Host distribution of intra- and inter-cellular mobile genetic elements in complex microbial communities

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The increasing prevalence of antimicrobial resistance (AMR) in bacteria is a global health crisis. The animal microbiota is a recognized hot spot of horizontal gene transfer (HGT) of AMR genes as it includes both susceptible and antimicrobial resistant commensal bacteria as well as diverse potentially pathogenic species. Understanding the evolution and persistence of mobile AMR determinants within the animal microbiota is imperative to address the dissemination of AMR in a One Health framework, inform policies to effectively mitigate AMR emergence, and evaluate how reducing antimicrobial use will impact persistence of established mobile AMR determinants after selection is removed. Although the use of non-therapeutic antimicrobials has been restricted in agriculture, AMR will continue to be a concern since high levels of resistance have been established over several decades, and therapeutic use of antibiotics will continue to be necessary in order to ensure the health and humane treatment of production animals. Emergence of AMR genes in pathogenic bacteria occurs by two different mechanisms of mobility - movement between genomic locations within a bacterial cell and transfer between two different bacteria. Typically, a previously unknown AMR gene first becomes associated with an intra-cellular mobile genetic element (MGE) that can facilitate movement to different sites within the original bacterial genome. Through these movements, the resistance gene can get mobilized into a larger inter-cellular MGE, such as a plasmid, which can facilitate transfer to a new bacterial host. These events commonly originate in commensal or environmental bacteria and exposure to antimicrobials drives the selection of strains harboring the AMR gene. Continued selection pressure results in dissemination to diverse taxa and favors the emergence of more successful MGE-AMR combinations as evidenced by the increasing prevalence of multi-drug resistant plasmids. My research program aims to identify the host distribution of both intra-cellular and inter-cellular MGEs in complex microbial communities and identify pathways of MGE dissemination that can help predict AMR emergence. I will use culture-enriched metagenomics and proximity ligation sequencing to examine the distribution of MGEs, focusing on swine gut communities due to the known prevalence of AMR and relevance to the pork industry. I will also develop a unified MGE ontology and classification pipeline for metagenomic data and develop methods for testing the mobility of novel MGEs that have yet to be experimentally characterized. I will use these methods to identify and classify MGEs in the swine gut and subsequently to measure changes in the abundance and dissemination of these MGEs in response to antimicrobial use. This research takes a community approach to understanding HGT within the swine microbiota and the evolutionary changes that occur under antibiotic selection in agricultural systems.