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.
Neurobiol Dis. 2021 Jan;148:105199. doi: 10.1016/j.nbd.2020.105199. Epub 2020 Nov 26.
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.
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.
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.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，其症状的发作和严重程度受到各种环境因素的影响。最近的发现强调了胃肠道微生物组在通过循环因子介导肠道-大脑轴双向通讯方面的重要性。我们使用 shotgun 测序技术，研究了 R6/1 转基因 HD 小鼠模型从 4 到 12 周龄（青少年到成年期）的肠道微生物组组成。还对这些小鼠的血浆进行了靶向代谢组学分析（每组 9 只），以研究肠道菌群失调对血浆代谢组谱的潜在影响。
每种物种、KEGG Orthologs 和细菌基因的模拟时间曲线显示，R6/1 小鼠的波动性较高，表明 HD 突变在肠道中的潜在早期影响。除了 12 周龄 R6/1 小鼠的肠道菌群失调外，肠道微生物组功能也受到干扰。特别是，丁酸代谢途径升高，表明肠道中保护性 SCFA 丁酸的产生增加。在 12 周龄的 R6/1 小鼠中，血浆中丁酸和丙酸的水平没有明显变化。宏基因组学和代谢组学的统计整合揭示了几种拟杆菌属与血浆中的 ATP 和哌啶酸呈负相关。
本研究揭示了 HD 肠道微生物组在疾病运动前症状阶段的不稳定性，这可能对宿主健康产生严重后果。在认知和运动功能显著障碍之前，HD 肠道微生物组功能的紊乱表明肠道在调节 HD 发病机制方面的潜在作用，可能通过介导肠道-大脑信号的特定改变的血浆代谢物。
