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

理论基础：肠道微生物群和肠道通透性的变化是与年龄相关的疾病的原因之一，甚至可能导致帕金森病(PD)的认知和运动功能障碍。帕金森病患者在神经症状出现前10年报告消化系统问题，接受帕金森病小鼠或患者排泄物的小鼠表现出运动功能受损、a-突触核蛋白神经病理和神经递质水平下降(PMID27912057)。肠道固有神经系统内α-突触核蛋白表达增加是对感染的正常反应，目的是动员免疫系统和对抗病原体(PMID31316206，PMID28651250)。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，神经毒性聚集体形成，破坏肠道神经系统，促进病理传播到大脑。总的来说，这些研究强烈地将肠道微生物群、局部肠道神经系统和炎症与PD的发展联系在一起，但决定微生物群组成的因素尚不完全清楚。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。使用的方法：PD或对照小鼠(和PD患者)的粪便样本将被用来利用最先进的猎枪代谢组学和元基因组学来表征肠道微生物组的组成和功能。将在肠道组织样本中研究噬菌体、细菌和宿主之间的相互作用，使用原位测序和块面扫描电子显微镜，然后建立计算模型来识别与PD相关的细菌和/或噬菌体。最后，我们将构建针对PD相关细菌的噬菌体，并在小鼠模型中进行测试。影响领域：这项研究可能会为肠道微生物群相关的神经退行性变的机制提供亟需的见解。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-宿主相互作用的了解，并有助于为治疗目的重塑肠道微生物区系的新策略。

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.