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; 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 多药耐药生物（MDROS）是对多种抗菌抗菌具有抗性的细菌 代理人。肠道MDRO构成对公共卫生的主要威胁，因为它们越来越难以治疗 并在肠道以外散布时会增加成本，发病率和死亡率。艰难梭菌 与MDROS具有许多相同的特征，并与MDROS一起被中心标记 作为疾病控制和预防作为国家优先事项。这些肠道MDROS没有更多的组 比养老院居民。一群脆弱的老年人的完美风暴 社区，细菌感染的发病率和死亡率增加，相应的高率 MDRO殖民化强调了疗养院作为研究的优先设置的重要性 MRDO负担。肠道微生物组可能是一个关键因素，因为它既影响从头的可能性 定植以及定植是否导致疾病。在此提案中，我们将：1）确定 使用新型快速应变特异性技术（分子反演）的疗养院社区中的关键MDRO 探针）; 2）评估病原生物的传播； 3）确定体内/体外如何衰老 微生物组可以诱导肠道炎症，从而促进MDRO定植。 4）确定 微生物营养不良和免疫衰老的程度增加了MDRO定殖的风险， 感染，脆弱。我们假设环境和临床因素（例如，药物） NH设置的特征有助于并塑造不植物的微生物组，从而有利于增加的风险 MDRO定殖。我们进一步假设微生物营养不良的程度将是 MDRO定殖，因此提供了一个新的靶标，可以打击NH环境中病原体患病率。 具体而言，在AIM 1中，我们将开发和实施一种无种植，高通量，低成本的方法 提供有关MDROS的深度应变水平分辨率和对传染病的加速流行病学研究。 此外，我们将得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。 AIM 2将确定微生物组可以影响上皮的机制 体内平衡，从而提供了一个结肠微环境，支持MDRO定植。 AIM 3将包括 对前瞻性疗养院队列的粪便和血液样本的分析，以确定相对 衰老微生物组营养不良对免疫衰老标志物的贡献增加了MDRO的风险 殖民化以及脆弱的风险。此外，我们将确定营养不良和 免疫衰老与在18个月的随访中发生未来感染的风险相关。定义这些关键 参数将为开发旨在预防的新型微生物组疗法的发展提供基础 疗养院感染并促进健康的衰老。这样，我们将进一步开发出新颖的方法 确定将优于当前诊断方法优越的传染性生物。