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

在行为模型中开发降低复杂性的肠道微生物组模型，Droso

基本信息

批准号：
9136688
负责人：
William Basil Ludington
金额：
$ 39.25万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136688
关键词：
Address Affect Antibiotics Bacteria Bacteriophages Behavior Behavioral Assay Biodiversity Biological Models Cells Clostridium difficile Collaborations Complex Compost Crohn&apos s disease Diabetes Mellitus Disease Dose Drosophila genus Drosophila melanogaster Ecology Ecosystem Equilibrium Event Feces Food Webs Freedom Genes Genetic Germ Gnotobiotic Goals Health Health behavior Hospitals Human Human Microbiome Human body Immune system Individual Infection Inflammatory Bowel Diseases Internet Lead Length of Stay Life Cycle Stages Link Maps Measures Medical Metabolic Metabolism Microbe Microbiology Modeling Modern Medicine Moods Mus Nature Nervous system structure Obesity Onset of illness Organism Output Pathway interactions Patients Phenotype Physiology Problem behavior Research Rest Risk Sewage Source System Testing Therapeutic Time Variant animal care base behavioral study enema administration fecal transplantation fly gut microbiome humanized mouse interest killings microbial microbiome pathogen public health relevance resistant strain targeted treatment theories tool

项目摘要

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.

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，但理解这些影响如何产生的问题显然很复杂。人类微生物组由来自 1000 个物种的 100 万亿个细胞和数百万个基因组成。正如“一个基因 = 一种功能”范式已在很大程度上从遗传学领域消失，转而支持理解相互作用途径如何导致表型一样，微生物学领域也已基本上开始认识到生态学是许多微生物组疾病状态的核心。。生态意味着生物和非生物因素相互作用产生系统级输出。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，这些物种在被消灭时会对生态系统产生反响影响，从而导致生态系统的稳定性经常失效，由于关键物种的丧失，许多其他物种因间接影响而被消灭。治疗微生物组疾病最棘手的问题之一是微生物组本身很难改变。虽然抗生素可以杀死绝大多数微生物，但当菌群恢复时，它们通常代表与患者开始时相同的菌群。患者微生物生态系统唯一广泛成功的改变是通过粪便移植，即通过灌肠将患者的整个肠道菌群替换为捐赠者的粪便。我的目标是使用关键物种概念作为一种策略，扰乱肠道菌群而不完全消除它们。通过绘制微生物食物网图，我的目标是确定候选关键物种。通过开发针对关键候选者的靶向噬菌体疗法，我的目标是重组微生物食物网以改变代谢输出，从而影响影响宿主代谢、情绪和行为的核心代谢物。我将从两个角度着手该项目：（i）我将建立一个模型，降低果蝇肠道微生物组的复杂性，这是研究行为输出的理想选择（ii）我将通过以下方式检查人源化小鼠肠道中的完整复杂性肠道微生物组：与无菌小鼠设施合作，从更与人类相关的角度测试苍蝇系统中建立的基本原理。