A landmark trial shows that antibiotic-free microbiota transplants alone aren’t enough to treat vaginal dysbiosis, yet new insights suggest the therapy could still succeed.
Study: Vaginal microbiota transplantation for treatment of vaginal dysbiosis without the use of antibiotics: a double-blind, randomised controlled trial in women with vaginal dysbiosis. Image credit: H_Ko/Shutterstock.com
Vaginal dysbiosis is relatively common in women of reproductive age, but effective treatment strategies are limited. A recent study in The Lancet reports that vaginal microbiota transplant (VMT) without antibiotic pretreatment did not significantly outperform placebo in restoring a Lactobacillus-dominated microbiome.
Disrupted vaginal microbiome linked to reproductive complications
The vagina is home to a diverse microbial community that contributes to its unique acidic environment. When the normal vaginal microbiome is disrupted, known as vaginal dysbiosis, the typically predominant Lactobacillus species is lost. Conversely, potential pathogens like Gardnerella species, Fannyhessea vaginae, and Prevotella species increase in abundance.
Vaginal dysbiosis is associated with multiple adverse health outcomes. These include infertility, pregnancy loss, and other pregnancy complications like preterm labor. Vaginal dysbiosis affects up to 52 % of women, depending on their geographic location and testing method.
Newer methods, such as DNA sequencing, have advanced the knowledge of the vaginal microbiome. The time-honored diagnostic criteria, such as Amsel’s criteria or Nugent’s scoring, are now complemented by molecular techniques. Yet treatment of this condition remains challenging, with up to 60 % of patients experiencing recurrence within a year.
VMT emerged in response to the challenges of treating recurrent vaginal dysbiosis and was first explored in a 2019 pilot study. In that study, five women with recurrent symptomatic dysbiosis received a Lactobacillus-dominated transplant from healthy donors, along with antibiotic therapy, resulting in an 80 % clinical remission rate.
This was followed by the successful treatment of a patient with a Gardnerella-dominated vaginal microbiome, who had severely symptomatic dysbiosis and recurrent pregnancy loss. She was offered antibiotic-free VMT to which she responded with vaginal microbiome conversion and a subsequent livebirth. This is now being followed by a randomized controlled trial (RCT) to replicate and extend the findings. In particular, donor strain engraftment was confirmed in this patient by DNA sequencing, whereas it was not in the original study. This step was therefore incorporated into the current study.
Randomised trial tests antibiotic-free microbiota transplant approach
The researchers conducted the trial at Copenhagen University Hospital. The trial enrolled 49 women between 18 and 40 years, who had molecular vaginal dysbiosis (including both symptomatic and asymptomatic participants) diagnosed at the molecular level.
All participants had <10 % relative abundance of Lactobacillus (all species), but >20 % of Gardnerella species, Fannyhessea vaginae, and Prevotella species. None were pregnant or had any other medical condition. They were randomized to receive a VMT or placebo in a 3:1 ratio, without antibiotics.
The women who donated the vaginal microbiome grafts were in the same age group and had a microbiome dominated by Lactobacillus (>80 %), with the other three taxa making up <5 %.
The study groups received up to three VMT or placebo treatments, respectively, once each in three successive menstrual cycles, without antibiotic pretreatment. They were then followed up for another six cycles to assess dysbiosis resolution: 70 % or higher relative abundance of Lactobacillus and less than 10 % combined relative abundance of the other three.
An extension of the study added antiseptic pretreatment before an additional VMT in women who persistently failed to respond.
VMT fails to improve microbiome restoration over placebo
The study shows that VMT failed to improve conversion to a normal vaginal microbiome in the dysbiosis group, compared to placebo, for up to six months after the last treatment. At this point, 11 % of VMT participants vs 25 % of placebo recipients had converted to Lactobacillus dominance.
However, the donor strain of Lactobacillus was successfully engrafted in the recipient in two of four women who converted and were subsequently tested. The established donor strain remained dominant for up to 199 days (the last test point).
In addition, the recipient vagina showed changes in local gene expression profiles in cervicovaginal secretions, suggesting altered immune activity, including reduced expression of some inflammatory and cytotoxicity-related genes. Despite this, no immunologic changes were observed in analyses of peripheral or menstrual blood immune cells, suggesting that any effects may be localized and modest rather than systemic.
During the extension phase, 27 women received additional treatment in an open-label design. Ten received pretreatment with antiseptic followed by VMT, ten received saline pretreatment followed by VMT, and seven received antiseptic without VMT.
Here, five of the ten women in the antiseptic arm successfully converted, compared with none in the saline plus VMT or antiseptic-only arms. Of the five who converted, three showed engraftment, one converted without engraftment, and one had insufficient data. The engraftment supports, but does not definitively prove, a causal link to VMT rather than these being spontaneous conversions, as in the placebo group.
In both parts of the study, Lactobacillus dominance was more pronounced among women who showed donor-strain engraftment. The antiseptic pretreatment might reduce bacterial load and biofilm burden in the vagina, weakening the tendency of dysbiosis to persist despite treatment. Gardnerella vaginalis is a prominent component of such biofilms.
However, the authors caution that this is only a hypothesis since the biofilm was not examined in this study. They also note the potential to improve graft quality by selecting donor microbiomes with bacteriostatic activity against dysbiosis-associated bacteria, as was done in the single-patient case report. No serious adverse events were observed in any group or at any stage of the trial.
Study limitations
The study used a small sample. The donor grafts were dominated by L. iners, characteristic of a less stable microbiota, whereas L. crispatus dominated in women who successfully converted. The dosing regimen, the preferred outcome in trials, and the use of more diverse and larger sample groups should be the focus of future studies.
Additional limitations include limited statistical power in the extension and substudy analyses, a slight shortfall in per-protocol sample size, a lack of detailed ethnicity data, and the single-country (Denmark) setting, which may limit generalisability.
Antiseptic pretreatment emerges as a potential strategy to improve outcomes
The study does not support the use of VMT without antibiotics for vaginal microbiome conversion under the conditions tested in this trial. Despite this, Lactobacillus engraftment and a subsequent favorable shift in the vaginal microenvironment occurred. These changes help to explain how VMT works while promoting further research into its potential use in vaginal dysbiosis.
According to the authors, this study represents one of the first placebo-controlled RCTs in this area and confirmed the procedure's feasibility and safety.
Moreover, the extension study suggests that antiseptic pretreatment may improve grafting rates and thereby enhance the treatment's efficacy. This may hold promise as a method to increase the success rates of VMT and translate it from the research setting to clinical practice.
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