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: 8822617
• 负责人: Tor C. Savidge
• 金额: $ 23.6万
• 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/8822617
• 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; 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; 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; 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 γ-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（由适用提供）：艰难梭菌是美国医院感染的主要原因，超过了抗抗生素的葡萄球菌和肠球菌。由于常见的患者危险因素，艰难梭菌感染（CDI）的高患病率（CDI）代表了医院和长期护理设施的主要健康问题；明显的高龄和合并症，抗菌素的使用和困难艰难梭菌 孢子消毒。新出现的高呼吸性艰难梭菌菌株也有助于CDI升级，导致疾病的严重程度和死亡率增加。此外，有35％的患者会经历复发性CDI，这是一个重大的临床问题，通常会导致临床结果不佳。尽管CDI的早期诊断对于最佳的临床管理和改善的预后至关重要，但准确预测CDI复发的诊断测定不存在，并且复发性CDI的危险因素仍然难以捉摸。 CDI复发的高频率以及未经迅速有效治疗的病例的临床结果差，强调了可以识别可以将可以发展为新诊断测定的疾病复发的准确生物标志物的需求。这是我们研究的主要目标。尽管已知受保护的肠道菌群的抗菌破坏与受感染个体的症状发展密切相关，但我们对CDI敏感性和复发性的理解仍然存在一个主要差距。在此修订后的应用中，我们证明了下一代DNA测序与全局代谢组学与微生物生态系统网络的集成为发现新的诊断和治疗方案提供了一个分析框架，以重复进行CDI。我们的多词方法的重要性是鉴定候选16S rRNA和生物化学生物标志物在继续发展复发性疾病的原发性CDI患者中（错误分类率为12％）。这些多词的研究导致了CDI患者的以下新观察：“使用基于分子的测试诊断CDI时，主要潜在缺乏症的鉴定。当使用敏感的核酸扩增测试时，指示了54％的误诊率，这些测试无法将CDI无法区分CDI与非对称C.艰难载体的识别和基于我们的γ-氨基酸的鉴定（GAB）的鉴定。 CDI复发的候选生物标志物，在住院的患者Zolpidem（Ambien）（GABA受体A激动剂）处开处方的患者中发现了4.88倍的CDI风险关联。 AIM 1的目标是验证较大的200个基于200名患者的队列中CDI复发的候选16S rRNA生物标志物，并将这些发现与临床元数据相关联。对于AIM 2，我们希望在同一200患者队列中验证CDI复发的候选代谢组生物标志物，并进行多摩变分析。我们预计单独或组合的多摩变生物标志物将准确预测CDI复发。考虑到完全缺乏复发性CDI诊断测定法，我们旨在开发一种或多种生物标志物作为黄金标准方法，该方法将验证其他具有不对称定殖的CDI分化的其他成本效益测定法，并鉴定出患有再生CDI风险的患者。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，新近采用的核酸扩增测试是高估了CDI事件的巨大估计。我们的初步数据表明，此类患者可能因明显误诊而导致的完全不适当的治疗选择，例如儿童的粪便菌群移植。