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

描述(由申请人提供)：我们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微生物群。正如一个基因=一个功能的范式已经从遗传学领域消失，转而支持理解相互作用的途径如何导致表型一样，微生物学领域已经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的网络相互作用，产生系统级的产出。发展生态学领域的核心概念之一是“关键物种”。在食物网(物种间相互作用的网络地图)中，Keystone物种与比普通物种多得多的物种相互作用，当这些物种被消灭时，这些物种对生态系统产生反响效应，从而导致生态系统的稳定性经常丧失，许多其他物种由于Keystone物种的丧失而被间接影响而被淘汰。治疗微生物组疾病最棘手的问题之一是微生物组本身对变化的抵抗力。虽然抗生素可以杀死绝大多数微生物，但当菌群恢复时，它们通常代表着患者开始时的相同菌群。对患者微生物生态系统的唯一广泛成功的改变是通过使用粪便移植，即患者的整个肠道菌群被使用灌肠的捐赠者的粪便取代。我的目标是使用Keystone物种概念作为一种策略，通过这种策略在不完全消除肠道菌群的情况下扰乱肠道菌群。通过绘制微生物食物网络图，我的目标是确定候选的关键物种。通过开发针对Keystone候选的有针对性的噬菌体疗法，我的目标是重组微生物食物网以改变代谢输出，从而影响影响宿主新陈代谢、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)我将建立一个模型，即果蝇中降低复杂性的肠道微生物组，这是研究行为输出的理想选择(Ii)我将通过与灵知生菌小鼠设施的合作，检查人源化小鼠肠道中的全复杂性肠道微生物组，以从更符合人类的角度测试苍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.