Prophage dynamics in gastric and enterohepatic environments: unraveling ecological barriers and adaptive transitions

Phage predation plays a critical role in shaping bacterial genetic diversity, with prophages playing a comparable role. However, the prevalence and genetic variability of prophages within the Helicobacter genus remain inadequately studied. Helicobacter species are clinically significant and occupy distinct digestive system regions, with gastric species (e.g. Helicobacter pylori) residing in the gastric mucosa and enterohepatic species colonizing the liver and intestines of various vertebrates. Here, we address this knowledge gap by analyzing prophage presence and diversity across 343 non-pylori Helicobacter genomes, mapping their distribution, comparing genomic features between gastric and enterohepatic prophages, and exploring their evolutionary relationships with hosts. We identified and analyzed a catalog of 119 new complete and 78 incomplete prophages. Our analysis reveals significant differences between gastric and enterohepatic species. Gastric prophages exhibit high synteny, and cluster in a few groups, indicating a more conserved genetic structure. In contrast, enterohepatic prophages show greater diversity in gene order and content, reflecting their adaptation to varied host environments. Helicobacter cinaedi stands out, harboring a large number of prophages among the enterohepatic species, forming a distinct cohesive group. Phylogenetic analyses reveal a co-evolutionary relationship between several prophages and their bacterial hosts-though exceptions, such as the enterohepatic prophages from H. canis, H. equorum, H. jaachi, and the gastric prophage from H. himalayensis-suggesting more complex co-evolutionary dynamics like host jumps, recombination, and horizontal gene transfer. The insights gained from this study enhance our understanding of prophage dynamics in Helicobacter, emphasizing their role in bacterial adaptation, virulence, and host specificity.