The impact of estrogen hormone therapy modality on urobiome dynamics in postmenopausal women

University Of Texas Dallas, Richardson TX

Investigators

Abstract

Project Summary Urinary tract infection (UTI) is among the most common adult bacterial infections worldwide and primarily impacts women. Recurrent UTI (rUTI), defined as ≥2 UTIs in 6 months or ≥3 UTIs in 12 months, has become one of the most challenging urologic diseases to manage, especially in postmenopausal women. Antibiotic therapy is rapidly losing efficacy as resistant uropathogens become more widespread. Reports currently estimate that 19-36% of UTIs in premenopausal women and ~50% of UTIs in postmenopausal (PM) women develop into rUTI. Alternate therapies are urgently needed to combat these life-changing infections. Estrogen depletion during menopause alters the urogenital mucosal environment and microbiome (i.e. loss of Lactobacillus predominance), thereby creating a more favorable environment for uropathogen colonization. Low-dose estrogen hormone therapy (EHT) is a widely available treatment that can reduce the incidence of rUTI in some PM women. EHT is hypothesized to reduce UTI recurrence by encouraging a transition to a Lactobacillus (Lb)-dominated female urogenital microbiome (FUM). Although vEHT generally exhibits superiority to placebo for prevention of rUTI, a key caveat noted by these studies is that up to 50% of women continue to experience rUTI. Studies have also observed that the vaginal microbiomes of non- responders were not colonized by lactobacilli. This observation lends strong support to the hypothesis that EHT protects against rUTI by modulating Lb colonization. However, it is currently unknown why vEHT does not promote urogenital Lb colonization in some women. We recently published a landmark study that rigorously defined key markers of rUTI susceptibility in the FUM of PM women. We found that urinary Lb abundance is strongly associated with EHT use. Strikingly, we observed strong and consistent enrichment of Lb in the FUM of women using oral and transdermal patch EHT, suggesting that these modalities may strongly promote urogenital Lb colonization. Conversely, Lb enrichment was highly variable in women using vEHT. In line with previous observations, 44% of vEHT users had no detectable urinary Lb. These data strongly support our premise that different EHT treatment modalities differentially impact the FUM. However, because no study has directly compared the effect of EHT modalities on FUM Lb colonization longitudinally, additional studies are needed to rigorously test this premise. We have assembled a multidisciplinary, collaborative team to conclusively fill these fundamental gaps in knowledge through testing the following hypotheses: (1) Oral EHT (oEHT) more drives a more stable transition to an Lb-dominant FUM than vEHT and (2) Increased FUM Lb abundance after start of EHT is directly correlated to increased urinary estrogen levels which may vary between estrogen modalities. When completed, this project will significantly expand our understanding of how to improve EHT treatment paradigms for more broadly effective enhancement of FUM Lb populations and rUTI prophylaxis in postmenopausal women.