Gut bacteria and the brain: the surprising impact of bacteriophages .

肠道细菌和大脑：噬菌体的惊人影响。

• 批准号: 2596661
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2596661
• 关键词: Gut; bacteria; brain; surprising; impact

Rationale: Changes in the gut microbiome and intestinal permeability are contributing to age-related conditions and may even cause cognitive and motor dysfunction in Parkinson's disease (PD). People with PD report digestive problems up to 10 years before neurological symptoms occur and mice that receive faecal matter from PD mice or patients, show impaired motor function, a--synuclein neuropathology and decreased levels of neurotransmitters (PMID27912057). Increased expression of a-synuclein, within the intrinsic nervous system of the gut, is a normal response to infection, aimed at mobilizing the immune system and fight pathogens (PMID31316206, PMID28651250). However, when the expression of a--synuclein exceeds its clearance, for example as a result of chronic infections, neurotoxic aggregates form, damaging the enteric nervous system, promoting propagation of pathology to the brain. Collectively, these studies strongly link the gut microbiome, the local gut nervous system, and inflammation to the development of PD, but factors determining microbiome composition are incompletely understood. Bacteriophages directly modulate bacterial composition and abundance in the gut and may be an overlooked factor influencing the development of age-related conditions. Approaches to be used: Faecal samples from PD or control mice (and PD patients) will be used to characterise the composition and function of the gut microbiome using state-of-the-art shotgun metabolomics and metagenomics. The interaction between phages, bacteria and the host, will be studied in gut tissue samples, using in-situ sequencing and block-face Scanning-Electro-Microscopy, followed by computational modelling to identify bacteria and/or phages associated with PD. Finally, we will build phages to target PD-associated bacteria, and test these in mouse models. Areas of impact: This studentship may provide much needed insight into the mechanisms underpinning neurodegeneration associated with the gut microbiome. Elucidating possible beneficial and detrimental roles of phages in the gut will increase understanding of interbacterial and bacteria-host interactions, and contribute to novel strategies to remodel the gut microbiota for therapeutic purposes.

理由：肠道微生物组和肠通透性的变化有助于与年龄相关的状况，甚至可能导致帕金森氏病（PD）的认知和运动功能障碍。患有PD的人在神经系统症状发生前长达10年报告的消化问题，并从PD小鼠或患者接受粪便质量的小鼠，运动功能受损，A- - 核蛋白神经病理学和神经递质水平降低（PMID27912057）。在肠道的内在神经系统中，A-核蛋白的表达增加是对感染的正常反应，旨在动员免疫系统并抗击病原体（PMID31316206，PMID28651250）。但是，当A-突触核蛋白的表达超过其清除率时，例如，由于慢性感染，神经毒性聚集体形成，损害了肠神经系统，从而促进了大脑病理学的传播。总的来说，这些研究将肠道微生物组，局部肠道神经系统和炎症与PD的发展联系起来，但是确定微生物组组成的因素尚不完全了解。噬菌体直接调节肠道中的细菌组成和丰度，可能是影响与年龄相关条件发展的因素。要使用的方法：使用最先进的shot弹枪代谢组学和元基因组学，使用PD或对照小鼠（和PD患者）（和PD患者）（和PD患者）的粪便样品来表征肠道微生物组的组成和功能。噬菌体，细菌和宿主之间的相互作用将在肠道组织样品中进行研究，使用原位测序和块面扫描 - 电子 - 微观显微镜，然后进行计算建模，以鉴定与PD相关的细菌和/或噬菌体。最后，我们将建立噬菌体以靶向与PD相关的细菌，并在小鼠模型中进行测试。影响领域：该学生可能会提供对与肠道微生物组相关的神经变性机制的急需洞察力。阐明噬菌体在肠道中可能的有益和有害作用将增加对细菌间和细菌 - 宿主相互作用的理解，并有助于为治疗目的重塑肠道菌群的新策略。