Enhancing insights into diseases through horizontal gene transfer event detection from gut microbiome

Abstract Horizontal gene transfer (HGT) phenomena pervade the gut microbiome and significantly impact human health. Yet, no current method can accurately identify complete HGT events, including the transferred sequence and the associated deletion and insertion breakpoints from shotgun metagenomic data. Here, we develop LocalHGT, which facilitates the reliable and swift detection of complete HGT events from shotgun metagenomic data, delivering an accuracy of 99.4%—verified by Nanopore data—across 200 gut microbiome samples, and achieving an average F1 score of 0.99 on 100 simulated data. LocalHGT enables a systematic characterization of HGT events within the human gut microbiome across 2098 samples, revealing that multiple recipient genome sites can become targets of a transferred sequence, microhomology is enriched in HGT breakpoint junctions (P-value = 3.3e-58), and HGTs can function as host-specific fingerprints indicated by the significantly higher HGT similarity of intra-personal temporal samples than inter-personal samples (P-value = 4.3e-303). Crucially, HGTs showed potential contributions to colorectal cancer (CRC) and acute diarrhoea, as evidenced by the enrichment of the butyrate metabolism pathway (P-value = 3.8e-17) and the shigellosis pathway (P-value = 5.9e-13) in the respective associated HGTs. Furthermore, differential HGTs demonstrated promise as biomarkers for predicting various diseases. Integrating HGTs into a CRC prediction model achieved an AUC of 0.87. Graphical Abstract Graphical Abstract