Aging Microbiome, Immunosenescence, and risk of Multi-drug Resistant Organism Colonization and Infection in the Nursing Home

摘要 多重耐药微生物（MDRO）是对一种以上抗菌剂产生耐药性的细菌 剂肠道MDRO对公共卫生构成重大威胁，因为它们越来越难以治疗 并且当它们扩散到肠道外时导致成本、发病率和死亡率增加。艰难梭菌 与MDRO具有许多相同的特征，并与MDRO沿着被中心标记为 将疾病控制和预防作为国家优先事项。没有任何一个群体比其他人更容易患上这些肠道MDRO 比疗养院的居民更好一个脆弱的老年人群体的完美风暴， 社区，细菌感染的发病率和死亡率增加， MDRO殖民强调养老院作为研究的优先设置的重要性，以减少 MRDO负担。肠道微生物组可能是一个关键因素，因为它影响了新生的可能性， 殖民化以及殖民化是否导致疾病。在本提案中，我们将：1）确定 使用新型快速菌株特异性技术（分子反转）在疗养院社区中的关键MDRO 探针）; 2）评估病原生物体的传播; 3）在体内/体外确定衰老如何影响细胞的生长。 微生物组可以诱导肠道炎症，从而促进MDRO定殖;以及4）确定微生物组中的微生物。 微生物生态失调和免疫衰老增加MDRO定植风险的程度， 感染和虚弱恶化我们假设环境和临床因素（例如，药物） NH环境的特征有助于并形成有利于增加感染风险的生态失调微生物组。 MDRO殖民化。我们进一步假设，微生物生态失调的程度将是主要的贡献者。 MDRO定植，从而提供了一个新的目标，以打击病原体流行的NH环境。 具体来说，在目标1中，我们将开发和实施一种免培养、高通量、低成本的方法， 提供MDRO的深层菌株水平分辨率，并加速传染病的流行病学研究。 此外，我们还将推导出一种基于微生物组的预测工具NH-MDI，以评估MDRO的个体风险。 殖民化目的2将确定微生物组影响上皮细胞的机制， 因此，本发明提供了一种维持体内平衡的方法，从而提供了支持MDRO定殖的结肠微环境。目标3将包括 对来自前瞻性疗养院队列的粪便和血液样本进行分析，以确定 衰老微生物群生态失调对MDRO风险增加的免疫衰老标志物的贡献 殖民化以及脆弱性恶化的风险。此外，我们将确定生态失调的程度， 免疫衰老与18个月随访中未来感染的风险相关。定义这些关键 这些参数将为开发旨在预防糖尿病的新型微生物组疗法提供基础。 养老院感染和促进健康老龄化。为此，我们将进一步开发新的方法， 鉴定出上级于现有诊断方法的传染性微生物。

ABSTRACT Multidrug resistant organisms (MDROs) are bacteria that have become resistant to more than one antimicrobial agent. Intestinal MDROs constitute a major threat to public health because they are increasingly difficult to treat and result in increased costs, morbidity, and mortality when they spread outside of the gut. Clostridium difficile shares many of the same characteristics as MDROs and along with MDROs has been labeled by the Centers for Disease Control and Prevention as a national priority. No group suffers more from these intestinal MDROs than nursing home residents. The perfect storm of a vulnerable group of frail older adults living in close communities, with increased morbidity and mortality from bacterial infections, and corresponding high rates of MDRO colonization emphasize the importance of the nursing home as a priority setting for studies to reduce MRDO burden. The intestinal microbiome may be a key factor as it influences both the likelihood of de novo colonization and whether colonization results in disease. In this proposal we will: 1) determine carriage rates of key MDROs in nursing homes communities using novel rapid strain-specific technology (molecular inversion probes); 2) assess the dissemination of pathogenic organisms; 3) determine in vivo/vitro how an aging microbiome can induce intestinal inflammation, thus promoting MDRO colonization; and 4) determining the extent to which both microbial dysbiosis and immunosenescence increases the risk of MDRO colonization, infection, and worsening frailty. We hypothesize that environmental and clinical factors (e.g., medication) characteristic of the NH settings contribute to and shape a dysbiotic microbiome that favors an increased risk of MDRO colonization. We further hypothesize the extent of microbial dysbiosis will be the major contributor of MDRO colonization, thus providing a novel target to combat pathogen prevalence within the NH environment. Specifically, in Aim 1 we will develop and implement a cultivation-free, high-throughput, low-cost approach to provide deep strain-level resolution of MDROs and accelerate epidemiological studies of infectious diseases. Further we will derive a microbiome-based predictive tool, the NH-MDI, to assess individual risk of MDRO colonization. Aim 2 will determine the mechanisms by which the microbiome can influence epithelial homeostasis, thus providing a colonic microenvironment supportive of MDRO colonization. Aim 3 will include analysis of stool and blood samples from a prospective nursing home cohort in order to determine the relative contribution of aging microbiome dysbiosis to markers of immunosenescence for increased risk of MDRO colonization as well as risk of worsening frailty. Further, we will determine the extent that dysbiosis and immunosenescence correlates with risk of future infection over 18 months of follow-up. Defining these crucial parameters will provide the basis for development of novel microbiome therapeutics aimed at the prevention of nursing home infections and promoting healthy aging. In doing so, we will further develop novel approaches to identify infectious organisms that will be superior to current diagnostic methods.