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，超过了耐药性大肠杆菌和肠球菌。艰难梭菌感染（CDI）的高患病率代表了医院和长期护理机构的主要健康问题，这是由于常见的患者风险因素;特别是高龄和合并症，使用抗菌药物和C.艰难 孢子消毒新出现的高毒力C.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%的患者将经历复发性CDI，这是一个重要的临床问题，通常会导致临床结局不佳。尽管CDI的早期诊断对于最佳临床管理和改善预后至关重要，但准确预测CDI复发的诊断测定并不存在，复发性CDI的风险因素仍然难以捉摸。CDI复发的高频率，加上没有及时有效治疗的病例的临床结果不佳，强调了需要鉴定可以开发成新的诊断测定的疾病复发的准确生物标志物。这是我们研究的主要目标。尽管已知抗微生物剂对保护性肠道菌群的破坏与感染个体的症状发展密切相关，但我们对CDI易感性和复发的理解仍存在重大差距。在这个修订后的申请中，我们证明了下一代DNA测序与全球代谢组学整合到微生物生态系统网络中，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鉴定了继续发展为复发性疾病的原发性CDI患者中的候选16 S rRNA和生化生物标志物（错误分类率为12%）。这些多组学研究在CDI患者中产生了以下新的观察结果：“当使用基于分子的检测来诊断CDI时，识别出一个主要的潜在缺陷。当使用敏感的核酸扩增试验不能区分CDI和无症状C时，误诊率为54%。艰难的姿态 “基于我们将γ-氨基丁酸（GABA）和GABA合成的前体作为CDI复发的候选生物标志物的鉴定，在服用唑吡坦（Ambien）的住院患者中确定了4.88倍的CDI风险关联，唑吡坦是一种GABA受体A激动剂。我们的目标1是在更大的200例患者队列中验证CDI复发的候选16 S rRNA生物标志物，并将这些发现与临床元数据相关联。对于目标2，我们期望在相同的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。我们期望多组学生物标志物-单独或组合-将准确预测CDI复发。考虑到完全缺乏复发性CDI诊断测定，我们的目标是开发一种或多种生物标志物用作金标准方法，其将验证其他成本有效的测定，从而能够区分CDI与无症状定植，以及鉴定处于复发性CDI风险中的患者。这种类型的诊断代表了优先的临床需求和主要的生物医学市场机会。我们还预计，新采用的核酸扩增检测大大高估了CDI的发病率。我们的初步数据表明，这类患者可能因明显的误诊而接受完全不适当的治疗选择，例如儿童粪便微生物群移植。