Metabolome-Based Biomarkers and Neutraceuticals in Clostridium Difficile Infection

艰难梭菌感染中基于代谢组的生物标志物和营养药物

• 批准号: 8925055
• 负责人: Tor C. Savidge
• 金额: $ 19.66万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925055
• 关键词: Adopted; Agonist; Algorithms; Aminobutyric Acids; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antitoxins; Biochemical; Biochemical Pathway; Biological Assay; Biological Markers; Child; Clinical; Clinical Management; Clostridium difficile; Clostridium perfringens; Comorbidity; Complex; Coupled; DNA Sequence; Data; Detection; Development; Diagnosis; Diagnostic; Diarrhea; Disease; Disinfection; Early Diagnosis; Ecosystem; Elderly; Enterococcus; Epidemic; Escherichia coli; Failure; Feces; Frequencies; GABA Agonists; GABA-A Receptor; Genetic screening method; Genus staphylococcus; Goals; Gold; Health; High Prevalence; Hospitals; Imagery; Incidence; Individual; Infection; Intestinal Diseases; Long-Term Care; Marketing; Mediating; Medical center; Metadata; Methods; Metronidazole; Microbe; Modeling; Molecular; Nosocomial Infections; Nucleic Acid Amplification Tests; Observational Study; Operative Surgical Procedures; Organism; Outcome; Pathogenesis; Pathway Analysis; Patient risk; Patients; Pharmaceutical Preparations; Predisposition; Public Health; Recurrence; Recurrent disease; Refractory; Relapse; Reproduction spores; Ribosomal RNA; Risk; Risk Factors; Sanofi brand of zolpidem tartrate; Severity of illness; Specimen; Structure; Symptoms; Taxon; Technology; Testing; Texas; Time; Transplantation; Validation; Vancomycin; Work; antimicrobial; base; candidate identification; cohort; cost effective; diagnostic assay; experience; gamma-Aminobutyric Acid; gut microflora; high risk; improved; innovation; insight; metabolomics; microbial; microbial community; microbiome; mortality; next generation; novel; novel diagnostics; outcome forecast; pathogen; prevent; programs; prospective; protective effect; pyrosequencing; rRNA Genes; zolpidem

DESCRIPTION (provided by applicant): Clostridium difficile is the leading cause of nosocomial infection in the U.S., outpacing both antibiotic-resistant staphylococcus and enterococcus. The high prevalence of Clostridium difficile infection (CDI) represents a major health problem for hospitals and long-term care facilities alike due to common patient risk factors; notably advanced age and comorbidity, use of antimicrobials and difficulty in C. difficile spore disinfection. Newly-emerged hypervirulent C. difficile strains have also contributed to CDI escalation resulting in increased disease severity and mortality. Furthermore, 35% of patients will experience recurrent CDI, a significant clinical issue that often results in poor clinical outcome. Despite the fact that early diagnosis of CDI is crucial for optimal clinical management and improved prognosis, diagnostic assays that accurately predict CDI recurrence do not exist and risk factors for recurrent CDI remain elusive. The high frequency of CDI recurrence, coupled with poor clinical outcomes for cases not promptly and effectively treated, underscores the need to identify accurate biomarkers of disease recurrence that can be developed into new diagnostic assays. This is the major goal of our study. Although antimicrobial disruption of the protective gut microflora is known to strongly correlate with the development of symptoms in infected individuals, there is still a major gap in our understanding of CDI susceptibility and recurrence. In this revised application, we demonstrate that integration of next generation DNA sequencing with global metabolomics into microbial ecosystem networks provides an analytical framework for the discovery of new diagnostic and treatment options for recurrent CDI. The significance of our multi-omics approach is the identification of candidate 16S rRNA and biochemical biomarkers in primary CDI patients who go on to develop recurrent disease (misclassification rate of 12%). These multi-omic studies led to the following novel observations in CDI patients: "Identification of a major potential deficiency when using molecular-based testing to diagnose CDI. A 54% misdiagnosis rate was indicated when using sensitive nucleic acid amplification tests that cannot discriminate CDI from asymptomatic C. difficile carriage. " Based on our identification of �-aminobutyric acid (GABA) and precursors of GABA synthesis as candidate biomarkers of CDI recurrence, a 4.88-fold higher CDI risk association was identified in hospitalized patients prescribed Zolpidem (Ambien), a GABA receptor A agonist. Our goal for Aim 1 is to validate candidate 16S rRNA biomarkers of CDI recurrence in a larger 200 patient based cohort and correlate these findings with clinical metadata. For Aim 2, we expect to validate candidate metabolomic biomarkers of CDI recurrence in the same 200 patient cohort and perform multi-omic analysis. We expect that the multi-omic biomarkers - alone or in combination - will accurately predict CDI recurrence. Considering the complete lack of recurrent CDI diagnostic assays, we aim to develop one or more biomarkers for use as a gold standard method that will validate other cost effective assays enabling differentiation of CDI from asymptomatic colonization, as well as identification of patients at risk for recurrent CDI. This type of diagnostic represents a priority clinical need and a major biomedical market opportunity. We also anticipate that newly adopted nucleic acid amplification testing is greatly overestimating CDI incidence. Our preliminary data indicate that such patients are likely receiving wholly inappropriate treatment options resulting from their apparent misdiagnosis e.g. fecal microbiota transplantation in children.

描述（由申请人提供）：艰难梭菌是美国医院感染的主要原因，超过了耐抗生素葡萄球菌和肠球菌。艰难梭菌感染 (CDI) 的高患病率是医院和长期的主要健康问题。由于常见的患者危险因素，特别是高龄和合并症、抗菌药物的使用以及艰难梭菌的困难，护理设施相似； 新出现的高毒力艰难梭菌菌株也导致 CDI 升级，导致疾病严重程度和死亡率增加。此外，35% 的患者会出现复发性 CDI，这是一个严重的临床问题，尽管临床结果不佳。事实上，CDI 的早期诊断对于临床治疗和改善预后至关重要，但目前尚不存在准确预测 CDI 复发的诊断方法，而且 CDI 复发的危险因素仍然难以捉摸。复发，加上未及时有效治疗的病例临床结果不佳，强调需要确定可开发为新诊断测定的准确的疾病复发生物标志物，尽管抗菌药物破坏了保护性肠道。众所周知，微生物区系与感染个体症状的发展密切相关，但我们对 CDI 易感性和复发的理解仍然存在重大差距。在这个修订后的申请中，我们证明了将下一代 DNA 测序与全球代谢组学整合到微生物生态系统中。网络为发现复发性 CDI 的新诊断和治疗方案提供了一个分析框架。我们的多组学方法的意义在于识别随后发展为复发性疾病的原发性 CDI 患者的候选 16S rRNA 和生化生物标志物。 12%）。这些多组学研究在 CDI 患者中得出了以下新的观察结果：“使用基于分子的检测来诊断 CDI 时发现了主要的潜在缺陷。当使用时，误诊率高达 54%。使用无法区分 CDI 和无症状艰难梭菌携带的敏感核酸扩增测试”根据我们对 β-氨基丁酸 (GABA) 和 GABA 合成前体作为 CDI 复发候选生物标志物的鉴定，CDI 风险关联性高 4.88 倍。在服用唑吡坦（Ambien）（一种 GABA 受体 A 激动剂）的住院患者中发现了这一点。我们的目标 1 是验证候选 16S rRNA 生物标志物。在更大的 200 名患者队列中研究 CDI 复发的情况，并将这些发现与临床元数据相关联。对于目标 2，我们希望在同一 200 名患者队列中验证 CDI 复发的候选代谢组学生物标志物，并进行多组学分析。组学生物标志物（单独或组合）将准确预测 CDI 复发 考虑到完全缺乏复发性 CDI 检测诊断，我们的目标是开发一种或多种生物标志物作为金标准方法，以验证其他具有成本效益的检测方法。能够区分 CDI 和无症状定植，以及识别有复发 CDI 风险的患者。我们还预计，新采用的核酸扩增检测会大大高估 CDI。我们的初步数据表明，此类患者可能因明显的误诊而接受了完全不适当的治疗方案，例如儿童粪便微生物移植。