Plasmids in the human gut reveal neutral dispersal and recombination that is overpowered by inflammatory diseases.

Plasmids are pivotal in driving bacterial evolution through horizontal gene transfer. Here, we investigated 3467 human gut microbiome samples across continents and disease states, analyzing 11,086 plasmids. Our analyses reveal that plasmid dispersal is predominantly stochastic, indicating neutral processes as the primary driver of their wide distribution. We find that only 20-25% of plasmid DNA is being selected in various disease states, constraining its distribution across hosts. Selective pressures shape specific plasmid segments with distinct ecological functions, influenced by plasmid mobilization lifestyle, antibiotic usage, and inflammatory gut diseases. Notably, these elements are more commonly shared within groups of individuals with similar health conditions, such as Inflammatory Bowel Disease (IBD), regardless of geographic location across continents. These segments contain essential genes such as iron transport mechanisms- a distinctive gut signature of IBD that impacts the severity of inflammation. Our findings shed light on mechanisms driving plasmid dispersal and selection in the human gut, highlighting their role as carriers of vital gene pools impacting bacterial hosts and ecosystem dynamics.