Geraldine Kong1, Susan Ellul2, Vinod K Narayana3, Komal Kanojia3, Harvey Tran Thai Ha1, Shanshan Li1, Thibault Renoir1, Kim-Anh Lê Cao4, Anthony J Hannan5. 1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne Brain Centre, Parkville, VIC 3010, Australia. 2. Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia. 3. Bio21 Institute and Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia; Metabolomics Australia, University of Melbourne, Parkville, VIC 3010, Australia. 4. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne Brain Centre, Parkville, VIC 3010, Australia; Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia. 5. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne Brain Centre, Parkville, VIC 3010, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: anthony.hannan@florey.edu.au.
Abstract
BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder with onset and severity of symptoms influenced by various environmental factors. Recent discoveries have highlighted the importance of the gastrointestinal microbiome in mediating the gut-brain-axis bidirectional communication via circulating factors. Using shotgun sequencing, we investigated the gut microbiome composition in the R6/1 transgenic mouse model of HD from 4 to 12 weeks of age (early adolescent through to adult stages). Targeted metabolomics was also performed on the blood plasma of these mice (n = 9 per group) at 12 weeks of age to investigate potential effects of gut dysbiosis on the plasma metabolome profile. RESULTS: Modelled time profiles of each species, KEGG Orthologs and bacterial genes, revealed heightened volatility in the R6/1 mice, indicating potential early effects of the HD mutation in the gut. In addition to gut dysbiosis in R6/1 mice at 12 weeks of age, gut microbiome function was perturbed. In particular, the butanoate metabolism pathway was elevated, suggesting increased production of the protective SCFA, butyrate, in the gut. No significant alterations were found in the plasma butyrate and propionate levels in the R6/1 mice at 12 weeks of age. The statistical integration of the metagenomics and metabolomics unraveled several Bacteroides species that were negatively correlated with ATP and pipecolic acid in the plasma. CONCLUSIONS: The present study revealed the instability of the HD gut microbiome during the pre-motor symptomatic stage of the disease which may have dire consequences on the host's health. Perturbation of the HD gut microbiome function prior to significant cognitive and motor dysfunction suggest the potential role of the gut in modulating the pathogenesis of HD, potentially via specific altered plasma metabolites which mediate gut-brain signaling.
BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder with onset and severity of symptoms influenced by various environmental factors. Recent discoveries have highlighted the importance of the gastrointestinal microbiome in mediating the gut-brain-axis bidirectional communication via circulating factors. Using shotgun sequencing, we investigated the gut microbiome composition in the R6/1 transgenic mouse model of HD from 4 to 12 weeks of age (early adolescent through to adult stages). Targeted metabolomics was also performed on the blood plasma of these mice (n = 9 per group) at 12 weeks of age to investigate potential effects of gut dysbiosis on the plasma metabolome profile. RESULTS: Modelled time profiles of each species, KEGG Orthologs and bacterial genes, revealed heightened volatility in the R6/1 mice, indicating potential early effects of the HD mutation in the gut. In addition to gut dysbiosis in R6/1 mice at 12 weeks of age, gut microbiome function was perturbed. In particular, the butanoate metabolism pathway was elevated, suggesting increased production of the protective SCFA, butyrate, in the gut. No significant alterations were found in the plasma butyrate and propionate levels in the R6/1 mice at 12 weeks of age. The statistical integration of the metagenomics and metabolomics unraveled several Bacteroides species that were negatively correlated with ATP and pipecolic acid in the plasma. CONCLUSIONS: The present study revealed the instability of the HD gut microbiome during the pre-motor symptomatic stage of the disease which may have dire consequences on the host's health. Perturbation of the HD gut microbiome function prior to significant cognitive and motor dysfunction suggest the potential role of the gut in modulating the pathogenesis of HD, potentially via specific altered plasma metabolites which mediate gut-brain signaling.
Authors: Mackenzie W Ferguson; Connor J Kennedy; Thulani H Palpagama; Henry J Waldvogel; Richard L M Faull; Andrea Kwakowsky Journal: J Cent Nerv Syst Dis Date: 2022-05-21
Authors: A D Rogachev; N A Alemasov; V A Ivanisenko; N V Ivanisenko; E V Gaisler; O S Oleshko; S V Cheresiz; S V Mishinov; V V Stupak; A G Pokrovsky Journal: Metabolites Date: 2021-02-25
Authors: Carolina Gubert; Chloe Jane Love; Saritha Kodikara; Jamie Jie Mei Liew; Thibault Renoir; Kim-Anh Lê Cao; Anthony John Hannan Journal: iScience Date: 2021-12-24