Systematic characterization of horizontally transferred biosynthetic gene clusters in the human gut microbiota using HTBGC‐Finder

The human gut microbiota contains biosynthetic gene clusters (BGCs) that encode bioactive secondary metabolites, which play pivotal roles in microbe-microbe and host-microbe interactions and serve as a rich source of pharmaceutical lead compounds. Understanding the horizontal transfer of BGCs can reveal insights into microbial adaptation, resource utilization, and evolutionary mechanisms, thereby advancing biotechnological applications. Despite its importance, horizontal transfer of BGCs within the gut microbiota remains poorly understood. In this study, we introduce a novel tool, the Horizontally Transferred Biosynthetic Gene Clusters Finder (HTBGC-Finder), designed to systematically identify potential horizontally transferred BGCs (HTBGCs) within the extensive human gut microbiota. Using HTBGC-Finder, we identified 81 potential HTBGCs, underscoring the prevalence and significance of horizontal gene transfer in shaping the genetic landscape of the gut microbiome. Remarkably, ribosomally synthesized and post-translationally modified peptides (RiPPs) constituted the majority of these HTBGCs (76 out of 81, 93.83%), exhibiting a significantly higher transfer rate compared to non-RiPPs (Chi-squared test, <i>p</i> < 0.001). Upon detailed examination of BGCs, cyclic-lactone-autoinducer (CLA) and RiPP recognition element (RRE)-containing BGCs were predominant, representing nearly three-quarters of the total (45, or 55.56%, and 14, or 17.28%, respectively). Notably, CLA BGCs also demonstrated a higher transfer rate than non-CLA BGCs (Chi-squared test, <i>p</i> < 0.001). Taxonomy profiling revealed that horizontal BGC transfer occurred exclusively in the phyla Bacteroidota (synonym Bacteroidetes) and Bacillota (synonym Firmicutes), with 50 and 31 instances, respectively. Furthermore, cross-phylum transfer events were observed, highlighting the complex interactions between the gut microbiota and host health. These findings offer valuable insights into the horizontal transfer dynamics of BGCs within the gut microbiome and their potential implications for host-microbiota interactions.