Prebiotics improve motor function, cognition and gut health in a preclinical model of Huntington's disease

Abstract

Huntington's disease (HD) is a currently incurable neurodegenerative disorder characterised by psychiatric, cognitive and motor deficits, as well as peripheral manifestations, including gastrointestinal (GI) and immunological impairments. The R6/1 mouse model of HD, expressing a mutant human huntingtin transgene, exhibits excellent construct and face validity. Evidence of gut dysbiosis has been reported in clinical and preclinical HD and is strongly associated with disease symptoms, including cognitive and behavioural outcomes. Recently, high dietary fibre was shown to rescue cognitive and affective deficits and improve gut function in HD mice, by unknown mechanisms. Hence, we aimed to evaluate the therapeutic potential of gut microbial modulation by prebiotics in the treatment of HD. Given the well-documented role of prebiotics such as fructooligosaccharide (FOS) and galactooligosaccharide (GOS) as substrates of beneficial microbes, we hypothesised that chronic supplementation of FOS + GOS (PREB intervention) would ameliorate the gut dysbiosis associated with HD and consequently attenuate other deficits in this preclinical model. 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 GI parameters and gut macroscopy Additionally, we profiled the gut microbiota in faecal samples collected at week 14 (using 16S rRNA gene sequencing) and assessed their derivatised short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs). Compared to vehicle controls, PREB improved the motor performance of female HD mice and enhanced the cognitive performance of female HD and WT mice. Furthermore, PREB increased caecal weight (both sexes), 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, as well as juxtauterine fat (in females). Furthermore, PREB decreased α-diversity and increased β-diversity in both sexes, including a remarkable increase in SCFA-producing microbes such as Bifidobacterium animalis in PREB-treated animals. 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. This prebiotic intervention has a strong safety profile and is directly translatable to future clinical trials of HD. 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 and other neurological disorders with similar manifestations.

Keywords: Brain-body interactions; Dementia; Gut dysbiosis; Gut microbiome; Gut-immune interactions; Inflammation; Microbiota-gut-brain axis; Movement disorder; Neurological disease; Psychiatric disorder.