Population Colonization Dynamics in Urinary Tract Infection

Abstract

Uropathogenic Escherichia coli (UPEC), the primary causative agent of urinary tract infection (UTI), is thought to reside in the gut before ascension into the urinary tract, yet a reproducible model for its transit between these host environments has never been developed. Here, we demonstrate that intra-species competition plays a key role in UPEC gut colonization. Resident Enterobacterales, particularly commensal E. coli, impose colonization resistance, whereas their absence or elimination enables stable UPEC persistence. In mouse lineages in which UPEC stably colonizes the gut, we reveal that spontaneous bacteriuria is regularly detected, providing a novel framework for studying UPEC movement along the gut-urogenital axis. Additionally, we show that active UTI promotes UPEC gut colonization, overcoming colonization resistance, and we provide evidence that the vaginal space is a crucial intermediary in UPEC transition from the gut to the urinary tract environment. Our findings suggest that UPEC expansion in these alternative host niches contributes to UTI recurrence. This is particularly problematic if antibiotic resistant populations colonize multiple host environments, as even susceptible populations fail to be cleared from the gut following UTI treatment. To further investigate UPEC’s adaptive strategies, we examined fosfomycin resistance mechanisms, identifying common and novel FosR mutations that link resistance to metabolic rewiring. Contrary to prior assumptions that FosR mutations elicit biological cost to the pathogen, we observed that uhp and pyk mutants establish infection comparably to wild type strains, and in some cases mice infected with the FosR mutants resolve UTIs less rapidly, suggesting a selective advantage in maintaining these resistant subpopulations. Our findings support a re-evaluation of fosfomycin clinical susceptibility standards, in which the observation of FosR subpopulations has previously been ignored. Collectively, this work underscores the need for further investigations into UPEC’s metabolic and ecological adaptations, informing treatment strategies and improving UTI management.