Developing a reduced complexity model gut microbiome in the behavior model, Droso

描述（由申请人提供）：肠道中的微生物影响我们的新陈代谢、情绪和行为，但理解这些影响是如何产生的问题显然是复杂的。来自1000个物种的100万亿个细胞和数百万个基因组成了人类的微生物群。正如一个基因=一个功能的范式在很大程度上已经从遗传学领域消失，而更倾向于理解相互作用的途径如何导致表型，微生物学领域也在很大程度上开始认识到生态学是许多微生物组疾病状态的核心。生态学意味着生物和非生物因素相互作用的网络产生系统级的输出。发展生态学领域的核心概念之一是“关键物种”。在食物网（物种之间相互作用的网络图）中，关键物种与比一般物种更多的物种相互作用，当这些物种被消灭时，它们会对生态系统产生回响效应，这样生态系统的稳定性往往会失效，许多其他物种也会因关键物种的消失而间接被消灭。治疗微生物群疾病的最棘手的问题之一是微生物群本身具有很强的变化能力。虽然抗生素可以杀死绝大多数微生物，但当菌群恢复时，它们通常与患者开始时的菌群相同。唯一广泛成功的改变患者体内微生物生态系统的方法是使用粪便移植，即通过灌肠将患者的整个肠道菌群替换为捐赠者的粪便。我的目标是利用关键物种的概念作为一种策略，通过这种策略来扰乱肠道菌群，而不是完全消灭它们。通过绘制微生物食物网，我的目标是确定候选的关键物种。通过开发针对关键候选物的靶向噬菌体疗法，我的目标是重构微生物食物网以改变代谢输出，从而影响影响宿主代谢、情绪和行为的核心代谢物。我将从两个角度着手这个项目：(I)我将在果蝇中建立一个模型，降低肠道微生物群的复杂性，这是研究行为输出的理想选择；（ii）我将通过与一个非生物小鼠设施合作，在人源化小鼠肠道中研究完全复杂的肠道微生物群，从与人类更相关的角度测试在果蝇系统中建立的基本原理。

DESCRIPTION (provided by applicant): Microbes in our guts influence our metabolism, moods, and behaviors, but the problem of understanding how these influences arise is demonstrably complex. 100 trillion cells from 1000 species with millions of genes make up the human microbiome. Just as the one gene = one function paradigm has largely evaporated from the field of genetics in favor of understanding how pathways of interactions lead to a phenotype, the field of microbiology has largely begun to recognize that ecology is at the core of many microbiome disease states. Ecology means that a web of biotic and abiotic factors interact to produce a system-level output. One of the core concepts that has developed the field of ecology is the 'keystone species'. In a food web (network map of the interactions between species), keystone species interact with many more species than the average species does and these species have reverberating effects on an ecosystem when they are eliminated, such that the stability of the ecosystem often fails and many other species are eliminated by indirect effects due to loss of the keystone species. One of the toughest problems in treating ailments of the microbiome is that microbiomes themselves are robust to change. While antibiotics can kill off the vast majority of microbes, when the flora recover, they usually represent the same flora the patient started with. The only widely successful change of the microbial ecosystem in patients is through the use of fecal transplants, whereby the entire gut flora of a patient is replaced with a donor's stool using an enema. My aim is to use the keystone species concept as a strategy by which to perturb the gut flora without eliminating them entirely. By mapping the microbial food web, I aim to determine candidate keystone species. By developing targeted bacteriophage therapies against the keystone candidates, I aim to restructure microbial food webs to change the metabolic output, thus affecting the core metabolites that affect host metabolism, mood, and behavior. I will approach the project from two angles: (i) I will establish a model, reduced complexity gut microbiome in the fruit fly, which is ideal for studying behavioral outputs (ii) I wll examine full- complexity gut microbiomes in humanized mouse guts through a collaboration with a gnotobiotic mouse facility to test fundamental principles established in the fly system from a more human- relevant perspective.