Inflammatory markers for improved recurrent UTI diagnosis in postmenopausal women.

Recurrent urinary tract infection (rUTI) severely impacts postmenopausal women. The lack of rapid and accurate diagnostic tools is a major obstacle in rUTI management as current gold standard methods have >24-h diagnostic windows. Work in animal models and limited human cohorts have identified robust inflammatory responses activated during UTI. Consequently, urinary inflammatory cytokines secreted during UTI may function as diagnostic biomarkers. This study aimed to identify urinary cytokines that could accurately diagnose UTI in a controlled cohort of postmenopausal women. Women passing study exclusion criteria were classified into no UTI and active rUTI groups, and urinary cytokine levels were measured by immunoassay. Pro-inflammatory cytokines IL-8, IL-18, IL-1ß, and monocyte chemoattractant protein-1 were significantly elevated in the active rUTI group, and anti-inflammatory cytokines IL-13 and IL-4 were elevated in women without UTI. We evaluated cytokine diagnostic performance and found that an IL-8, prostaglandin E2, and IL-13 multivariable model had the lowest misclassification rate and highest sensitivity. Our data identify urinary IL-8, prostaglandin E2, and IL-13 as candidate biomarkers that may be useful in the development of immunoassay-based UTI diagnostics.

Recurrent urinary tract infection and estrogen shape the taxonomic ecology and function of the postmenopausal urogenital microbiome.

Postmenopausal women are severely affected by recurrent urinary tract infection (rUTI). The urogenital microbiome is a key component of the urinary environment. However, changes in the urogenital microbiome underlying rUTI susceptibility are unknown. Here, we perform shotgun metagenomics and advanced culture on urine from a controlled cohort of postmenopausal women to identify urogenital microbiome compositional and function changes linked to rUTI susceptibility. We identify candidate taxonomic biomarkers of rUTI susceptibility in postmenopausal women and an enrichment of lactobacilli in postmenopausal women taking estrogen hormone therapy. We find robust correlations between Bifidobacterium and Lactobacillus and urinary estrogens in women without urinary tract infection (UTI) history. Functional analyses reveal distinct metabolic and antimicrobial resistance gene (ARG) signatures associated with rUTI. Importantly, we find that ARGs are enriched in the urogenital microbiomes of women with rUTI history independent of current UTI status. Our data suggest that rUTI and estrogen shape the urogenital microbiome in postmenopausal women.

Urinary prostaglandin E2 as a biomarker for recurrent UTI in postmenopausal women.

Urinary tract infection (UTI) is one of the most common adult bacterial infections and exhibits high recurrence rates, especially in postmenopausal women. Studies in mouse models suggest that cyclooxygenase-2 (COX-2)-mediated inflammation sensitizes the bladder to recurrent UTI (rUTI). However, COX-2-mediated inflammation has not been robustly studied in human rUTI. We used human cohorts to assess urothelial COX-2 production and evaluate its product, PGE2, as a biomarker for rUTI in postmenopausal women. We found that the percentage of COX-2-positive cells was elevated in inflamed versus uninflamed bladder regions. We analyzed the performance of urinary PGE2 as a biomarker for rUTI in a controlled cohort of 92 postmenopausal women and PGE2 consistently outperformed all other tested clinical variables as a predictor of rUTI status. Furthermore, time-to-relapse analysis indicated that the risk of rUTI relapse was 3.6 times higher in women with above median urinary PGE2 levels than with below median levels. Taken together, these data suggest that urinary PGE2 may be a clinically useful diagnostic and prognostic biomarker for rUTI in postmenopausal women.