The microbiome and aging in Clostridioides difficile infection

艰难梭菌感染中的微生物组和衰老

• 批准号: 10442824
• 负责人: VINCENT B YOUNG
• 金额: $ 73.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442824
• 关键词: Address; Adipose tissue; Affect; Age; Aging; Animal Model; Animals; Antibiotics; Bioinformatics; Biological Models; Breeding; Cardiovascular Diseases; Chronic; Clinical; Clostridium difficile; Communicable Diseases; Development; Diabetes Mellitus; Digestion; Disease; Disease Outcome; Disease model; Ecosystem; Elderly; Environment; Exhibits; Food; Fostering; Geriatrics; Germ-Free; Goals; Health; Immune; Immune response; Immune system; Immunology; Indigenous; Individual; Infection; Inflammation; Investigation; Longevity; Malignant Neoplasms; Mediating; Microbiology; Modeling; Morbidity - disease rate; Mus; Neurodegenerative Disorders; Obesity; Organism; Outcome; Phenotype; Physiology; Play; Predisposition; Prevention; Recurrence; Resources; Risk; Role; Severities; Severity of illness; Shapes; Structure; Testing; Therapeutic; Work; adverse outcome; age effect; age related; aged; experience; experimental study; fecal transplantation; frailty; gut microbiota; host microbiota; host-microbe interactions; improved; insight; microbiome; microbiome research; microbiota; microbiota transplantation; mortality; mouse model; novel; older patient; pathogen; pathogenic bacteria; restoration; senescence

ABSTRACT The indigenous microbiota plays a critical role in the health of their host by contributing to an ecosystem (the microbiome) that reflects a stable environment shaped by the host and the resident microbes. Normal resident microbes contribute to homeostatic functions including fostering immune system maturation, protecting against pathogen invasion and assisting digestion of food. Conversely, many age-associated conditions such as cardiovascular disease, neurodegenerative diseases, cancer and diabetes have been associated with abnormal host-microbe interactions. The ultimate goal of this work is to develop therapeutic strategies and tactics that permit us to foster beneficial host-microbe interactions and improve disease outcomes in older adults. In order to accomplish this goal, we need to understand how the microbiota changes over the lifespan of the individual and how this alters host function. The specific objective of this proposal is to understand how age-related changes in the microbiota alters susceptibility to outcomes of infection with the pathogen Clostridioides difficile. C. difficile infection (CDI) following disruption of the gut microbiota due to antibiotic administration causes significant morbidity and mortality. Elderly patients are more susceptible to CDI and are at increased risk of developing disease-related complications following infection. We hypothesize that changes in the microbiota and host related to aging underlie the increased susceptibility to CDI that contributes to worse outcome of infection in older adults. We will test our hypothesis with 3 specific aims conducted in a robust animal model of CDI. 1) Compare and contrast the structure and function of the microbiome over the age range of mice. 2) Determine the role that the microbiome has on shaping host immune responses related to age using CDI as a model disease condition. 3) Investigate the possibility of manipulating the host and the indigenous microbiota to alter health and disease. In this proposal, we intend to perform detailed investigations on the effects of aging on the microbiome and the outcome of C. difficile infection. We will leverage a murine model of CDI for these studies. The results of these studies should provide important insights on the relationship between advancing age, the host and the microbiota that could improve our ability to deal with CDI and other conditions that are influenced by the microbiota over the lifespan.

摘要 本土微生物区系对寄主的健康起着至关重要的作用，因为它们对生态系统( 微生物群)，反映了由寄主和驻留微生物形成的稳定环境。常住居民 微生物有助于体内平衡功能，包括促进免疫系统成熟，保护 病原体入侵和帮助食物消化。相反，许多与年龄相关的疾病，如 心血管疾病、神经退行性疾病、癌症和糖尿病与异常 宿主与微生物的相互作用。这项工作的最终目标是开发治疗战略和战术， 使我们能够促进有益的宿主-微生物相互作用，并改善老年人的疾病结局。按顺序 为了实现这一目标，我们需要了解微生物区系在人的一生中如何变化 以及这是如何改变宿主功能的。这项建议的具体目标是了解与年龄有关的 微生物区系的变化改变了对艰难梭状芽胞杆菌感染结果的敏感性。 艰难梭菌感染(CDI)--抗生素给药引起肠道微生物区系紊乱 严重的发病率和死亡率。老年患者更容易患CDI，并有更高的风险 感染后出现与疾病相关的并发症。我们假设微生物区系的变化和 与衰老相关的宿主对CDI的易感性增加，从而导致更糟糕的感染结果 在老年人身上。我们将在一个健壮的CDI动物模型中用3个特定的目标来检验我们的假设。1) 比较和对比不同年龄段小鼠的微生物组的结构和功能。2)确定 以CDI为模型疾病的微生物群在塑造与年龄相关的宿主免疫反应中的作用 条件。3)调查操纵宿主和本土微生物区系以改变健康和 疾病。在这项建议中，我们打算对老化对微生物组的影响进行详细的调查 艰难梭菌感染的结局。我们将利用CDI的小鼠模型进行这些研究。结果是 这些研究应该为年龄增长、宿主和健康之间的关系提供重要的见解 微生物区系，可以提高我们处理CDI和其他受 整个生命周期中的微生物区系。