Urinary tract infections (UTIs) represent a major burden across the population, although
key facets of their pathophysiology and host interaction remain unclear. Escherichia
coli epitomizes these obstacles: this gram-negative bacterial species is the most
prevalent agent of UTIs worldwide and can also colonize the urogenital tract in a
phenomenon known as asymptomatic bacteriuria (ASB). Unfortunately, at the level of
the individual E. coli strains, the relationship between UTI and ASB is poorly defined,
confounding our understanding of microbial pathogenesis and strategies for clinical
management. Unlike diarrheagenic pathotypes of E. coli, the definition of uropathogenic
E. coli (UPEC) remains phenomenologic, without conserved phenotypes and known genetic
determinants that rigorously distinguish UTI- and ASB-associated strains. This article
provides a cross-disciplinary review of the current issues from interrelated mechanistic
and diagnostic perspectives and describes new opportunities by which clinical resources
can be leveraged to overcome molecular challenges. Specifically, we present our work
harnessing a large collection of patient-derived isolates to identify features that
do (and do not) distinguish UTI- from ASB-associated E. coli strains. Analyses of
biofilm formation, previously reported to be higher in ASB strains, revealed extensive
phenotypic heterogeneity that did not correlate with symptomatology. However, metabolomic
experiments revealed distinct signatures between ASB and cystitis isolates, including
in the purine pathway (previously shown to be critical for intracellular survival
during acute infection). Together, these studies demonstrate how large-scale, wild-type
approaches can help dissect the physiology of colonization versus infection, suggesting
that the molecular definition of UPEC may rest at the level of global bacterial metabolism.