Decoding Antibiotic-induced Susceptibility to Clostridium difficile Infection

解读抗生素诱导的艰难梭菌感染易感性

基本信息

批准号：
9333177
负责人：
ROBERT A BRITTON
金额：
$ 149.47万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-20 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333177
关键词：
Address Adopted Adult Affect Algorithms Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antibody Response Antitoxins Appearance Autistic Disorder Bacterial Drug Resistance Bile Acids Biochemical Pathway Bioinformatics Bioreactors Butyric Acids Child Childhood Clinical Clostridium difficile Communities Community Networks Consumption Control Groups Coupled Coupling DNA Data Data Set Dependency Development Diarrhea Diet Digestive System Disorders Disaccharides Disease Disease Progression Drug resistance Ecosystem Epidemic Epidemiology Etiology Evaluation Feces GABA Agonists Geography Germination Goals Health Services Heme Hospitals Human Human Microbiome Immunity Infection Inflammatory disease of the intestine Intestinal Diseases Intestines Life Link Logistic Regressions Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Metadata Metagenomics Metronidazole Metronidazole resistance MicroRNAs Microbe Modeling Molecular Nosocomial Infections Outcome Outcome Measure Pathogenesis Patient risk Patients Population Predisposition Prospective Studies Publishing Recurrence Refractory Relapse Reproduction spores Research Research Personnel Resistance Resolution Resources Ribotypes Risk Risk Factors Role Shotguns Signal Transduction Structure Systems Biology Technology Testing Texas Treatment Failure Treatment outcome Trehalose Virulence Work antimicrobial base clinical phenotype clinical risk cohort enteric pathogen experience gamma-Aminobutyric Acid gulf coast gut microbiome gut microbiota high risk host-microbe interactions in vivo innovation insight metabolomics methicillin resistant Staphylococcus aureus microbial microbial community microbiome microbiota novel diagnostics novel therapeutics outcome forecast pathogen patient registry primary outcome profiles in patients public health relevance secondary outcome temporal measurement trait whole genome zolpidem

项目摘要

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)).

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群体规模框架，该框架描述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，并强调了这一点。宏基因组学和代谢组学探索疾病状态下宿主与病原体相互作用的能力，我们将采用这种系统生物学方法来扩展我们已发表的和初步的发现，因为它们与艰难梭菌感染有关。（CDI）、儿童和成人的抗生素耐药性和治疗结果通过与我们的儿科和成人 HMP 参考数据集进行比较，我们提供了关于抗生素如何影响多个生命阶段的肠道生态系统的急需的见解，因为幼儿通常是无症状的 CDI 携带者。尽管成年人经常出现症状感染，但我们提出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视角，我们工作的新颖之处在于我们发现了一种肠道生态系统。难于前线抗生素治疗，其结果是 CDI 患者的治疗失败，我们的项目目标是通过新确定的分子和生化途径的表征，结合尖端的多组学来识别调节宿主对艰难梭菌易感性的微生物。通过实时测量患者的抗生素耐药性和临床表型，预计将产生宝贵的资源，为宿主对 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： CDI 发展中宿主-微生物相互作用的无偏纵向多组学研究目标 2：影响 CDI 治疗结果的宿主-微生物相互作用的有针对性的机制研究，我们期望定义能够影响 CDI 治疗结果的宿主-微生物相互作用。可以预测 CDI 患者的抗生素治疗失败，并提供丰富的资源 - 部分由我们自己正在进行的 CDI 患者登记处、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（宏基因组学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)）。