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

 描述（由申请方提供）：E.大肠杆菌序列型131（ST 131），又称ST 131-H30，已成为大肠杆菌的优势肠外致病菌。在美国，它每年杀死数千名患者。多药耐药性是ST 131-H30的一个标志-包括产生CTX-M-15超广谱β-内酰胺酶（ESBL）-使其临床管理特别具有挑战性。ST 131-H30比其他菌株更频繁和持久地定殖的能力被认为是其不成比例的疾病负担的重要原因。然而，在我们的初步研究中，我们观察到一些人尽管长期家庭暴露，但未能成为ST 131-H30的定植者。这有力地表明，除了ST 131- H30的内在性状之外的因素影响定殖。我们知道，在人类胃肠道中，ST 131-H30并不单独存在，而是作为复杂微生物群落的一个次要组成部分，在其中它可能会受到激烈的种间和种内竞争。在我们之前对其他身体部位的微生物组研究中，我们观察到了肠道细菌和机会致病菌之间可预测的关系。这使我们假设胃肠道微生物群的不同组成部分，包括产生细菌素的E。大肠杆菌菌株，可以竞争性排除ST 131-H30。方法：通过利用600名参与者正在进行的纵向研究，他们将提供> 7，000份粪便标本，我们将进行两项病例对照研究，以确定尽管家庭持续暴露于ST 131-H30，但仍保持12个月无ST 131-H30的个体的独特微生物群与ST 131-H30持续定殖12个月的个体（精英定殖者）和在研究期间新获得ST 131-H30的个体（获得者）相比，我们将使用指示菌种和决策树分析来鉴定对ST 131-H30 GI定殖的抗性最具预测性的菌种。该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。为了探讨种内竞争，我们将确定Escherosal E。使用体外抑制测定来鉴定对ST 131-H30具有拮抗作用的大肠杆菌菌株，并且将通过使用来自纵向和横截面群组的数据评估拮抗菌株与ST 131-H30排除的关联来交叉验证体外结果。创新：我们的方法是创新的，试图定义影响ST 131-H30的GI定植的机制;其重点是精英非定植者;其在正在进行的纵向流行病学研究中的微生物组的种间和种内调查;以及其鉴定对单一毒性E. coli亚克隆。本研究的预期结果是鉴定可以将ST 131-H30从胃肠道排除的肠道细菌。随着新出现的耐药性中和了我们目前抗生素的有效性，我们必须找到新的方法来防止多药耐药定植病原体的传播。这些结果可能导致新的益生菌策略，用于中断ST 131-H30和未来多重耐药定植病原体的传播。

 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.