Mycoplasma genitalium in Women: Natural History, Clinical Sequelae, and Host-Microbiome-Mediated Clearance - Mycoplasma genitalium (MG) is an emerging, highly drug-resistant sexually transmitted infection (STI) with serious implications for women’s health. MG prevalence reaches up to 20% in young U.S. women and has been linked to cervicitis and pelvic inflammatory disease (PID), a leading cause of infertility, ectopic pregnancy, and chronic pelvic pain. Evidence linking MG to these sequelae is largely cross-sectional, leaving major gaps and key questions unanswered. How often do asymptomatic, untreated infections lead to clinical syndromes such as cervicitis or PID? How does infection duration influence the risk of symptomatic disease? Is MG, independent of co-infections, associated with the development of vaginitis or upper genital tract complications? And while the vaginal microbiome is established as a driver of STI incidence, recent evidence suggests it may also influence spontaneous clearance, a paradigm this study will test for MG. CDC guidelines indicate MG testing for refractory cervicitis and PID, while multiplex assays have fueled off-guideline screening and testing without a strong evidence base. Treatment is complicated by antibiotic resistance: doxycycline is ineffective, macrolide resistance is widespread, and fluoroquinolone resistance is increasing. MG is now on the CDC’s antimicrobial resistance “watch list.” To address these gaps, we will leverage the NIH Longitudinal Study of Vaginal Flora (LSVF), a cohort of 3,620 women followed quarterly for one year before the commercial availability of MG tests. This repository offers a rare opportunity to define MG’s natural history in an untreated population. LSVF includes >13,219 archived cervicovaginal lavage samples with exceptionally detailed vulvovaginal symptom assessments and pelvic examinations documenting discharge characteristics, cervical inflammation, mucopurulence, and pelvic tenderness. The specific aims are to 1) define the epidemiology of MG and identify demographic, behavioral, and clinical factors (e.g., antibiotics, intravaginal practices, co- infections) that influence infection burden; 2) determine whether MG is independently associated with syndromes (vaginitis, cervicitis, PID), controlling for bacterial vaginosis, vulvovaginal candidiasis, and other co- infections, and evaluate the contribution of asymptomatic infection and infection duration to sequelae; and 3) identify microbial and immune factors associated with MG spontaneous clearance. Building on our prior research, which linked Lactobacillus dominance to the spontaneous clearance of chlamydia, we will examine if similar patterns hold for MG. We will assess if metronidazole, demonstrated in a randomized trial of PID to reduce MG prevalence, is associated with clearance in this large real-world cohort, potentially through effects on BV bacteria and restoration of Lactobacillus. Finally, we will profile vaginal microbiome-immune interactions that influence MG clearance. This large natural history study will resolve key clinical questions about MG and elucidate molecular pathways that influence its persistence and clearance. Findings will advance microbiome science as a foundation for STI prevention, safeguard fertility, and improve women’s reproductive health.
