Mechanism of Colonization Resistance

项目摘要 抗生素治疗削弱了定殖抗性，从而增加了感染的风险。 肠杆菌科是坦率的（如非伤寒沙门氏菌血清型）或机会的（如 碳青霉烯类耐药肠杆菌科）病原体。然而，主机如何有助于 对致病性肠杆菌科的定殖抗性仍不完全清楚。 宿主使用“栖息地过滤器”来选择允许在环境中存活和生长的微生物特征。 宿主，从而塑造微生物群落的组成、空间组织和大小。我们 目的是阐明宿主如何有助于对病原体的定殖抗性， 并开发旨在恢复这种非特异性免疫的方法 在抗生素治疗期间发挥作用。我们假设，一个机械的理解如何 宿主有助于对致病性肠杆菌科的定殖抗性将促进 开发针对宿主信号通路的药物，以加强定植 阻力我们将在两个具体目标中检验我们假设的不同方面。具体目标1 将确定上皮代谢的转变为致病性 肠杆菌科克服微生物群衍生的短链脂肪酸的生态位修饰。 具体目标2将为靶向宿主的药物可以加强的想法提供原理证明 定植抗性，从而使得有可能保留这种非特异性免疫功能 积极的抗生素治疗。成功完成拟议工作将提供 对微生物组的关键功能的机械见解，这将在 对微生物发病机理、微生物群研究和肠道生物学感兴趣的研究人员。

PROJECT SUMMARY Antibiotic treatment impairs colonization resistance, thereby increasing the risk of infection with Enterobacteriaceae that are frank (e.g. non-typhoidal Salmonella serovars) or opportunistic (e.g. carbapenem-resistant Enterobacteriaceae) pathogens. However, how the host contributes to colonization resistance against pathogenic Enterobacteriaceae remains incompletely understood. The host uses “habitat filters” to select for microbial traits permitting survival and growth in the host, thereby shaping composition, spatial organization and size of microbial communities. Our goal is to elucidate how the host contributes to colonization resistance against pathogenic Enterobacteriaceae and to develop approaches aimed at restoring this nonspecific immune function during antibiotic therapy. We hypothesize that a mechanistic understanding of how the host contributes to colonization resistance against pathogenic Enterobacteriaceae will facilitate the development of drugs that target host signaling pathways to strengthen colonization resistance. We will test different aspects of our hypothesis in two specific aims. Specific Aim 1 will identify resources that a shift in epithelial metabolism provides for pathogenic Enterobacteriaceae to overcome niche modification by microbiota-derived short-chain fatty acids. Specific Aim 2 will provide a proof-of-principle for the idea drugs targeting the host can strengthen colonization resistance, thus making it possible to preserve this nonspecific immune function during active antibiotic therapy. Successful completion of the proposed work will provide mechanistic insights into a key function of the microbiome, which will be of wide appeal among researchers interested in microbial pathogenesis, microbiota research, and intestinal biology.