Thesis defense Matteo Buffoni

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Addressing antimicrobial resistance (AMR) demands a comprehensive, integrated One Health approach, acknowledging the critical interconnectedness of human, animal, and environmental health. This PhD thesis investigated complex factors driving the emergence and dissemination of mobile AMR, largely mediated by plasmids, from farm animal reservoirs to human-associated bacteria. Specifically, this thesis explored connections between factors influencing resistance at the farm animal-human interface and the molecular dynamics governing resistance gene transfer and stability, aiming to provide a multi-level understanding of this urgent global health challenge.

This thesis began by examining how farm management practices might influence the gut microbiome and the mobile resistome, the reservoir of transferable resistance genes in farm animals. It was observed that interventions varied in their ecological impact; for instance, using Black Soldier Fly Larvae oil in pigs appeared "ecologically neutral," not significantly altering the gut microbiome. In contrast, anticoccidial strategies in chickens acted as "ecologically selective" pressures, potentially shifting gut bacterial communities and enriching for specific mobile resistance genes, including plasmid fragments carrying diverse ARGs. These findings highlighted the dynamic nature of AMR reservoirs in farm environments.

Building on this, the thesis delved into the molecular mechanisms governing the transfer and stability of these mobile resistance elements. Focusing on IncI1-blaCTX-M-1, a clinically important plasmid-AMR combination recognized for its significant zoonotic potential, it was observed that it could readily transfer from chicken E. coli donors to both human and chicken E. coli recipients in vitro at relevant physiological temperatures. This suggested that initial cross-species transfer may not be significantly restricted by host origin or temperature. However, this transfer did not necessarily guarantee establishment. It was identified that these plasmids exhibited significantly lower stability and higher loss rates in human E. coli strains compared to chicken strains. Furthermore, plasmids that managed to persist in new hosts often underwent rapid genetic adaptations, typically through deletions of costly accessory genes. While such adaptations might reduce metabolic burden, they could also inadvertently compromise the plasmid's long-term persistence.

In conclusion, this thesis offers a multi-scale view of AMR dissemination, indicating that the risk of transmission from farm animals to humans may not be a simple linear path, but rather a probabilistic process potentially governed by a series of sequential barriers. Although the animal-human interface can be permeable to resistance plasmids, their successful establishment in human hosts evidently confronts significant stability challenges and adaptive pressures. Effective One Health strategies must therefore be multi-faceted: they should promote agricultural practices that minimize the initial ecological selection for resistance, while simultaneously seeking to understand, and perhaps even exploit, the molecular incompatibilities that limit the persistence of ARGs after they have crossed species lines.