E. coli ST131-H30 colonization: defining community and population level antagonism in the gastrointestinal microbiome

大肠杆菌 ST131-H30 定植：定义胃肠道微生物群中的群落和群体水平拮抗作用

• 批准号: 9020203
• 负责人: Lance Bradley Price
• 金额: $ 18.19万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-20 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020203
• 关键词: Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Adhesion; Biological Assay; Case-Control Studies; Clinical; Clinical Management; Communities; Complex; Cross-Sectional Studies; Cyclophosphamide; Cystitis; Data; Decision Modeling; Decision Trees; Detection; Disease; Doctor of Philosophy; Effectiveness; Epidemiologic Studies; Epidemiology; Escherichia coli; Exclusion; Exposure to; Extended-spectrum β-lactamase; Frequencies; Future; Gastrointestinal tract structure; Goals; Health; Household; Human; Human Microbiome; In Vitro; Individual; Infection; Integration Host Factors; Investigation; Lead; Life; Longitudinal Studies; Mediating; Minor; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Natural Resistance; Nature; Outcome Study; Participant; Patients; Population; Predisposition; Preventive measure; Price; Probiotics; Production; Productivity; Public Health; Pyelonephritis; Research; Research Personnel; Resistance; Role; Science; Scientist; Site; Specimen; Structure; Taxon; Testing; United States National Institutes of Health; Virulent; Work; bacteriocin; base; beta-Lactamase; cohort; combat; commensal microbes; fluoroquinolone resistance; gastrointestinal; gastrointestinal bacteria; gut microbiome; innovation; killings; microbial community; microbiome; microbiota; multi-drug resistant pathogen; novel; novel strategies; pathogen; pathogenic Escherichia coli; pathogenic bacteria; prevent; resistant strain; stem; trait; transmission process; urinary

 DESCRIPTION (provided by applicant): A virulent subclone of E. coli sequence type 131 (ST131), called ST131-H30, has become the dominant extraintestinal pathogenic E. coli lineage in the US, where it kills thousands of patients each year. Multidrug resistance is a hallmark of ST131-H30-including production of the CTX-M-15 extended spectrum beta-lactamase (ESBL)-making its clinical management particularly challenging. The ability of ST131-H30 to colonize more frequently and persistently than other strains is thought to be important to its disproportional dis- ease burden. Yet, in our preliminary studies, we have observed that some people fail to become colonized with ST131-H30 despite prolonged household exposure. This strongly suggests that factors other than ST131- H30's intrinsic traits influence colonization. We know that, in the human GI tract, ST131-H30 does not live alone, but rather, as a minor component of a complex microbial community, within which it may be subjected to intense inter- and intra-species competition. In our previous microbiome studies of other body sites, we observed predictable relationships between commensal bacteria and opportunistic pathogens. This led us to hypothesize that distinct components of the GI microbiota, including bacteriocin-producing E. coli strains, may competitively exclude ST131-H30. Approach: By leveraging an ongoing longitudinal study of 600 participants, who will contribute > 7,000 fecal specimens, we will conduct two case-control studies to identify the microbiota unique to individuals who remain free of ST131-H30 for 12 months despite ongoing household exposure to ST131-H30 (elite non-colonizers), as compared to individuals with persistent colonization by ST131-H30 for 12 months (elite colonizers) and individuals who newly acquire ST131-H30 during the study (acquirers). We will identify bacterial species most predictive of resistance to ST131-H30 GI colonization using indicator species and decision tree analysis. The decision model will be validated using fecal microbiota data from an additional 300 participants from another cross-sectional survey. To explore intra-species competition, we will identify commensal E. coli strains antagonistic to ST131-H30 using in vitro inhibition assays, and will cross-validate the in vitro results by assessing the antagonistic strains' association with ST131-H30 exclusion using data from the longitudinal and cross-sectional cohorts. Innovation: Our approach is innovative in attempting to define mechanisms that influence GI colonization with ST131-H30; its focus on elite non-colonizers; its inter- and intra- species investigation of the microbiome within an ongoing longitudinal epidemiologic study; and its goal of identifying commensal bacteria antagonistic to a single virulent E. coli subclone. The expected outcome of this study is to identify commensal bacteria that can exclude ST131-H30 from the GI tract. With emerging resistance neutralizing the effectiveness our current antibiotic armamentarium, we must find new ways to prevent the spread of multidrug-resistant colonizing pathogens. These results could lead to novel, probiotic strategies for interrupting the transmission of ST131-H30 and future multidrug-resistant colonizing pathogens.

 描述（由适用提供）：一种称为ST131-H30的大肠杆菌序列（ST131）的有毒亚克隆，已成为美国的主要外部致病性大肠杆菌谱系，每年杀死数千名患者。 Multidrug抗性是CTX-M-15扩展频谱β-内酰胺酶（ESBL）（ESBL）的ST131-H30产生的标志 - 尤其具有挑战性。与其他菌株相比，ST131-H30更频繁，更持久地定居的能力对其不利的偏见很重要。然而，在我们的初步研究中，我们观察到，尽管家庭暴露延长，但有些人仍未被ST131-H30殖民。这强烈表明，除了ST131-H30的内在特征以外的其他因素会影响定殖。我们知道，在人类的胃肠道中，ST131-H30并不是一个人生活，而是作为复杂微生物群落的次要组成部分，在该社区中可能会受到激烈的跨性别竞争和激烈的竞争。在我们以前对其他身体部位的微生物组研究中，我们观察到共生细菌与机会性病原体之间的可预测关系。这导致我们假设胃肠道菌属的不同组成部分（包括造成细菌蛋白的大肠杆菌菌株）可能会竞争地排除ST131-H30。 Approach: By leveraging an ongoing longitudinal study of 600 participants, who will contribute > 7,000 fecal specimens, we will conduct two case-control studies to identify the microbiota unique to individuals who remain free of ST131-H30 for 12 months dopite ongoing household exposure to ST131-H30 (elite non-colonizers), as compared to individuals with persistent colonization by ST131-H30 for 12 months (elite殖民者）和在研究期间新近获取ST131-H30的个人（收购方）。我们将使用指标物种和决策树分析来确定最可预测对ST131-H30 GI定殖的抗性的细菌。决策模型将使用来自另一项横断面调查的另外300名参与者的粪便微生物群数据进行验证。为了探索种类内的竞争，我们将使用体外抑制作用评估来确定与ST131-H30拮抗与ST131-H30的竞争，并通过使用longududial和横截面组中的数据来评估拮抗菌株与ST131-H30排除量来评估拮抗菌株与ST131-H30排除的关联，从而跨验证体外结果。创新：我们的方法在试图定义影响gi殖民的机制方面具有创新性。它专注于精英非殖民者；它通过正在进行的纵向流行病学研究对微生物组进行了种类和内物种的投资；它的目的是鉴定与单个有毒大肠杆菌亚克隆拮抗的共生细菌。这项研究的预期结果是确定可以从GI区排除ST131-H30的共生细菌。随着新兴的抗性中和我们当前的抗生素武器群的有效性，我们必须找到新的方法来防止多药耐药的定殖病原体的传播。这些结果可能会导致新颖的益生菌策略，以中断ST131-H30的传播以及未来的多药抗性殖民病原体。