Estrogenic Modulation of Uropathogenic Escherichia coli Infection Pathogenesis in a Murine Menopause Model

Abstract

Recurrent urinary tract infections (UTIs), primarily caused by uropathogenic Escherichia coli (UPEC), annually affect over 13 million patients in the United States. Menopausal women are disproportionally susceptible, suggesting estrogen deficiency is a significant risk factor for chronic and recurrent UTI. How estrogen status governs susceptibility to UTIs remains unknown, and whether hormone therapy protects against UTIs remains controversial. Here, we used a mouse model of surgical menopause by ovariectomy and demonstrate a protective role for estrogen in UTI pathogenesis. We found that ovariectomized mice had significantly higher bacteriuria, a more robust inflammatory response, and increased production of the proinflammatory cytokine interleukin-6 (IL-6) upon UPEC infection compared to sham-operated controls. We further show that response of the urothelial stem cell niche to infection, normally activated to restore homeostasis after infection, was aberrant in ovariectomized mice with defective superficial urothelial cell differentiation. Finally, UPEC-infected ovariectomized mice showed a significant increase in quiescent intracellular bacterial reservoirs, which reside in the urothelium and can seed recurrent infections. Importantly, this and other ovariectomy-induced outcomes of UTI were reversible upon estrogen supplementation. Together, our findings establish ovariectomized mice as a model for UTIs in menopausal women and pinpoint specific events during course of infection that are most susceptible to estrogen deficiency. These findings have profound implications for the understanding of the role of estrogen and estrogen therapy in bladder health and pathogen defense mechanisms and open the door for prophylaxis for menopausal women with recurrent UTIs.

Estrogen Supports Urothelial Defense Mechanisms

“…Thus, excessive exfoliation might eventually turn into an infection-promoting effect. In addition, delayed and incomplete differentiation of the basal cell layers in the absence of estrogen was recently demonstrated in the mouse urinary tract during E. coli infection (41). We furthermore speculated that the strength of cell-cell contacts influences the disposition of urothelial cells to exfoliation after pathogen-induced apoptosis in single umbrella cells.…”

The Bladder Is Not Sterile: History and Current Discoveries on the Urinary Microbiome

“…Other microbial niches, such as the vaginal tract, are greatly altered in the absence of estrogen. Given that estrogen alters the bladder epithelium [33, 34], and that estrogen improves the incidence of UTIs [35–37] and urgency urinary incontinence (UUI) [38–40], it is very likely that the microbiome will be altered following menopause which could be a contributing factor to many lower urinary tract symptoms associated with age.…”

Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections

“…A recent study found that vaginal estradiol therapy in post-menopausal women altered the expression of antimicrobial peptides and cell junction proteins in epithelial cells isolated from voided urine, suggesting that estrogen therapy modulates the mucosal barrier of the lower urinary tract (240). In support of these translational findings, several studies of experimental UTI in ovariectomized mice have demonstrated that altering estrogen levels has profound effects on UTI pathogenesis (240–242). Thus, vaginal estrogen therapy remains a safe and viable therapeutic option for post-menopausal women suffering from rUTI.…”