Abstract

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide. Consequently, they are one of the leading indications for antibiotic prescription. Despite the typically successful treatment of an acute UTI, recurrent infections are exceedingly common, particularly among women. Nearly a quarter of otherwise healthy women will suffer recurrent UTIs (rUTI) after a primary UTI; why these select individuals are continually afflicted is unkown. There are no successful therapeutics to treat rUTI representing a gap not just in the medical toolkit but in our understanding of why rUTI is so prevalent. There are many hypotheses for the risk factors in rUTI, from host genetics to epigenetic remodeling of the bladder. One key area of focus has been on the niches uropathogens occupy among the host’s symbiotic microbial communities, including the gastrointestinal and the vaginal microbiotas. Uropathogenic E. coli (UPEC) is known to colonize the host gastrointestinal tract thereby forming a reservoir that can seed recurrent infections in the urinary tract. This dynamic has been coined the “gut-bladder axis”, and work has recently been undertaken in the field to discern the features underpinning it. Through this research it has been observed that women with rUTI have altered gastrointestinal microbiotas raising the question of whether these broader community-level changes may alter susceptibility to infection through immunomodulatory mechanisms. The gastrointestinal microbiota has been shown to regulate the immune functioning at other distant organ sites including the lung and brain, standing to reason that the bladder might also be under regulatory control by the gut microbiota. In this dissertation I explore the hypothesis that the gut microbiota acts as a modulator of UTI by altering infection severity. Using gnotobiotic models, I demonstrate that the presence of a microbiota alters the severity of a bladder infection by modulating local complement production in the bladder. Unique microbiotas induce different amounts of bladder complement that UPEC can hijack to invade into uroepithelial cells of the bladder leading to worse infections with increased UPEC burden in the urine and urinary tract tissues. In another model, I find that the presence of UPEC as a member of the gastrointestinal microbiota worsens acute bladder infection through a mechanism independent of seeding bladder infections from the gut reservoir. In addition, I explore an overlooked reservoir of pathogens, the bacteria that can colonize intrauterine devices (IUDs). While the vaginal microbiota has been found to potentially harbor uropathogens, the bacterial colonization of IUDs and any connections to UTI susceptibility or patient health has gone largely unexamined. While I do not find any direct connections between UTI and IUD colonizers, I do find that patient gynecologic history correlates with a microbial composition on IUDs characteristic of bacterial vaginosis (BV). This is notable as BV has been implicated in the increased risk of both reproductive tract and urinary tract infections. These findings indicate that IUDs may play a larger role in the health of the female urogenital system than previously recognized. Together, the work of this thesis identifies new gut-bladder axis dynamics whereby the composition of the gastrointestinal microbiota alters severity of UTI. Additionally, I identify alterations to IUD bacterial colonization correlated to patient gynecological history. These novel findings expand our knowledge of the symbiotic bacterial reservoirs that shape female urogenital health, revealing new potential targets for the prevention and treatment of rUTI.

Committee Chair

Scott Hultgren

Committee Members

Andrew Kau; Ashlee Earl; Christina Stallings; Drew Schwartz; Eli Roberson; Megan Baldridge

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-12-2026

Language

English (en)

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