB effectively modulated the HD core phenotype, particularly motor coordination, cognition and GI parameters as described above, and remodelled the gut microbiota of HD mice. Our findings suggest that targeting the gut microbiota in HD is a plausible clinical strategy and may inform novel therapeutic approaches to delay the onset and/or progression of this debilitating condition.