FocusURINARY TRACT INFECTION

Estrogen and Recurrent UTI: What Are the Facts?

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Science Translational Medicine  19 Jun 2013:
Vol. 5, Issue 190, pp. 190fs23
DOI: 10.1126/scitranslmed.3006423

Abstract

Estrogen therapy promotes resistance to urinary tract infections in postmenopausal women by altering lower urinary tract mucosal defense mechanisms (Lüthje et al., this issue).

Urinary tract infections (UTIs) are among the most common bacterial infections in humans, and women are particularly afflicted by recurrent UTI (rUTI). Although a lifetime history of UTI is a risk factor for rUTI in both pre- and postmenopausal women, behavioral risk factors for rUTI in premenopausal women, such as sexual activity and contraceptive use, do not play as big of a role in rUTI after menopause (1). However, urinary bladder functional disorders, such as urinary incontinence and incomplete bladder emptying, increase with age and may put otherwise healthy postmenopausal women at greater risk for rUTI.

This altered risk profile may be owed in part to underlying changes in the vaginal, periurethral, and lower urethral environments that result from decreased levels of estrogen and lower urogenital mucosal atrophy. Estrogen is known to play a critical role in modulating the mucosal barrier to infection in the lower urogenital tract (2), including promoting a healthy microbiota that consists predominantly of lactobacilli that thrive in and help to maintain a low-pH environment (3). With menopause, the microbiota changes and lactobacilli are replaced by other communities, including Enterobacteriaceae such as uropathogenic Escherichia coli (UPEC), which cause over 85% of UTIs. However, the specific mechanisms by which estrogen alters mucosal defense against UTI are poorly understood. In a study in this issue of Science Translational Medicine, Lüthje et al. found that vaginal estrogen supplementation enhances lower urinary tract mucosal defense mechanisms in postmenopausal women, and that ovariectomy renders mice more susceptible to experimental UTI (4). These findings support the use of topical vaginal estrogen therapy in the prevention of UTI, beyond its effects on the vaginal microbiota.

EXPERIMENTING WITH ESTROGEN

Clinicians have long recommended the use of exogenous estrogen as a prophylactic therapy for women at risk for rUTI, with the hope that it will offset or reverse the changes to the lower urogenital mucosa that accompany menopause. However, the clinical data in support of this approach are not conclusive. Several studies indicate that vaginal estrogen delivery is protective against rUTI in postmenopausal women compared with placebo-treated or untreated patients (1). In contrast, other studies say that oral estrogen replacement therapy (ERT) is not efficacious against rUTI in this population and potentially has serious side effects (1). This discrepancy in efficacy against rUTI may reflect a requirement for a higher estrogen dose locally at the vaginal and periurethral mucosal surfaces, or differential effects of systemic versus vaginal estrogen delivery on bladder or upper urinary tract mucosal responses or the systemic immune response.

To better understand the role of estrogen and estrogen therapy on UTI, the use of animal infection models is desirable but presents its own set of challenges. These include differences in vaginal microbiota composition between species, as well as practical considerations, such as the use of transurethral catheterization to directly infect the urinary bladder. Nevertheless, the molecular pathogenesis of urinary bladder infection (cystitis) in the mouse model is fairly well understood, and includes mechanisms that affect UPEC adherence, invasion, and replication within the cytoplasm of bladder epithelial (urothelial) cells during acute infection and the formation of intracellular bacterial communities (IBCs) (Fig. 1) (5). UPEC are also now known to be able to latently persist for months within intracellular Lamp1+ vesicles as quiescent intracellular reservoirs (QIRs), potentially serving as seeds for recurrent infections (Fig. 1) (5). Therefore, in the mouse model one can examine the effects of changes in estrogen levels on acute and chronic UPEC infection, independent of its effects on bacterial colonization of the lower urethral and vaginal mucosae.

Fig. 1 Estrogen affects UTI pathogenesis in many ways.

Colonization of the vaginal and periurethral mucosa by UPEC commonly precedes the development of UTI in the urinary bladder. Processes and host factors that play a role in UTI pathogenesis are depicted: Those that have been shown to be modulated by estrogen therapy are in blue text; those hypothesized to be affected by estrogen are in orange text.

CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE

In 2007, Nowicki and colleagues used ovariectomized young mice to study the role of ERT in UTI (6). They demonstrated in a model of chronic kidney infection that systemic high-dose ERT increased the susceptibility of C3H/HeJ mice to severe kidney infection with UPEC. C3H/HeJ mice are particularly susceptible to kidney infection because they are genetically prone to vesicoureteral reflux (VUR) and lack toll-like receptor 4 (TLR4) signaling. Because the severity of kidney infection usually increases with increased immunosuppression, their results suggest that high-dose ERT was blunting the innate immune response in the kidneys. However, this model is not optimized for examining the effect of estrogen on bladder infections, setting the stage for the current study.

EXPLAINING ESTROGEN’S EFFECTS

In this issue, the article by Lüthje et al. took an important step forward by investigating the effect of estrogen supplementation on human urothelial cells and in a mouse model of postmenopausal cystitis (4). The authors isolated epithelial cells from midstream urine specimens, collected from pre- and postmenopausal women before and after undergoing 2 weeks of daily vaginal estrogen therapy, and performed gene expression analysis. They hypothesized that local estrogen therapy would alter the expression of genes that directly modulate the mucosal barrier, such as genes that encode antimicrobial peptides and affect cell-cell junctions. They found that expression of the genes encoding the antimicrobial peptide hBD3 and the tight junction protein ZO-1 in epithelial cells were lower in postmenopausal women, as compared with premenopausal women, but were strongly induced with estrogen therapy (Fig. 1). Expression of antimicrobial and cell junction genes were also modestly up-regulated by 5637 human bladder carcinoma cells in vitro after treatment with estrogen, indicating that one way that estrogen alters the mucosal defense of the lower urinary tract is to directly affect the epithelial barrier in ways that enhance resistance to bacterial colonization and maintain the integrity of the epithelial barrier.

A key avenue of research going forward would be to investigate whether this estrogenic effect changes with UPEC infection as exfoliation of urothelial cells is an important host defense mechanism that allows the epithelial barrier to eliminate infected cells while maintaining barrier function to some degree (Fig. 1). Lüthje et al. (4) found that postmenopausal women as compared with premenopausal women were more prone to urothelial exfoliation during UTI, perhaps owing to the decreased expression of cell junction proteins. They suggest that urothelial exfoliation acts as a double-edged sword, eliminating infected superficial cells but also exposing the underlying epithelial cells (Fig. 1). In this vein, estrogen may prevent excessive exfoliation. This is an intriguing finding and an enticing hypothesis that requires further study and confirmation.

The authors then moved into an animal model to investigate the effects of ovariectomy on the course of experimental UTI in C57BL/6J mice, which are resistant to VUR and ascending kidney infection. They found that ovariectomy resulted in higher bacterial burdens in the bladder at 24 hours after infection and higher residual bladder titers at 7 days after infection, which is indicative of an increased QIR burden. Some of the ovariectomized mice had marked and diffuse bacterial colonization accompanied by exfoliation of the uroplakin-expressing superficial facet cells at 24 hours after infection. This is reminiscent of what has been reported in C3H mice (7), which are more susceptible to chronic cystitis because they mount a severe acute inflammatory response. Interestingly, Wang, et al. recently described similar increases in acute bacterial burdens, acute bladder inflammation, and QIR persistence at 14 days after infection in ovariectomized C57BL/6J mice infected with UPEC (8). Thus, estrogen therapy likely has a direct effect on the course of cystitis, independent of any estrogenic effect on UPEC colonization of the periurethral and lower urethral mucosa.

The most intriguing finding by Lüthje, et al. was that postmenopausal women had lower expression of a proposed UPEC type 1 pilus adhesin (FimH) receptor, uroplakin Ia (UPIa), by urothelial cells and that vaginal estrogen therapy restored UPIa expression (4). Similarly, in ovariectomized mice the superficial facet cells of the bladder expressed less UPIa protein, and in two different urothelial cell lines, preincubation with estrogen enhanced UPEC invasion in vitro. These findings seem to contradict the authors’ clinical data as well as the mouse data, in which ovariectomized mice had higher acute and chronic bacterial burdens. Lüthje et al. attempt to reconcile these data by hypothesizing that increased UPEC invasion alters the kinetics of the mucosal immune response to colonization, which seems to be a possible scenario that requires further study.

However, it is also possible that estrogen is having other effects, such as directly altering the character of the mucosal immune response, which overshadow the increased FimH receptor expression and that are not modeled in vitro. Wang et al. demonstrated that urothelial regeneration in response to UPEC infection was altered in ovariectomized mice (8). Estrogen could be modulating the terminal differentiation of the superficial cells, thereby altering the expression, glycosylation, and secretion of other surface molecules, some of which may have competing effects on bacterial adherence and invasion (Fig. 1). For example, it was recently shown that ERT in ovariectomized C57BL/6J mice altered the dynamics of the bladder glycosaminoglycan layer during acute UPEC infection (9). Furthermore, estrogen may modulate endocytic pathways downstream of FimH-mediated invasion, such as IBC formation or the TLR4-dependent exocytosis of invasive bacteria (Fig. 1) (10).

LOOKING FORWARD

Millions of women suffer from rUTI, for which effective clinical management strategies are sorely lacking. This—coupled with the recent global emergence of multidrug-resistant UPEC isolates in the community—makes it imperative that we pursue targeted, alternative, nonantibiotic strategies for preventing rUTI. This study by Lüthje et al. (4) supports the use of vaginal estrogen as a prophylactic therapy against rUTI in postmenopausal women—not just for its effect on the urogenital microbiota and lower urethral resistance to uropathogens, but because estrogen seems to directly enhance the resistance of the bladder to both acute UTI and QIR persistence by UPEC. The translational data from postmenopausal women undergoing vaginal estrogen supplementation is a real strength of this study, and this approach should be used to study the expression of other factors important for mucosal defense in UTI.

One limitation of this study was that the authors did not attempt ERT in their animal model to show whether estrogen restored resistance in ovariectomized mice. Wang et al. found that QIR persistence and acute inflammation, but not acute bacterial burdens, were reduced to normal levels in ovariectomized mice with systemic ERT, but the effect of vaginal estrogen therapy was not investigated. Improvements in the animal model would include the innovation of a vaginal estrogen delivery model, as well as developing a humanized vaginal microbiota mouse model in which the lower urogenital tract is populated by a Lactobacillus microbiota. With all the therapeutic possibilities, the role of estrogen in modulating mucosal defense and microbial invasion pathways merits further study in both animals and people.

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