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

基本原理：肠道微生物组和肠道通透性的变化有助于与年龄相关的疾病，甚至可能导致帕金森病（PD）的认知和运动功能障碍。PD患者在出现神经系统症状之前长达10年就会报告消化问题，接受PD小鼠或患者粪便的小鼠表现出运动功能受损、突触核蛋白神经病理学和神经递质水平下降（PMID 27912057）。在肠道的内在神经系统内，α-突触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对抗病原体（PMID 31316206，PMID 28651250）。然而，当α-突触核蛋白的表达超过其清除时，例如由于慢性感染，形成神经毒性聚集体，损害肠神经系统，促进病理向脑的传播。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的发展密切相关，但决定微生物组组成的因素尚未完全了解。噬菌体直接调节肠道中的细菌组成和丰度，可能是影响年龄相关疾病发展的一个被忽视的因素。拟采用的办法：来自PD或对照小鼠（和PD患者）的粪便样品将用于使用最先进的鸟枪代谢组学和宏基因组学来鉴定肠道微生物组的组成和功能。将使用原位测序和块面扫描电子显微镜在肠道组织样本中研究细菌、细菌和宿主之间的相互作用，然后进行计算建模以识别与PD相关的细菌和/或细菌。最后，我们将建立靶向PD相关细菌的抗体，并在小鼠模型中进行测试。影响领域：这种学生身份可能会提供急需的洞察与肠道微生物组相关的神经退行性变的基础机制。阐明大肠杆菌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微生物群的新策略。

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.