Genomic Diversity and Fitness of E. coli Strains Recovered from the Intestinal and Urinary Tracts of Women with Recurrent Urinary Tract Infection

Comparative genomic and functional studies reveal that E. coli strains from women with recurrent urinary tract infection can move between gut and urinary tract without a fitness trade-off. UTI Bugs Without Barriers Urinary tract infections (UTIs) are among the most common infections in women, with uropathogenic Escherichia coli (UPEC) being the major cause. Recurrent infections are troublesome and can persist for years. Studies in mice have led to the realization that UPEC strains can specialize so that once they enter the urinary tract they can invade bladder tissue, forming protected bacterial communities that contribute to recurrent UTIs. A prevailing view is that recurrent UTIs also represent repeated movement of UPEC strains from the gut to the bladder. This migration is thought to be unidirectional, reflecting a view that fitness (ability to succeed) in the bladder comes at a cost of loss of fitness in the gut. We reexamined this fitness “trade-off” by characterizing the genomes of urine and fecal E. coli isolates obtained from four healthy women, enrolled in a large patient study of recurrent UTI, who each had three recurrent UTIs. In two women, the dominant UPEC strain in both their urine and feces was the same throughout all three UTIs. In the other two, the UPEC strain present in both urine and feces in the initial UTI episode was replaced by a different strain at the third recurrence. In mouse models of bladder infection and gut colonization, the strain that dominated in the later UTI episode had increased fitness in both habitats compared to the strain it replaced. Increased fitness correlated with genetic differences affecting nutrient utilization and virulence. Thus, recurrent UTI is complex and may involve strains moving freely, without fitness trade-offs, between the bladder and the gut in addition to invasion of bladder tissue. Whereas further human studies are needed to assess the role of gut bacteria and their genetic characteristics during recurrent UTI, this broader view could lead to new approaches for prevention, diagnosis, and treatment of this troublesome infection. Urinary tract infections (UTIs) are common in women, and recurrence is a major clinical problem. Most UTIs are caused by uropathogenic Escherichia coli (UPEC). UPEC are generally thought to migrate from the gut to the bladder to cause UTI. UPEC form specialized intracellular bacterial communities in the bladder urothelium as part of a pathogenic mechanism to establish a foothold during acute stages of infection. Evolutionarily, such a specific adaptation to the bladder environment would be predicted to result in decreased fitness in other habitats, such as the gut. To examine this prediction, we characterized 45 E. coli strains isolated from the feces and urine of four otherwise healthy women with recurrent UTI. Multilocus sequence typing and whole genome sequencing revealed that two patients maintained a clonal population in both these body habitats throughout their recurrent UTIs, whereas the other two exhibited a wholesale shift in the dominant UPEC strain colonizing both sites. In vivo competition studies in mouse models, using isolates taken from one of the patients with a wholesale population shift, revealed that the strain that dominated her last UTI episode had increased fitness in both the gut and the bladder relative to the strain that dominated in preceding episodes. Increased fitness correlated with differences in the strains’ gene repertoires and carbohydrate and amino acid utilization profiles. Thus, UPEC appear capable of persisting in both the gut and urinary tract without a fitness trade-off, emphasizing the need to widen our consideration of potential reservoirs for strains causing recurrent UTI.