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.

抽象的 土著菌群通过促进生态系统（该生态系统）在其宿主的健康中起着至关重要的作用（ 微生物组）反映了由宿主和驻留微生物塑造的稳定环境。普通居民 微生物有助于稳态功能，包括促进免疫系统成熟，防止 病原体入侵并协助食物消化。相反，许多与年龄相关的条件，例如 心血管疾病，神经退行性疾病，癌症和糖尿病与异常有关 宿主 - 微鸟相互作用。这项工作的最终目标是制定治疗策略和策略 允许我们促进有益的宿主 - 微生物相互作用并改善老年人的疾病结局。为了 为了实现这一目标，我们需要了解微生物群在个人的寿命中如何变化 以及该如何改变主机功能。该提议的具体目标是了解与年龄相关的方式 微生物群的变化改变了对梭状芽胞杆菌艰难梭菌感染结果的敏感性。 艰难梭菌感染（CDI）因抗生素给药原因而破坏肠道菌群后 显着的发病率和死亡率。老年患者更容易受到CDI的影响，并且有增加的风险 感染后发展与疾病有关的并发症。我们假设微生物群和 与衰老有关的宿主是对CDI的敏感性增加的构成，这会导致感染结果较差 在老年人中。我们将以3个在CDI的鲁棒动物模型中进行的3个特定目标来检验我们的假设。 1） 在小鼠的年龄范围内比较和对比微生物组的结构和功能。 2）确定 微生物组在使用CDI作为模型疾病的年龄相关的宿主免疫反应中的作用 健康）状况。 3）调查操纵宿主和土著微生物群以改变健康的可能性 疾病。在此提案中，我们打算对衰老对微生物组的影响进行详细研究 以及艰难梭菌感染的结果。我们将利用CDI的鼠模型进行这些研究。结果 这些研究应提供有关晋级年龄，宿主与宿主之间关系的重要见解 微生物群可以提高我们应对CDI和其他受到影响的能力 寿命中的微生物群。