Decoding Antibiotic-induced Susceptibility to Clostridium difficile Infection

 描述(由申请人提供)：人类微生物组计划(HMP)联盟建立了一个独特的种群规模框架，该框架表征了人类宿主与其微生物群落之间的关系。这些数据为宿主对微生物群落结构的影响提供了强有力的初步证据，并强调了元基因组学和代谢组学在探索疾病状态下宿主-病原体相互作用的能力。我们将采用这样的系统生物学方法来扩展我们发表的和初步的发现，因为它们与艰难梭菌感染(CDI)、抗生素耐药性和儿童和成人的治疗结果有关。通过与我们的儿科和成人HMP参考数据集的比较，我们提供了急需的洞察力，了解抗生素如何在多个生命阶段影响肠道生态系统。由于幼儿通常是艰难梭菌的无症状携带者，而成年人通常会出现症状感染，我们拟议的研究提供了调节艰难梭菌毒力和耐药性的肠道生态系统的发展前景。我们工作的新奇之处在于我们发现了一种前线难以企及的肠道生态系统 抗生素治疗，其结果是CDI患者的治疗失败。我们的项目目标是通过表征新发现的分子和生化途径来识别调节宿主对艰难梭菌易感性的微生物。尖端的多重组学、抗生素耐药性的实时测量和患者的临床表型的结合有望产生一个宝贵的资源，为研究宿主对CDI的易感性提供新的发现。为了实现这些目标，我们将追求两个目标：目标1：对CDI发展中的宿主-微生物相互作用进行无偏见的纵向多组学研究。目的2：对影响CDI治疗结果的宿主-微生物相互作用进行有针对性的机制研究。通过这些纵向多组学研究，我们希望定义可预测CDI患者抗生素治疗失败的宿主-微生物相互作用，并提供丰富的资源-部分支持我们自己正在进行的CDI患者登记、德克萨斯州卫生服务部、自闭症之声、TMC消化疾病中心和综合微生物组中心(宏基因组和微生物组研究中心(CCMR)和德克萨斯州儿童微生物组中心(TCMC))。

 DESCRIPTION (provided by applicant): The Human Microbiome Project (HMP) consortium established a unique population-scale framework which characterized the relationship between the human host and its microbial communities. These data provide strong initial evidence for host influences on microbial community structure and underscores the capacity for metagenomics and metabolomics to explore host-pathogen interactions in disease states. We will adopt such a systems biology approach to extend our published and preliminary findings as they relate to Clostridium difficile infection (CDI), antibiotic resistance and treatment outcome i children and adults. By comparisons with our pediatric and adult HMP reference datasets, we provide much needed insight into how antibiotics affect intestinal ecosystems over multiple life stages. Because young children are generally asymptomatic carriers of C. difficile whereas adults often become symptomatically infected, our proposed studies provide a developmental perspective of intestinal ecosystems that modulate C. difficile virulence and drug resistance. The novelty of our work is our discovery of an intestinal ecosystem that is refractory to frontline antibiotic therapy, the result of which is treatment failure in CDI patients. Our project goal is t identify microbes that regulate host susceptibility to C. difficile through characterization of newy-identified molecular and biochemical pathways. The combination of cutting edge multi-omics, coupled with real-time measurement of antibiotic resistance and clinical phenotyping in patients is expected to generate a valuable resource that provides new discovery into host susceptibility to CDI. To achieve these objectives we will pursue two aims: Aim 1: Unbiased longitudinal multi-omic studies of host-microbe interactions in CDI development. Aim 2: Targeted mechanistic studies of host-microbe interactions that affect treatment outcome in CDI. Through these longitudinal multi-omics studies, we expect to define host-microbe interactions that are predictive of antibiotic treatment failure in CDI patients and provide a rich array of resources - supported in part by our own ongoing CDI patient registry, the Texas Department of State Health Services, Autism Speaks, the TMC Digestive Disease Center and integrated microbiome centers (Center for Metagenomics and Microbiome Research (CCMR) and Texas Children's Microbiome Center (TCMC)).