The increase in community-associated (human) Clostridioides difficile infections (CDI) and detection of genetically similar, toxigenic C. difficile (CD) isolates in asymptomatic pets and humans suggest the potential role of household pets in the spread of CDI in humans. However, in-depth studies on pet CD carriage, the prevalence rate of CD in pet-owner pairs, and evolutionary and transmission dynamics of CD in the pet-human-environment interfaces are lacking. Without filling this knowledge gap, understanding the role of pets in community-associated CDI in humans and the development of control strategies against community-acquired CDI would be difficult. The long-term goal is to delineate the source of human CDI in the community. The overall objective is to determine the prevalence of CD in pets and model the transmission and evolutionary dynamics of CD, which has distinct human, animal, and gut-microbial ecology components. Our central hypothesis is that dogs and cats act as a reservoir for human community-associated CDI, and the pet-human interfaces in a community drive the interhost adaptation and transmission of CDI in humans. The rationale for the proposed research is that, once it is known whether and how the pet-human-environment interfaces play a role in CDI transmission, appropriate strategies can be developed to prevent community-associated CDI in humans. The central hypothesis will be tested by pursuing the following specific aims: 1: Determine the prevalence of CD in dogs, cats, and humans in different pet-human interfaces; 2: Determine the genetic relationship of CD in pets and humans isolated at different settings and evaluate potential zoonotic transmission pathways using whole-genome sequence- based phylo-genomics; 3: Determine shared and specific gut bacterial ecological variations in pets and humans that permit or exclude CD colonization; 4: Model CD transmission dynamics at pet-human interfaces in different eco-epidemiological settings. We will develop a spatial-explicit stochastic agent-based model to understand CD transmission dynamics under diverse epidemiological settings. In addition, CD from paired pet-human populations will be subjected to whole-genome sequencing to determine the evolution and transmission dynamics in the pet-human interface. Furthermore, the influence of gut microbial ecology on CD colonization in paired human-pet cohorts will be determined; machine learning modeling will determine microbial species associations that favor CD colonization. The results are expected to provide the epidemiologic, genomic, and social basis for the pet-borne transmission of CDI.
