Longitudinal Gut Microbiota Tracking Reveals the Persistent Spread of Mobile Genes and HGT-Driven Community Stabilization

Horizontal gene transfer (HGT) is a major driver of bacterial evolution, but its role in shaping the human gut microbiome over time remains poorly understood. Here, we present a longitudinal metagenomic analysis of 676 fecal samples from 338 individuals collected ~4 years apart, using a newly developed workflow to detect recent HGT events from metagenome-assembled genomes. We identified 5,644 high-confidence HGT events occurring within the past ~10,000 years across 116 gut bacterial species. We find that species pairs with a HGT relationship were significantly more likely to maintain stable ecological relationships over the 4-year period, suggesting that gene exchange contributes to ecological stability. Notably, HGT and strain replacement act together to disseminate mobile genes in the population. Furthermore, our observation that an individual's mobile gene pool remains highly personalized and stable over time indicates that host lifestyles drive specific gene transfer. For example, proton pump inhibitor usage was linked to increased transfer of multidrug transporter genes. Our findings demonstrate, at individual gut microbiome level, that HGT is both an integral and stabilizing force in the human gut ecosystem and an important mechanism for disseminating adaptive functions, underscoring their potential for tracking host lifestyle.