The microbiome and aging in Clostridioides difficile infection

摘要 土著微生物群通过促进生态系统（即 微生物组），其反映了由宿主和常驻微生物形成的稳定环境。普通的居民房需要 微生物有助于体内平衡功能，包括促进免疫系统成熟， 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、癌症和糖尿病已经与异常 宿主-微生物相互作用这项工作的最终目标是制定治疗策略和战术， 使我们能够促进有益的宿主-微生物相互作用，改善老年人的疾病结果。为了 为了实现这一目标，我们需要了解微生物群在个体生命周期中的变化 以及这如何改变宿主功能。本提案的具体目标是了解与年龄有关的 微生物群的变化改变了对病原体艰难梭菌感染结果的易感性。 C.由于抗生素给药原因导致肠道微生物群破坏后的艰难梭菌感染（CDI） 严重的发病率和死亡率。老年患者更容易患CDI， 感染后出现疾病相关并发症。我们假设微生物群的变化和 与衰老相关的宿主对CDI的易感性增加，导致感染结果更差 在老年人中。我们将通过在稳健的CDI动物模型中进行的3个特定目标来检验我们的假设。第一章 比较和对比小鼠年龄范围内微生物组的结构和功能。2)确定 微生物组在形成与年龄相关的宿主免疫反应方面的作用，使用CDI作为模型疾病 条件3)调查操纵宿主和本地微生物群以改变健康的可能性， 疾病在这项提案中，我们打算对衰老对微生物组的影响进行详细调查。 和C.艰难感染我们将利用CDI的小鼠模型进行这些研究。结果 这些研究应该提供重要的见解之间的关系，年龄增长，主机和 微生物群，可以提高我们处理CDI和其他条件的能力， 微生物群落的变化。

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.