Menstrual phase targeted therapy: a novel strategy to improve clearance and reduce recurrence of bacterial vaginosis

About This Grant

Bacterial vaginosis (BV) is a highly prevalent polymicrobial vaginal condition characterized by the overgrowth of anaerobic bacteria such as Gardnerella. Affecting millions of people annually, BV is strongly associated with increased risk of sexually transmitted infections and serious reproductive sequelae. Despite its incidence and clinical burden, BV remains notoriously challenging to treat, with standard metronidazole therapy failing in 50% of patients and recurrence rates approaching 80% within a year. However, the current treatment guidelines overlook dynamic shifts in vaginal physiology, particularly those driven by menstruation and host immune activation, highlighting a critical gap in our understanding of therapeutic failure. Menstruation introduces transient but predictable changes to the vaginal environment, including increased bioavailable iron concentrations, epithelial turnover, and immune activation, that collectively reshape host–microbe interactions. Preliminary data demonstrate that total bacterial load decreases and the BV-associated taxa present upregulate redox enzyme genes (e.g., nitroreductase, ferredoxin) required for metronidazole activation during menses. Concurrently, menstrual bleeding results in a proinflammatory immune response, yet the cause and relevance to antibiotic efficacy remain unclear. This proposal will define menstruation as a critical window that can be leveraged to improve BV therapy outcomes. Aim 1a will characterize the temporal transcriptional dynamics of the host and vaginal microbiome across the menstrual cycle using high-resolution, longitudinal metatranscriptomic data. Utilizing the same well-characterized cohort, Aim 1b will investigate host immune responses resulting from changes in the host and microbiome triggered by menses. These data will reveal how host and bacterial function interact across the menstrual cycle, clarify why pro-inflammatory immune markers increase during menstruation, and determine the role of the vaginal microenvironment in BV treatment when it is administered during menstruation. Aim 2 will evaluate the therapeutic efficacy of menstruation-timed metronidazole delivery using a 3D organotypic vaginal epithelial model colonized with clinically relevant microbial consortia. The model will simulate menstrual conditions via heme supplementation and assess bacterial clearance, host immune responses, and host-microbial gene expression under temporally distinct regimens. The significance of this work lies in its potential to transform BV treatment paradigms by introducing a biologically synchronized, temporally informed strategy to enhance antimicrobial efficacy and microbiome restoration. The innovation stems from integrating host physiological rhythms with microbial therapeutics—an intersection largely unexplored in BV research. By repurposing FDA-approved agents and aligning their use with endogenous biological cycles, this project offers a highly translatable framework for clinical implementation. This F32 proposal will provide robust training in human immunobiology, epidemiologic methods, and in vitro tissue modeling, building toward a career focused on translational approaches to improve reproductive health.