Supraphysiologic Vaginal Estrogen Therapy in Aged Mice Mitigates Age-Associated Bladder Inflammatory Response to Urinary Tract Infections

Abstract

Importance Bladder diseases characterized by chronic inflammation are highly prevalent in older women, as are recurrent urinary tract infections (rUTIs). Recurrent urinary tract infections lead to chronic inflammation of the bladder mucosa and cause lower urinary tract symptoms that persist even after the infection is cleared. Vaginal estrogen therapy (VET) has long been used for the treatment of rUTIs; however, its mechanism of action remains unclear.Objectives The objective of this study was to examine the mechanism(s) by which VET affects bladder inflammation and response to rUTIs. Study Design Here, we induced surgical menopause in aged (18 months old) mice followed by VET. Mice were then infected with uropathogenic Escherichia coli, and course of infection was investigated. Inflammatory cytokine response was assessed before and during infection using enzyme-linked immunosorbent assay. RNA sequencing analysis was used to compare the inflammatory status of the young versus aged bladder and principal changes confirmed via quantitative reverse transcriptasepolymerase chain reaction to determine the effects of VET on bladder inflammation. Impact on age-associated bladder tertiary lymphoid tissue formation was evaluated histologically. ResultsIn the ovariectomized aged model, VET not only mitigated uterine atrophy but was also associated with reduced rUTIs, number of bacterial reservoirs, dampened immune response, and promotion of terminal differentiation of urothelial cells. Bladder tertiary lymphoid tissue lesions were also reduced with VET, with an associated decrease in signals important for bladder tertiary lymphoid tissue formation. Finally, we determined that VET reverses age-associated upregulation of inflammatory genes and pathways. Conclusions Our data suggest that VET is effective by reducing age-associated hyperinflammatory conditions in bladder mucosa and in enhancing the host response to infection.

Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency in Postmenopausal Women

“…12,13 Recent work from our group shows that vaginal estrogen therapy in old female mice appears to promote regression of these CC/TLT lesions in part by reducing levels of TLT-promoting chemokines. 14 Our study in postmenopausal women showed that antibiotics were associated with relatively rapid CC resolution. This is consistent with findings from De Nisco et al showing presence of TLTs associated with diverse bacterial species in bladder biopsy samples from postmenopausal women with rUTIs undergoing cystoscopy, 15 and from Crivelli et al 16 and Ordonez et al 17 showing electrofulguration by cauterization of CC/TLT led to improved outcomes in women with antibiotic-refractory rUTIs.…”