What goes around comes around: Plasmid-mediated antibiotic resistance dissemination at the farm animal-human interface

The escalating crisis of antimicrobial resistance (AMR), characterized as a "silent pandemic" responsible for an estimated 1.14 million deaths globally in 2021, demands a rigorous One Health framework. This approach acknowledges that AMR dynamics are driven by deep interconnectedness between human, animal, and environmental domains. Specifically, the farm animal-human interface represents a critical nexus for the dissemination of plasmid-mediated antibiotic resistance. This research aims to bridge the gap between broad ecological factors prevalent in agricultural settings and the precise molecular mechanisms governing the movement and establishment of resistance plasmids from livestock reservoirs to human-associated bacteria.

Central to this dissemination is the gut microbiome, which acts as a vast biological reservoir for antimicrobial resistance genes (ARGs). These genes are frequently carried on mobile genetic elements (MGEs), particularly plasmids, which facilitate rapid horizontal gene transfer (HGT) via conjugation. To elucidate how agricultural inputs influence this reservoir, this research first examined the impact of diverse farming practices. Investigations revealed contrasting ecological outcomes: while the administration of Black Soldier Fly Larvae (BSFL) oil in pigs proved ecologically neutral, exerting minimal impact on the fecal microbiome, anticoccidial strategies in chickens imposed strong selective pressures. These pressures significantly reshaped the microbial landscape and co-selected for specific resistome profiles, illustrating how agricultural management can actively modulate the pool of mobile ARGs.

Transitioning from ecological observation to molecular dissection, the study focused on the cross-species transmission of the high-priority IncI1-blaCTX-M-1 plasmid. In vitro experiments demonstrated that host origin is not an immediate barrier to HGT; the plasmid transferred efficiently between avian and human Escherichia coli isolates. However, a pivotal distinction emerged between initial transfer and long-term establishment. Post-transfer analyses revealed that the plasmid exhibited significantly lower stability in human hosts compared to avian hosts. This instability triggered rapid genetic adaptations, including large-scale deletions of metabolically costly regions such as conjugation machinery. This phenomenon, identified here as a "paradox of plasmid refinement," indicates that while adaptive changes may aid immediate survival by reducing metabolic burden, they can inadvertently compromise the plasmid’s long-term genomic integrity and transmissibility.

In conclusion, this research offers a multi-scale perspective on AMR dissemination. It illustrates that while agricultural practices act as potent ecological drivers creating reservoirs of mobile ARGs, the journey from farm to human is not a simple linear path. Successful plasmid transfer across species barriers does not automatically equate to establishment. Instead, persistence in a novel host is a probabilistic process governed by plasmid identity, host compatibility, and adaptive evolutionary trade-offs. These findings emphasize the existence of natural, albeit imperfect, biological buffers that impede the establishment of livestock-associated resistance in humans, underscoring the need for One Health strategies that account for both ecological selective pressures and molecular establishment barriers.