Chongtham Anjalika, Yoo Jung Hyun, Chin Theodore M, Akingbesote Ngozi D, Huda Ainul, Marsh J Lawrence, Khoshnan Ali
Biology and Bioengineering, California Institute of Technology (Caltech), Pasadena, CA, United States.
Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States.
Front Neurosci. 2022 Jun 2;16:902205. doi: 10.3389/fnins.2022.902205. eCollection 2022.
Changes in the composition of gut microbiota are implicated in the pathogenesis of several neurodegenerative disorders. Here, we investigated whether gut bacteria affect the progression of Huntington's disease (HD) in transgenic (fruit fly) models expressing full-length or N-terminal fragments of human mutant huntingtin (HTT) protein. We find that elimination of commensal gut bacteria by antibiotics reduces the aggregation of amyloidogenic N-terminal fragments of HTT and delays the development of motor defects. Conversely, colonization of HD flies with (), a known pathobiont of human gut with links to neurodegeneration and other morbidities, accelerates HTT aggregation, aggravates immobility, and shortens lifespan. Similar to antibiotics, treatment of HD flies with small compounds such as luteolin, a flavone, or crocin a beta-carotenoid, ameliorates disease phenotypes, and promotes survival. Crocin prevents colonization of in the gut and alters the levels of commensal bacteria, which may be linked to its protective effects. The opposing effects of and crocin on HTT aggregation, motor defects, and survival in transgenic models support the involvement of gut-brain networks in the pathogenesis of HD.
肠道微生物群组成的变化与几种神经退行性疾病的发病机制有关。在此，我们研究了肠道细菌是否会影响在表达人类突变型亨廷顿蛋白（HTT）全长或N端片段的转基因（果蝇）模型中亨廷顿病（HD）的进展。我们发现，用抗生素消除共生肠道细菌可减少HTT淀粉样N端片段的聚集，并延缓运动缺陷的发展。相反，用一种已知的与神经退行性变和其他疾病有关的人类肠道致病共生菌对HD果蝇进行定殖，会加速HTT聚集、加重运动不能并缩短寿命。与抗生素类似，用小分子化合物（如黄酮类化合物木犀草素或β-胡萝卜素藏红花素）处理HD果蝇，可改善疾病表型并促进存活。藏红花素可防止致病共生菌在肠道定殖，并改变共生细菌的水平，这可能与其保护作用有关。致病共生菌和藏红花素对转基因果蝇模型中HTT聚集、运动缺陷和存活的相反作用支持了肠-脑网络参与HD发病机制的观点。
