Defining omic-signatures in recurrent Clostridium difficile infection

定义复发性艰难梭菌感染的组学特征

• 批准号: 10060735
• 负责人: GARY P. WANG
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10060735
• 关键词: Antibiotic Therapy; Bile Acids; Biodiversity; Biological Markers; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cholesterol; Clinical Research; Clostridium difficile; Complication; Computational Technique; Computing Methodologies; Data; Development; Evolution; Future; Genes; Genomics; Health Care Costs; Health care facility; Healthcare; Healthcare Systems; Hospitals; Indigenous; Individual; Infection; Kinetics; Knowledge; Lead; Mass Fragmentography; Measures; Medical; Metabolic; Metabolic Pathway; Metagenomics; Methods; Microbe; Microbiology; Monitor; Morbidity - disease rate; Patients; Preventive; Primary Prevention; Prospective Studies; Recovery; Recurrence; Research; Resistance; Resolution; Ribosomal RNA; Risk; Risk Factors; Role; Sampling; Statistical Methods; Structure; Testing; Therapeutic; Uncertainty; Veterans; Work; acute care; base; candidate marker; clinical risk; deep sequencing; enteric pathogen; fecal transplantation; gut microbiome; gut microbiota; healthcare-associated infections; innovation; insight; metabolomics; metagenome; microbial; microbial community; microbial composition; microbiome; microbiome analysis; microbiome research; microbiota; microbiota metabolites; mortality; novel; novel strategies; prevent; preventive intervention; prospective; recurrent infection; screening; success; virtual

ABSTRACT Clostridium difficile infection (CDI) is one of the most prevalent and devastating healthcare-associated infections. Following standard antibiotic therapy, up to 25% of individuals with CDI develop one or more recurrences. Persistent or repeated episodes are difficult to treat and are a significant hardship for patients. The high success rate of fecal microbiota transplant for recurrent CDI provides powerful insight into the importance of restoring normal gut microbiota. However, to date, there are no microbiological or “omic” (microbiomic, metagenomic, metabolomic) predictors of C. difficile recurrence. The objective of this proposal is to determine temporal dynamics of microbial profiles and “omic” signatures associated with C. difficile recurrence. Our hypothesis is that patients who do not develop a C. difficile recurrence share an identifiable set of microbes, genes, and fecal metabolites in the gut microbiota. The rationale is that once the temporal dynamics of microbial and “omic” signatures associated with C. difficile recurrence are well defined, candidate microbial or “omic” biomarkers can be validated prospectively, ultimately allowing the development of strategies to prevent recurrent CDI. Specific preemptive therapy (e.g. microbiome manipulation) may then be developed on the basis of microbial compositions, genes, or metabolites of that microbiota. This novel approach offers an innovative method for preventing recurrent CDI. We will test the hypothesis by pursuing the following Specific Aims: 1) Determine the composition and structure of gut microbiota longitudinally in subjects following CDI, 2) Determine the metagenome of C. difficile gut microbiota, and 3) Perform global metabolomic analyses using LC-HRMS and GC-MS, including cholesterol and bile acid metabolites, to determine key metabolites in C. difficile gut microbiota. The approach is innovative because it will utilize a combination of unbiased, culture-independent 16S rRNA deep sequencing, metagenomic, and metabolomic approach and innovative computational techniques and multivariate statistical methods to identify “omic” signatures in gut microbiota associated with C. difficile recurrence. The proposed research is significant because there are virtually no data on the relationship between gut microbiota, omic signatures and C. difficile recurrence. This proposal will define “omic” signatures that can be validated in future studies, ultimately leading to novel strategies based on “omic” profiles for primary prevention of recurrent CDI.

抽象的 艰难梭菌感染 (CDI) 是最普遍、最具破坏性的医疗相关疾病之一 感染。标准抗生素治疗后，高达 25% 的 CDI 患者会出现一种或多种 复发。持续或反复发作​​很难治疗，对患者来说是一个巨大的困难。 粪便微生物群移植治疗复发性 CDI 的高成功率提供了深入了解 恢复正常肠道微生物群的重要性。然而，迄今为止，还没有微生物学或“组学” 艰难梭菌复发的（微生物组、宏基因组、代谢组）预测因子。该提案的目标是 确定与艰难梭菌相关的微生物谱和“组学”特征的时间动态 复发。我们的假设是，没有出现艰难梭菌复发的患者共享一组可识别的组 肠道微生物群中的微生物、基因和粪便代谢物。理由是，一旦时间 与艰难梭菌复发相关的微生物动态和“组学”特征已明确定义，候选 微生物或“组学”生物标志物可以进行前瞻性验证，最终允许开发 预防 CDI 复发的策略。然后可以进行特定的先发制人治疗（例如微生物组操纵） 基于该微生物群的微生物组成、基因或代谢物而开发。这部小说 方法提供了一种预防 CDI 复发的创新方法。我们将通过追求 具体目标如下： 1) 纵向确定受试者肠道微生物群的组成和结构 按照 CDI，2) 确定艰难梭菌肠道微生物群的宏基因组，以及 3) 进行全局代谢组学 使用 LC-HRMS 和 GC-MS 进行分析，包括胆固醇和胆汁酸代谢物，以确定关键 艰难梭菌肠道微生物群中的代谢物。该方法是创新的，因为它将结合使用 无偏见、独立于培养物的 16S rRNA 深度测序、宏基因组和代谢组学方法以及 创新的计算技术和多变量统计方法来识别肠道中的“组学”特征 与艰难梭菌复发相关的微生物群。拟议的研究意义重大，因为 实际上没有关于肠道微生物群、组学特征和艰难梭菌复发之间关系的数据。这 提案将定义可以在未来研究中验证的“组学”签名，最终产生新颖的结果 基于“组学”概况的策略用于复发性 CDI 的一级预防。