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

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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.