Changes in the Genital Microbiome and Inflammation Among Women Using 30-Day <i>L. Rhamnosus/L. Reuteri</i> Probiotic in Combination with Intravaginal Estradiol: Findings from a Pilot, Open-Label, Phase I Clinical Trial

Abstract A dysbiotic genital microbiome can cause inflammation, higher sexually transmitted infection risk, and long-term effects even when asymptomatic. Probiotic Lactobacillus species can potentially improve the genital microbial environment, especially among women with bacterial vaginosis (BV). Further, the hormone estradiol has been linked to mucosal health and better Lactobacillus colonization. We evaluated the impact of intravaginal estradiol, with/without use of Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14, administered vaginally or orally, on the genital microbiome and inflammation. Through this pilot Phase I, randomized, open-label trial, fifty premenopausal African, Caribbean, and Black women, were randomized to four study arms: intravaginal estradiol (Estring©; 7.5mg/day); vaginal probiotic (RepHresh Pro-B™) twice daily; combination of Estring© and vaginal RepHresh Pro-B™ (twice daily); or the Estring© and oral RepHresh Pro-B™ (twice daily), for 30 days. Baseline BV status was determined by Nugent scoring. The genital microbial composition was measured by 16S rRNA gene sequencing, and inflammation using a 48-plex Luminex cytokine assay. By mid-intervention, probiotic Lactobacillus taxa were detected in the genital tract in the vaginal probiotic only (p<0.01) and vaginal probiotic + Estring arms (p=0.03), but not with oral administration, although abundances returned to baseline levels post-treatment. 51.3% of participants experienced an overall positive shift in microbial composition by end-of-treatment. At follow-up, despite the decrease in probiotic species abundances, total Lactobacillus abundance, mostly L. iners , remained higher compared to pre-treatment (68.9% vs 60.9%), with lower overall alpha diversity (p=0.04). Further, this change was accompanied by a consistent decrease in inflammation from baseline to end-of-intervention (p=0.04), and 7 days post-treatment (p=0.05), significantly so at all visits among those with an overall positive microbial shift (all p<0.05). Overall, our findings demonstrate that microbiome-targeted interventions have the capacity to positively modulate the genital microbial and inflammatory milieu, with factors such as the route of administration playing a key role. Panel: Research in context Evidence before this study The vaginal microbiome is a critical determinant of reproductive health and HIV susceptibility. Bacterial vaginosis (BV) is a genital condition characterized by the depletion of protective Lactobacillus species and an overabundance of dysbiotic anaerobes, which leads to high inflammation levels and increased risk of sexually transmitted infection acquisition. Treating with antibiotics, which is the standard of care for BV, leads to recurrence rates exceeding 50% within a year. Promising studies assessing the effectiveness of live probiotics have been shown in some studies to decrease BV recurrence rates, but have yielded inconsistent results, especially with oral delivery. Additionally, low-dose intravaginal estrogen was found to enhance Lactobacillus dominance in postmenopausal women. However, its combined effect with probiotics in premenopausal women, including among African, Caribbean, and Black (ACB) women who are disproportionately affected by BV and HIV, remains poorly understood. Added value of this study This randomized, open-label, phase I trial was, to our knowledge, the first to compare oral versus vaginal delivery of L. rhamnosus GR-1 and L. reuteri RC-14, with or without intravaginal estrogen, among premenopausal ACB women. Vaginally-administered probiotics were successfully detected in the vaginal tract, albeit temporarily, led to increased Lactobacillus abundance, reduced BV-associated anaerobes abundance, and decreased overall genital inflammation levels. Importantly, these shifts in microbial composition, including an increase in Lactobacillus spp. abundance persisted beyond treatment with vaginal probiotic use. Implications of all the available evidence Our findings suggest that vaginal probiotic use with/without estrogen can support the establishment of a more optimal vaginal microbiome and reduce inflammation - two factors central to genital health and HIV prevention. Route of administration was key to detection of the probiotic taxa in the genital tract. Larger studies are needed to determine the longer-term impact of these microbial and immune improvements on BV recurrence and risk of sexually transmitted infection acquisition.

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