Impact of pet contact on antimicrobial-associated dysbiosis and Clostridioides difficile infection

项目总结 艰难梭状芽胞杆菌感染(CDI)是与医疗相关的最常见的原因之一 感染性腹泻并导致严重的发病率和死亡率。CDI发生在本机肠道 微生物组被破坏，最常见的是在抗菌治疗之后，随之而来的生物失调导致 微生物多样性减少，某些细菌类群的丰度发生变化，以及丧失定殖力 对艰难梭菌的耐药性。恢复“功能完整”的肠道微生物群对于清除C。 困难和不适当的修复可导致反复的CDI。从大米中回收肠道微生物 人们对生物失调知之甚少，而与拥有并重新获得能够 提供对艰难梭菌的定植抵抗力还不是很清楚。而动物蓄水池可以作为 潜在的病原菌来源，由候选人和其他调查人员研究发现，宠物 所有权可以防止艰难梭菌的定居和再次感染。此外，微生物区系是共享的 在宠物和它们的主人之间，宠物的微生物群包含提供定植的细菌分类群 对艰难梭菌的耐药性。基于这些数据，拟议的研究将1)检验以下假设： 观察到的宠物饲养的保护作用是由于共享提供定居的微生物群 宠物和主人对艰难梭菌的抵抗力；2)确定宠物接触是否会缓解 与抗菌剂相关的肠道微生物群的破坏并促进其恢复；以及3)评估 宠物接触降低抗菌药后艰难梭菌定植和感染的可能性 心理治疗。这将通过对患者/宠物的肠道微生物群进行纵向采样来实现。 60岁以上(即CDI风险最高)接受预防性抗菌药治疗的患者中的单位 非肠道适应症(牙种植体)。 这项研究将进一步确定CDI的流行病学和病理生理学特征， 加强对这种疾病的治疗选择。动物是保护动物的来源这一基本前提 微生物区系而不是艰难梭菌的储存库代表了CDI流行病学的范式转变，可能 确定动物接触是一种新的基于微生物组的治疗形式。拟议的研究将形成一个 为独立从事以患者为中心的研究奠定基础，致力于理解和缓解 抗菌素相关的生物失调和CDI。候选人将获得执导一部大型、 高级统计和生物信息学方法的观察性微生物组研究和基本培训 有必要分析患者水平的因素与微生物生态之间的相互作用。这项研究 建议与利用大学广泛资源的职业发展计划相匹配 这充分利用了一个最好的指导委员会，该委员会具有广泛的互补性 在传染病流行病学、深度测序方法、生物信息学和微生物学方面的专业知识。

PROJECT SUMMARY Clostridioides difficile infection (CDI) is one of the most common causes of healthcare-associated infectious diarrhea and results in significant morbidity and mortality. CDI occurs when the native gut microbiome is disrupted, most often following antimicrobial therapy, and the consequent dysbiosis results in a decrease in microbial diversity, changes in abundance of certain bacterial taxa, and loss of colonization resistance against C. difficile. Restoration of a “functionally intact” gut microbiome is critical to clearing C. difficile, and inadequate restoration can lead to recurrent CDI. The recovery of the gut microbiome from dysbiosis is poorly understood, and factors associated with having and re-gaining a microbiome capable of providing colonization resistance against C. difficile are not well known. While animal reservoirs can serve as potential sources of pathogenic bacteria, studies by the candidate and other investigators found that pet ownership protects against colonization and re-infection with C. difficile. Moreover, microbiota are shared between pets and their owners, and the microbiomes of pets contain bacterial taxa that provide colonization resistance against C. difficile. Based on these data, the proposed research will 1) test the hypothesis that the observed protective effects of pet ownership are due to sharing of microbiota that provide colonization resistance against C. difficile between pets and owners; 2) determine whether pet contact mitigates antimicrobial-associated disruption of the gut microbiome and enhances its recovery; and 3) assess whether pet contact decreases the likelihood of colonization and infection with C. difficile following antimicrobial therapy. This will be accomplished though longitudinal sampling of the gut microbiome within the patient/pet unit among patients older than 60 years (i.e., at greatest risk of CDI) receiving prophylactic antimicrobials for non-enteric indications (dental implants). The study will further define epidemiologic and pathophysiologic characteristics of CDI that could enhance therapeutic options for this disease. The underlying premise that animals are a source of protective microbiota rather than a reservoir of C. difficile represents a paradigm shift in CDI epidemiology that may identify animal contact as a novel microbiome-based form of therapy. The proposed study will form a foundation for an independent career in patient-oriented research dedicated to understanding and mitigating antimicrobial-associated dysbiosis and CDI. The candidate will acquire experience in directing a large, observational microbiome study and essential training in the advanced statistical and bioinformatics methods necessary to analyze the interaction between patient-level factors and microbial ecology. The research proposal is paired with a career development plan that makes use of the extensive resources of the University of Pennsylvania and that capitalizes on a superlative mentoring committee with broad, complementary expertise in infectious diseases epidemiology, deep sequencing methods, bioinformatics, and microbiology.