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

疗养院微生物群老化、免疫衰老以及多重耐药微生物定植和感染的风险

• 批准号: 10584709
• 负责人: Vanni Bucci
• 金额: $ 71.82万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584709
• 关键词: Acceleration; Address; Affect; Age; Aging; Algorithms; Antibiotics; Bacteria; Bacterial Infections; Blood specimen; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic; Clinical; Clostridium difficile; Colon; Colonic inflammation; Communicable Diseases; Communities; Data; Data Collection; Deterioration; Development; Diagnostic Procedure; Disease; Elderly; Enrollment; Epithelium; Exhibits; Frail Elderly; Functional disorder; Future; Genomics; Genotype; Goals; Health; Health Policy; High Prevalence; High-Throughput Nucleotide Sequencing; Home environment; Homeostasis; Immune System Diseases; Immune system; In Vitro; Individual; Infection; Infectious Agent; Inflammaging; Inflammation; Inflammatory; Intervention; Intestines; Knowledge; Label; Methods; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Nursing Homes; Organism; Organism Strains; Pathogenicity; Performance; Peripheral; Pharmaceutical Preparations; Population; Predisposition; Prevalence; Prevention; Public Health; Residencies; Resistance; Resolution; Risk; Risk Factors; Sampling; Shapes; Site; System; T-Lymphocyte; Technology; Testing; Time; Vulnerable Populations; age related; antimicrobial drug; cohort; combat; cost; cost effective; dysbiosis; epidemiology study; follow-up; frailty; gut colonization; gut dysbiosis; gut inflammation; gut microbiome; healthy aging; host microbiome; immune function; immunosenescence; improved; in vivo; indexing; intestinal epithelium; large scale data; microbial; microbiome; microbiome alteration; microbiome analysis; microbiome composition; microbiome signature; microbiome therapeutics; mortality; multi-drug resistant pathogen; novel; novel strategies; pathogen; pathogenic microbe; predictive tools; prevent; prospective; residence; risk prediction; stool sample; systemic inflammatory response; transmission process

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.

抽象的 多重耐药微生物 (MDRO) 是对一种以上抗菌药物产生耐药性的细菌 代理人。肠道多重耐药菌对公共健康构成重大威胁，因为它们越来越难以治疗 当它们扩散到肠道外时，会导致成本、发病率和死亡率增加。艰难梭菌 与 MDRO 具有许多相同的特征，并且与 MDRO 一起被中心标记 将疾病控制和预防作为国家优先事项。没有哪个群体遭受这些肠道多重耐药菌的影响更大 比疗养院的居民。一群住在附近的体弱老年人的完美风暴 社区，细菌感染的发病率和死亡率增加，相应的感染率也很高 MDRO 定植强调了疗养院作为研究优先场所的重要性，以减少 MRDO 负担。肠道微生物组可能是一个关键因素，因为它影响从头发生的可能性 定植以及定植是否导致疾病。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 探针）； 2）评估病原生物的传播； 3) 确定体内/体外衰老的方式 微生物组可诱发肠道炎症，从而促进 MDRO 定植； 4) 确定 微生物失调和免疫衰老在多大程度上增加了 MDRO 定植的风险， 感染，身体虚弱恶化。我们假设环境和临床因素（例如药物） NH 环境的特征会导致并形成失调的微生物组，从而有利于增加感染的风险 MDRO定植。我们进一步假设微生物失调的程度将是 MDRO 定植，从而为在新罕布什尔州环境中对抗病原体流行提供了一个新的目标。 具体来说，在目标 1 中，我们将开发并实施一种免培养、高通量、低成本的方法 提供多重耐药菌的深度菌株水平分辨率并加速传染病的流行病学研究。 此外，我们将推导出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。目标 2 将确定微生物组影响上皮细胞的机制 体内平衡，从而提供支持 MDRO 定植的结肠微环境。目标 3 将包括 对前瞻性疗养院队列的粪便和血液样本进行分析，以确定相对 衰老微生物群失调对免疫衰老标志物的影响，导致 MDRO 风险增加 定植以及虚弱恶化的风险。此外，我们将确定生态失调和 免疫衰老与 18 个月随访期间未来感染的风险相关。定义这些关键的 参数将为开发旨在预防的新型微生物组疗法提供基础 疗养院感染和促进健康老龄化。在此过程中，我们将进一步开发新方法 识别优于当前诊断方法的传染性生物体。