A landmark trial shows that antibiotic-free microbiota transplantation alone is not sufficient to treat vaginal dysbiosis, but new insights suggest this treatment may still be successful.
Study: Vaginal microbiota transplantation without antibiotics: a double-blind randomized controlled trial in women with vaginal microbiota. Image credit: H_Ko/Shutterstock.com
Vaginal dysbiosis is relatively common in women of reproductive age, but effective treatment strategies are limited. In recent research, lancet reported that vaginal microbiota transplantation (VMT) without antibiotic pretreatment was not significantly more effective than placebo in restoring a lactobacillus-dominated microbiota.
Disruption of the vaginal microbiome is associated with 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), typically the predominant Lactobacillus species are lost. Conversely, potential pathogens such as Gardnerella spp. fanny hesea scabbardthe abundance of Prevotella spp.
Vaginal dysbiosis is associated with multiple adverse health outcomes. These include other pregnancy complications such as infertility, miscarriage, and premature birth. Depending on geographic location and testing method, abnormal vaginal flora can affect up to 52% of women.
New methods such as DNA sequencing have advanced our knowledge of the vaginal microbiome. Time-honored diagnostic criteria such as Amsel’s criteria and Nugent’s scoring are now complemented by molecular techniques. However, treatment of this condition remains difficult, with up to 60% of patients experiencing a recurrence within a year.
VMT emerged in response to the challenge of treating recurrent vaginal endocrinopathy and was first studied in a pilot study in 2019. In that study, five women with recurrent symptomatic dysbiosis received lactobacillus-based transplants from healthy donors along with antibiotic therapy, achieving a clinical remission rate of 80%.
This was followed by the successful treatment of a patient with a Gardnerella-dominated vaginal microbiome who had severe symptomatic dysbiosis and infertility. She was advised antibiotic-free VMT, which was followed by vaginal microbiome transformation and subsequent delivery. Randomized controlled trials (RCTs) are currently being conducted to replicate and extend these results. Notably, donor strain engraftment was confirmed in this patient by DNA sequencing, but not in the original study. Therefore, this step was incorporated into the current study.
Randomized trial tests antibiotic-free microbiota transplantation approach
Researchers conducted the trial at Copenhagen University Hospital. The study enrolled 49 women aged 18 to 40 with molecularly diagnosed molecular endocrinopathy (including both symptomatic and asymptomatic participants).
All participants had relative abundances of lactic acid bacteria (all species) <10%, but Gardnerella species abundance >20%. fanny hesea scabbardand Prevotella spp. None were pregnant or had other medical conditions. They were randomized to receive VMT or placebo in a 3:1 ratio without antibiotics.
Women who donated vaginal microbiome grafts were in the same age group and had microbiomes dominated by lactic acid bacteria (>80%), with the other three taxa accounting for <5%.
The study group received up to three VMT or placebo treatments, once in three consecutive menstrual cycles, without prior antibiotic treatment. They were then followed up for six additional cycles to assess gut microbiota resolution. The relative abundance of lactic acid bacteria was more than 70%, and the relative abundance of the other three was less than 10%.
In an extension of the study, antiseptic pretreatment was added before additional VMT for women who did not have a sustained response.
VMT fails to improve microbiome recovery over placebo
This study shows that VMT failed to improve conversion to a normal vaginal microbiome in the dysbiosis group compared to placebo for up to 6 months after last treatment. At this point, 11% of VMT participants vs. 25% of those taking placebo had converted to lactobacillus dominance.
However, the Lactobacillus donor strain successfully engrafted into recipients in two of the four women who were converted and subsequently tested. The established donor strain remained dominant for up to 199 days (last test point).
Furthermore, in recipient vaginas, changes were observed in the local gene expression profile of cervicovaginal secretions, suggesting changes in immune activation, including decreased expression of some inflammatory genes and cytotoxicity-related genes. Nevertheless, no immunological changes were observed in analysis of peripheral blood or menstrual blood immune cells, suggesting that the effects may be local and mild rather than systemic.
In the extension phase, 27 women received additional treatment in an open-label design. 10 received disinfectant pretreatment followed by VMT, 10 received saline pretreatment followed by VMT, and 7 received disinfectant without VMT.
Here, 5 out of 10 women in the antiseptic treatment group successfully converted, compared to none in the saline and VMT or antiseptic treatment groups. Of the 5 who converted, 3 showed engraftment, 1 converted without engraftment, and 1 had insufficient data. Transplantation, rather than spontaneous conversion as was the case in the placebo group, supports but does not conclusively prove a causal relationship with VMT.
In both parts of the study, the predominance of lactobacilli was more pronounced among women who showed engraftment of the donor strain. Pretreatment with antiseptics may reduce the bacterial load and biofilm load in the vagina and attenuate the tendency of gut microbiota to persist despite treatment. Gardnerella vaginalis is a prominent component of such biofilms.
However, the authors caution that this is just a hypothesis, as biofilms were not investigated in this study. They also note the possibility of improving graft quality by selecting a donor microbiome with bacteriostatic activity against dysbiosis-associated bacteria, as was done in a single-patient case report. No serious adverse events were observed in any group or at any stage of the study.
Research limitations
This study used a small sample. The majority of donor grafts are L. Reiner, Features of While the stability of the microbiota is low; L. crispatus An overwhelming number of women have successfully converted. Dosing regimens, favorable results in trials, and the use of more diverse and larger sample groups should be the focus of future studies.
Additionally, there are limitations such as limited statistical power in extended and substudy analyses, a slight lack of sample size per protocol, lack of detailed ethnicity data, and a single country (Denmark) setting, which may limit generalizability.
Disinfection pretreatment emerges as a potential strategy to improve outcomes
This study does not support the use of VMT without antibiotics for vaginal microbiome transformation under the conditions tested in this trial. Nevertheless, engraftment of lactic acid bacteria and subsequent favorable changes in the vaginal microenvironment occurred. These changes help explain how VMT functions and encourage further research on its potential use in vaginal endocrine abnormalities.
According to the authors, this study is one of the first placebo-controlled RCTs in this field and confirms the feasibility and safety of the technique.
Furthermore, extended studies suggest that pretreatment with preservatives may improve engraftment rates and thereby increase treatment efficacy. This may be a promising way to increase the success rate of VMT and transfer it from research to clinical settings.
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