Drug-microbiome-host interactions in Parkinson's disease

帕金森病的药物-微生物组-宿主相互作用

• 批准号: 2881438
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2881438
• 关键词: Drug; microbiome; host; interactions; Parkinson

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.

人类肠道居住着一个由数万亿微生物组成的复杂群落，统称为肠道微生物群，它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帕金森病 (PD) 等神经退行性疾病的病理生理学联系起来，这种疾病目前影响 1% 的 60 岁以上人口。PD 主要影响大脑中的多巴胺能神经元。因此，改善帕金森病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，它们会与肠道中存在的数千种微生物相互作用。事实上，大规模筛选表明，相当一部分人类靶向药物（包括 PD 药物）到达肠道的浓度可以在体外抑制多种肠道细菌的生长。此外，腹泻和便秘是PD药物常见的副作用。总而言之，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 药物对成分的影响和人类肠道微生物群的活性，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，例如离体厌氧孵化、微生物生态生理学方法、下一代测序和生物信息学。将使用 PD 转基因小鼠模型结合微生物群操作程序，在体内评估微生物群对药物有效性的作用。这个跨学科项目的结果将加深我们对 PD 药物如何塑造微生物组的理解，并有可能识别可以操纵关键的微生物组参与者来增强当前 PD 疗法的有效性。理想的候选人必须主要对微生物学感兴趣，并愿意做一些动物实验。