Different gut microbiome dysbioses impact the evolutionary fate of hypervirulent Klebsiella pneumoniae.

The intestinal microbiota acts as a barrier against pathogen colonization, yet how specific ecological perturbations shape the evolutionary fate of invading pathogens remains unclear. Here, we show that the mode of gut perturbation and type of dysbiosis determine whether hypervirulent Klebsiella pneumoniae (hvKp) persist or clear from the intestines. Transient ampicillin exposure creates a permissive, low-diversity intestinal niche dominated by facultative anaerobes, which supports long-term, high-density hvKp colonization. The dysbiotic state creates an altered redox environment to favor these oxygen-using bacteria and is associated with the rapid emergence of hypomucoid variants. This occurs via contractions in the poly-T tract in the promoter of the rmpA regulator that controls capsule hypermucoviscosity, as well as mutations in the poly-G tract within the coding sequence. This evolutionary trajectory reflects a virulence-persistence trade-off in high-nutrient, low-competition environment. Conversely, osmotic perturbation via laxative treatment elicits only a transient window of colonization-susceptibility that is rapidly closed by the recovery of a Bacteroides-enriched community that is consistent with their ability to actively suppress pathogen colonization via short-chain fatty acids (SCFAs). Furthermore, SCFAs such as butyrate are more effective in inhibiting hypomucoid rmpA variants relative to wild-type bacteria, providing a possible explanation for how an osmotically perturbed gut microbiome constrains the expansion of these mutants. These findings provide insights into how transient antibiotic exposure could potentially drive long-term intestinal pathobiont colonization while laxative-induced osmotic perturbations do not rewire the energy and metabolic landscape of the gut microbiome, enabling rapid recovery and colonization resistance despite an initial plunge in diversity. Our work reveals that the specific mode of perturbation affects the trajectory for pathogen adaptation, and highlights the potential role of commensal competition in constraining pathogen evolution.