Mechanistic basis of urinary Lactobacillus enrichment by estrogen hormone therapy

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Proposal Summary/Abstract The medical burden of urinary tract infection (UTI) is significant as they directly contribute to 1% of all clinical visits in the United States. Annual medical expenses attributed to UTI currently exceed $3.5 billion. As a global health concern, UTIs mainly affect women and commonly progress into recurrent UTI (rUTI) when a patient experiences 3 or more UTIs in a 12 month period. The risk of rUTI increases with age, leading to disproportionately high incidence rates in postmenopausal (PM) women. Effective therapies for rUTI are severely limited as most treatment strategies rely on long-term antibiotic therapy with the goal of achieving sterility within the urinary tract. However, even healthy urine is not sterile, and it has been confirmed that a microbial community resides in the healthy urinary tract of PM women, termed here the urobiome. To date, most therapeutic strategies for rUTI do not consider the preservation or restoration of the resident microbiota of the urinary or urogenital tract. Interestingly, the urobiome has been shown to be interconnected with the vaginal microbiome and vaginal D(-)Lactate-producing lactobacilli, such as Lactobacillus crispatus, have been shown to protect against bacterial vaginosis. Vaginal lactobacilli have been associated with circulating estrogen levels and early clinical studies found that estrogen hormone therapy (EHT) is strongly associated with vaginal lactobacilli enrichment in PM women. Interestingly, EHT is now widely becoming recognized as an effective treatment option for rUTI in PM women, but the mechanism behind this observation is unknown. We have observed a strong association between EHT use and urinary L. crispatus enrichment in our metagenomic analysis of the urobiome of a controlled cross-sectional cohort of PM women (n=75). These observations have led me to ask a fundamental question: How does estrogen enrich for Lactobacillus communities in the urobiome? This proposal centers around the following hypothesis: EHT, as a treatment for rUTI, enhances Lactobacillus colonization of the urinary tract by stimulating host production of nutrient sources and scaffolding attachment sites needed for colonization. To test these hypotheses, I will characterize the effect of EHT treatment on the metabolism of cultured primary urothelial cells and use a curated biobank of bacterial isolates from our de-identified human cohorts to study colonization of co-cultures of urothelial cells and L. crispatus in the presence and absence of estrogen. The long-term goal of this proposal is to leverage the insight gained from testing these hypotheses to identify alternate therapeutic targets for effective and safe adjunct therapies for rUTI. A central theme of this proposal is to use the scientific goals as a vehicle to achieve critical training goals I and my sponsors believe will greatly help in my future independent research career.