Drug-microbiome-host interactions in Parkinson's disease

人类肠道中居住着由数万亿微生物组成的复杂群落，统称为肠道微生物群，它们影响宿主的生理机能和对疾病的易感性。越来越多的证据将肠道细菌与神经退行性疾病的病理生理学联系起来，如帕金森病（PD），目前影响60岁以上人口的1%。PD主要影响脑中的多巴胺能神经元。因此，改善PD症状的疗法主要包括补充多巴胺水平的药物。当这些药物口服时，它们与肠道中存在的数千种微生物相互作用。事实上，大规模筛选显示，包括PD药物在内的相当大比例的人类靶向药物以可以抑制体外几种肠道细菌生长的浓度到达肠道。此外，腹泻和便秘是PD药物的常见副作用。总之，这些发现强调了PD靶向药物在塑造肠道微生物组方面的潜力，但这些药物对复杂微生物群群落的直接影响尚不清楚。这个跨学科项目旨在详细研究i）PD药物对人体肠道微生物群组成和活性的影响，以及ii）这可能对宿主产生的影响。该项目将采用最先进的微生物生态学技术，如离体厌氧培养、微生物生态生理学方法、下一代测序和生物信息学。将在体内评估微生物群对药物有效性的作用，使用PD转基因小鼠模型与微生物群操作程序相结合。这个跨学科项目的结果将促进我们对PD药物如何塑造微生物群的理解，并可能确定可被操纵以增强当前PD治疗有效性的关键微生物群参与者。理想的候选人必须主要感兴趣在微生物学方面，并愿意做一些动物实验。

The human intestine is inhabited by a complex community of trillions of microbes, together known as the gut microbiota, which influences both host physiology and susceptibility to disease. Accumulating evidence links gut bacteria to pathophysiology of neurodegenerative disorders such as Parkinson's disease (PD), a disease currently affecting 1% of the population over the age of 60. PD predominantly impacts dopaminergic neurons in the brain. Thus, therapies to ameliorate PD symptoms primarily consist of pharmaceutical drugs that replenish dopamine levels. As these drugs are taken orally, they interact with thousands of microbial species present in the gut. Indeed, large-scale screenings have revealed a significant proportion of human-targeted drugs, including PD drugs, reach the intestine at concentrations that can inhibit growth of several gut bacteria in vitro. Additionally, diarrhea and constipation are common side effects of PD drugs. Altogether, these findings underscore the potential of PD-targeted drugs in shaping the gut microbiome, but the direct impact of these drugs on complex microbiota communities is not known.This interdisciplinary project aims to investigate in detail i) the impact of PD drugs on composition and activity of the human gut microbiota and ii) the repercussions this may have on the host. The project will employ state-of-the-art microbial ecology techniques such as ex vivo anaerobic incubations, microbial ecophysiology methods, next-generation sequencing and bioinformatics. The role of the microbiota on the effectiveness of the drugs will be evaluated in vivo, using a transgenic mouse model of PD in combination with microbiota manipulation procedures.Results from this interdisciplinary project will advance our understanding of how PD drugs shape the microbiome and potentially identify key microbiome players that can be manipulated to augment the effectiveness of current PD therapies.The ideal candidate must be primarily interested in microbiology and be willing to do a few animal experiments.