Mechanism of Colonization Resistance

项目总结 抗生素治疗削弱了对定居的抵抗力，从而增加了感染 直率(例如，非伤寒沙门氏菌血清型)或机会性(例如， 耐碳青霉烯类肠杆菌科)病原菌。然而，主持人如何为 对致病性肠杆菌科细菌的定植耐药性仍不完全清楚。 寄主使用“栖息地过滤器”来选择微生物特征，以允许在 因此决定了微生物群落的组成、空间组织和大小。我们的 目的是阐明寄主对病原菌的定殖抗性是如何起作用的。 肠杆菌科，并开发旨在恢复这种非特异性免疫的方法 在抗生素治疗过程中发挥作用。我们假设，机械地理解 宿主有助于定植对致病性肠杆菌科细菌的耐药性将有助于 靶向宿主信号通路以加强定植的药物的开发 抵抗。我们将在两个具体目标中测试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提供的资源 肠杆菌科通过微生物群衍生的短链脂肪酸克服生态位修饰。 特定目标2将为针对宿主的药物可以增强的想法提供原则证明 抗定殖性，从而使保存这种非特异性免疫功能成为可能 在积极的抗生素治疗期间。拟议工作的圆满完成将提供 对微生物组的关键功能的机械论见解，这将在 对微生物发病机制、微生物区系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.