Critical functions of the gut microbiota that mediate recovery from recurrent Clostridium difficile infection

摘要 复发性艰难梭菌感染（CDI）影响20-30%的患者， 最初的疾病发作。假设肠道微生物群，即肠道内的微生物群落， 胃肠道，参与复发的发展和恢复。基于微生物的 促进“健康”细菌生长的治疗，如粪便微生物群移植（FMT）， 成为复发性CDI的有效治疗方法。然而，从根本上说， 了解微生物负责的功能，有助于殖民抵抗C。 很难我们对反复感染的小鼠模型进行了表征，并观察到小鼠粪便物质 来自健康小鼠的能够介导C.很难以前的研究使用无菌 小鼠已经成功地建立了针对C.与人类微生物群的关系。相反 对此，我们观察到来自健康人的FMT在我们的模型中不能解决CDI。虽然FMT 在处理改变了微生物群组成的情况下，我们观察到几种代谢物的水平不足。我们 复发性CDI的小鼠模型为我们提供了一种了解群落结构如何组装的方法 提供对CDI的定殖抗性，使我们能够区分 对C.很难我们假设限制C.艰难 定植和生长依赖于简洁的微生物群群落的组装。科学 本提案的目的是阐明微生物群落的结构和功能之间的联系 能够介导对CDI的抗性或从CDI中恢复。我们的目标是通过以下具体目标来实现这一目标：1） 定义介导对C.（2）困难; 确定微生物群落中分解CDI的代谢途径。本建议的培训目标是 以补充学员的微生物生态学背景与生物信息学和实验技能， 关注微生物群落的功能，以支持候选人过渡到独立的， 翻译研究员完成这些目标将使您更全面地了解如何 微生物的功能是提供定植抗性，帮助预防或治疗CDI的迫切需要， 重要的卫生保健相关感染。与杰出的指导团队和机构合作， 在环境中，该提案将为候选人提供科学技能和职业指导，使其成为一名 在一个跨学科领域的独立调查员，包括微生物生态学和感染 疾病

ABSTRACT Recurrent Clostridium difficile infection (CDI) affects 20-30% of patients following successful treatment of an initial disease episode. It is hypothesized that the gut microbiota, the microbial community within the gastrointestinal tract, is involved in the development of and recovery from recurrence. Microbial-based treatments that promote the growth of `healthy' bacteria, such as fecal microbiota transplantation (FMT), have emerged as an effective treatment method for recurrent CDI. Nevertheless, there is a fundamental lack of knowledge of the microbes responsible for functions that contribute to colonization resistance against C. difficile. We have characterized a murine model of recurrent infection, and observed that murine fecal material from healthy mice is capable of mediating efficient clearance of C. difficile. Previous studies using germ-free mice have successfully established colonization resistance against C. difficile with human microbiota. Contrary to this, we observed that FMT from healthy humans did not resolve CDI in our model. While both FMT treatments changed the microbiota composition, we observed deficient levels of several metabolites. Our mouse model of recurrent CDI provides us with a method to understand how community structures assemble to provide colonization resistance against CDI, enabling us to differentiate the critical microbial features in colonization resistance against C. difficile. We hypothesize that the metabolic environment that limits C. difficile colonization and growth is dependent on the assembly of succinct microbiota communities. The scientific objective of this proposal is to elucidate the link between the structure and function of a microbial community capable of mediating resistance to or recovery from CDI. We aim to do this using the following specific aims: 1) define structural features in microbial communities that mediate colonization resistance to C. difficile and 2) identify metabolic pathways in microbial communities that resolve CDI. The training objective of this proposal is to complement the trainee's background in microbial ecology with bioinformatic and experimental skills that focus on functions of microbial communities to support transition of the candidate into an independent, translational investigator. Completion of these aims will result in more comprehensive knowledge of how microbes function to provide colonization resistance, aiding the critical need to prevent or treat CDI, an important healthcare-associated infection. In conjunction with the exceptional mentoring team and institutional environment, this proposal will provide the candidate with scientific skills and career mentorship to become an independent investigator in an inter-disciplinary field encompassing both microbial ecology and infectious disease.