Epidemiologic and molecular basis of the gut-urinary tract axis in urinary tract infection

ABSTRACT: Uropathogenic Escherichia coli (UPEC) is the causative agent of urinary tract infection (UTI) in 75-95% of all cases. UTI is a major health problem in the United States and globally. In the United States, UTls decrease quality of life for 15 million people (mostly women), cause significant economic loss (>S9.7B when including sequelae), and drain our antibiotic arsenal yearly (15% of all antibiotics prescribed in the US go to treating this disease). Sequelae ofUTI include: i) chronic recurrent UTI (rUTI); ii) complications during pregnancy; iii) kidney infection; and iii) sepsis (25% of sepsis cases are traced back to urinary origin. Yearly, over 1 million women in the US are referred to urologists because of rUTI treatment difficulties, which are being exacerbated by the rapid spread of antibiotic resistance in UPEC. Few studies have considered the role of multiple habitats UPEC colonize including the gastrointestinal tract (GIT) and urogenital sites (periurethral area and vagina) prior to entering the bladder and causing UTI. The GIT and vagina have long been considered reservoirs for UPEC, but surprisingly, little is known regarding how UPEC establish and maintain residence throughout and between these body habitats. This proposal uses innovative technologies to investigate UTI holistically, elucidating molecular details of the dynamics of E. coli in its multiple host habitats. Previous work revealed that the microbiota of the GIT is dysbiotic in rUTI patients. E. coli residing within the dysbiotic GIT of rUTI patients have a distinct transcriptional profile, compared to E. coli in the GIT of healthy controls. Importantly, the transcriptional state of a UPEC inoculum matters for bladder infection, suggesting that the GIT transcriptional state may serve to prime successful adaptation of E. coli in the bladder or other host reservoirs. Thus, this proposal investigates the "whole body problem" of rUTI involving multiple host reservoirs of E. coli, which serve as "staging areas" for uropathogens, and the gut-bladder axis, which manifests as dysbiosis in the GIT microbiota influencing the local and systemic immune state. This proposal seeks to: i) characterize the role of the GIT microbial community, inflammation and antibiotic treatment in invoking a distinct uropathogen transcriptomic state observed in rUTI women (Aim 1); ii) assess whether the transcriptional state of E.coli and dysbiotic microbiota that is associated with rUTI result in a differential ability to colonize the bladder (Aim 2); and iii) assess the role of intermediate bacterial urogenital reservoirs, specifically how the vaginal or periurethral microbiotas facilitate or preclude colonization and subsequent transition of E. coli to the bladder (Aim 3). Accomplishing these aims will greatly increase our understanding of rUTI, which afflicts millions of women, giving much needed insight into the role of transcriptional adaptation of E. coli in different reservoirs including the GIT and urogenital sites. This work will reveal how adaptations affect or prime E. coli residence in subsequent reservoirs and/or in the bladder and the role of GIT inflammation and antibiotic treatments on the gut-bladder axis, which will lead to new and better antibiotic-sparing therapeutics.