Defining omic-signatures in recurrent Clostridium difficile infection

摘要 艰难梭菌感染（CDI）是最普遍和最具破坏性的医疗保健相关疾病之一。 感染.在标准抗生素治疗后，高达25%的CDI患者会出现一种或多种 反复发作。持续或重复发作很难治疗，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的高成功率为CDI的治疗提供了强有力的见解。 恢复正常肠道菌群的重要性。然而，迄今为止，没有微生物或“组学” （微生物组学、宏基因组学、代谢组学）预测C.难以复发。本提案的目的是 以确定与C.艰难 复发我们的假设是，没有发展成C。难以识别的复发共有一个可识别的集合 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C.明确定义了难治性复发， 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复发的战略。然后可以进行特定的先发制人治疗（例如微生物组操纵）。 基于微生物组成、基因或该微生物群的代谢物而开发。这本小说 这种方法提供了一种预防CDI复发的创新方法。我们将通过追踪 以下具体目标：1）纵向确定受试者肠道微生物群的组成和结构 2）确定C.艰难的肠道微生物群，和3）进行整体代谢组学 使用LC-HRMS和GC-MS分析，包括胆固醇和胆汁酸代谢产物，以确定关键的 C.艰难的肠道微生物群。这种方法是创新的，因为它将利用以下几种方法的组合： 无偏的、不依赖于培养的16 S rRNA深度测序、宏基因组学和代谢组学方法， 创新的计算技术和多元统计方法来识别肠道中的“组学”特征 与C.难以复发。这项研究意义重大，因为 几乎没有关于肠道微生物群、组学特征和C.难以复发。这 该提案将定义“组学”签名，可以在未来的研究中验证，最终导致新的 基于“组学”特征的复发性CDI一级预防战略。

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.