| project name | Community-acquired urinary tract infection (UTI) is among the most common bacterial infections. When a patient suffers 3 UTIs per year, it is defined as recurrent UTI (rUTI). Postmenopausal (PM) women are a rapidly growing and underserved demographic group who are severely affected by rUTI with a >50% recurrence rate. In this population, rUTI can persist for years, reducing quality of life and imposing a significant healthcare burden. rUTI is most often treated by long-term antibiotic therapy, but development of antibiotic resistance and allergy leave physicians with fewer treatment options after each episode. The majority of rUTIs develop in women with a history of UTI, suggesting that changes in the urogenital (UG) environment after UTI predispose women to rUTI. Although much is known about the microbiomes of the gut, skin and mouth, the urobiome is poorly understood. Here, we characterize the urobiome of PM women by metagenomic analysis of three human cohorts: 1) PM women with no UTI history (n=25), 2) remittent rUTI (recent history of rUTI but currently no UTI, n=25), and 3) relapsed rUTI (recent history of rUTI with current UTI, n=25). We have employed a hybrid approach, combining advanced urine culture with culture-independent shotgun metagenomic sequencing to generate an unbiased, metagenome-wide analysis of the taxonomic and functional genomic ecology of the PM urobiome in health and rUTI. Our results suggest that a history of rUTI strongly shapes the taxonomic and functional ecology of the urobiome. We find that there may be a robust protective commensal population within the urobiome of women who do not experience UTI, which is depleted or absent in patients with rUTI history. Integration of clinical metadata has detected an almost exclusive enrichment of putative protective species belonging to the genus, Lactobacillus, in women taking estrogen hormone therapy (EHT). However, our data suggests that the modality of EHT may strongly affect urobiome Lactobacillus enrichment. We have used functional metagenomic profiling to identify microbial metabolic pathways, and antimicrobial resistance genes (ARGs) enriched between cohorts. Our data suggest distinct metabolic and ARG signatures of the urobiome between cohorts. When completed, this project will significantly advance our understanding of the relationship of the urobiome to rUTI pathogenesis and will lay the framework for future, targeted research endeavors towards the development of novel antibiotic and probiotic therapies for rUTI. |
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