TY - JOUR
T1 - Dietary fibre confers therapeutic effects in a preclinical model of Huntington's disease
AU - Gubert, Carolina
AU - Kong, Geraldine
AU - Costello, Callum
AU - Adams, Cameron D.
AU - Masson, Bethany A.
AU - Qin, Wendy
AU - Choo, Jocelyn
AU - Narayana, Vinod K.
AU - Rogers, Geraint
AU - Renoir, Thibault
AU - Furness, John B.
AU - Hannan, Anthony J.
N1 - Funding Information:
We thank members of the Hannan Laboratory, past and present, for useful discussions and technical advice which informed this study. We also thank all of the Florey Institute's animal and behavioral facility staff for their valuable contribution with the care of the mice used in this study as well as the support with the software for the behavioral analyses. CG is a Hereditary Disease Foundation (HDF) Fellow. AJH has been supported by a National Health and Medical Research (NHMRC) Principal Research Fellowship and Ideas Grant, an EU-JPND Grant (co-funded by NHMRC), the DHB Foundation (Equity Trustees), the Flicker of Hope Foundation and the Margaret Friend Trust. AJH and TR have been supported by an NHMRC Project Grant. TR has been supported by an NHMRC Dementia Fellowship and currently holds a Ronald Philip Griffiths Fellowship from the University of Melbourne.
Funding Information:
CG is a Hereditary Disease Foundation (HDF) Fellow. AJH has been supported by a National Health and Medical Research (NHMRC) Principal Research Fellowship and Ideas Grant, an EU-JPND Grant (co-funded by NHMRC), the DHB Foundation (Equity Trustees), the Flicker of Hope Foundation and the Margaret Friend Trust. AJH and TR have been supported by an NHMRC Project Grant. TR has been supported by an NHMRC Dementia Fellowship and currently holds a Ronald Philip Griffiths Fellowship from the University of Melbourne.
Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2024/2
Y1 - 2024/2
N2 - Huntington's disease (HD) is a neurodegenerative disorder involving psychiatric, cognitive and motor deficits, as well as peripheral symptoms, including gastrointestinal dysfunction. The R6/1 HD mouse model expresses a mutant human huntingtin transgene and has been shown to provide an accurate disease model. Recent evidence of gut microbiome disruption was shown in preclinical and clinical HD. Therefore, we aimed to assess the potential role of gut microbial modulation in the treatment of HD. The R6/1 HD mice and wild-type littermate controls were randomised to receive diets containing different amounts of fibre: high-fibre (10 % fibre), control (5 % fibre), or zero-fibre (0 % fibre), from 6 to 20 weeks of age. We characterized the onset and progression of motor, cognitive and affective deficits, as well as gastrointestinal function and gut morphological changes. Faeces were collected for gut microbiome profiling using 16S rRNA sequencing, at 14 and 20 weeks of age. When compared to the control diet, high-fibre diet improved the performance of HD mice in behavioral tests of cognitive and affective function, as well as the gastrointestinal function of both HD and wild-type mice. While the diets changed the beta diversity of wild-type mice, no statistical significance was observed at 14 or 20 weeks of age within the HD mice. Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC) models were performed to evaluate microbiota composition, which identified differences, including a decreased relative abundance of the phyla Actinobacteriota, Campylobacterota and Proteobacteria and an increased relative abundance of the families Bacteroidaceae, Oscillospiraceae and Ruminococcaceae in HD mice when compared to wild-type mice after receiving high-fibre diet. PICRUSt2 revealed that high-fibre diet also decreased potentially pathogenic functional pathways in HD. In conclusion, high-fibre intake was effective in enhancing gastrointestinal function, cognition and affective behaviors in HD mice. These findings indicate that dietary fibre interventions may have therapeutic potential in Huntington's disease to delay clinical onset, and have implications for related disorders exhibiting dysfunction of the gut-brain axis.
AB - Huntington's disease (HD) is a neurodegenerative disorder involving psychiatric, cognitive and motor deficits, as well as peripheral symptoms, including gastrointestinal dysfunction. The R6/1 HD mouse model expresses a mutant human huntingtin transgene and has been shown to provide an accurate disease model. Recent evidence of gut microbiome disruption was shown in preclinical and clinical HD. Therefore, we aimed to assess the potential role of gut microbial modulation in the treatment of HD. The R6/1 HD mice and wild-type littermate controls were randomised to receive diets containing different amounts of fibre: high-fibre (10 % fibre), control (5 % fibre), or zero-fibre (0 % fibre), from 6 to 20 weeks of age. We characterized the onset and progression of motor, cognitive and affective deficits, as well as gastrointestinal function and gut morphological changes. Faeces were collected for gut microbiome profiling using 16S rRNA sequencing, at 14 and 20 weeks of age. When compared to the control diet, high-fibre diet improved the performance of HD mice in behavioral tests of cognitive and affective function, as well as the gastrointestinal function of both HD and wild-type mice. While the diets changed the beta diversity of wild-type mice, no statistical significance was observed at 14 or 20 weeks of age within the HD mice. Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC) models were performed to evaluate microbiota composition, which identified differences, including a decreased relative abundance of the phyla Actinobacteriota, Campylobacterota and Proteobacteria and an increased relative abundance of the families Bacteroidaceae, Oscillospiraceae and Ruminococcaceae in HD mice when compared to wild-type mice after receiving high-fibre diet. PICRUSt2 revealed that high-fibre diet also decreased potentially pathogenic functional pathways in HD. In conclusion, high-fibre intake was effective in enhancing gastrointestinal function, cognition and affective behaviors in HD mice. These findings indicate that dietary fibre interventions may have therapeutic potential in Huntington's disease to delay clinical onset, and have implications for related disorders exhibiting dysfunction of the gut-brain axis.
KW - Dementia
KW - Depression
KW - Dietary fibre
KW - Gut microbiome
KW - Huntington's disease
KW - Microbiota-gut-brain axis
KW - Neurodegenerative disorder
UR - http://www.scopus.com/inward/record.url?scp=85182188108&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2023.12.023
DO - 10.1016/j.bbi.2023.12.023
M3 - Article
C2 - 38142919
AN - SCOPUS:85182188108
SN - 0889-1591
VL - 116
SP - 404
EP - 418
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -