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Innovative Research on Modifying Vaginal Microbiome to Treat Bacterial Vaginosis

In This Article

  • Massachusetts General Hospital physician-investigator Caroline Mitchell, MD, MPH, is revolutionizing therapies against recurrent bacterial vaginosis (BV)
  • BV is the most common cause of vaginitis and has high recurrence rates
  • Researchers at Mass General are evaluating the efficacy of vaginal fluid transplantation to alter the vaginal microbiome and prevent a recurrence
  • The study will determine features of healthy vaginal microbiota that protect against the condition and are optimizable for use in preventative therapies

Innovative research at Massachusetts General Hospital is evaluating the efficacy of vaginal fluid transplantation to prevent recurrent bacterial vaginosis (BV), the most common vaginal condition among women. BV has been historically under-addressed and presents a recurrence rate of up to 50% following treatment.

"The frustrations shared by clinicians and patients concerning this condition are based largely on the complicated nature of vaginal health and the limited research targeting this area," says Caroline Mitchell, MD, MPH, physician-investigator in the Vincent Center for Reproductive Biology at Massachusetts General Hospital. Her lab is leading a first-of-its-kind clinical trial to better understand the vaginal microbiome and determine the therapeutic efficacy of vaginal fluid transplantation to prevent recurrent BV.

"Both my clinical and research experience emphasize how little is known about how to promote healthy bacterial communities in the vagina. What a disservice this is to our patients and the critical need to address this situation," she says.

Targeting BV Symptoms and Treatment Limitations

BV describes a shift in the balance of vaginal flora from a Lactobacillus-dominant environment to one characterized by an increased diversity of bacterial communities. Although clinically defined by vaginal discharge, odor, and an elevated vaginal pH, BV symptoms are nonspecific, with one epidemiological study published in Sexual Transmitted Diseases reporting that approximately 84% of cases are asymptomatic.

The Centers for Disease Control and Prevention guidelines for treating BV involve oral or topical antibiotics. With the consistently high recurrence rate, Dr. Mitchell notes that other therapeutic options must be identified. "Given the increased focus on personalized medicine in recent decades and the technology currently available, repeatedly applying the same treatment for something that affects a quarter of women worldwide is unacceptable," she says.

The Modifying Organisms Transvaginally in Females (MOTIF) Trial

The MOTIF trial evaluates the use of vaginal microbiota transplantation (VMT) to augment antibiotic treatment in women with a history of recurrent BV and promote the establishment of a Lactobacillus-dominant vaginal microbiome. The rationale is to manually reinstate a whole community of "good" bacteria following antibiotic administration to promote the selective establishment of the healthy vaginal microbiota. The ultimate goal of this trial is to directly translate the discoveries into effective strategies for BV treatment and prevention.

The trial includes an initial phase focused on establishing the procedure's safety, followed by a second, longer phase involving a larger cohort of donors and patients. However, the research's unique approach and complicated nature have introduced unforeseen challenges. "What we've discovered in the initial phase is the significant challenge of identifying donors based on the stringency of our exclusion criteria," explains Dr. Mitchell.

Because the physiology of the human vagina is unique among mammals, the use of animal models for in vivo investigations in early phases is precluded in this study. Instead, vaginal fluid donations will be directly administered to patients. As a result, Dr. Mitchell's team employs especially rigorous donor screening. An additional recruitment issue involves the timeline, as investigators collect donor vaginal fluid for a month, during which donors must abstain from sexual activity.

Dr. Mitchell also acknowledges that the status of the study as a randomized, placebo-controlled trial has been a complicating factor in the enrollment of some potential VMT recipients. One inclusion criterion stipulates a history of recurrent BV, defined as three or more documented episodes in the previous 12 months. However, "women who have had recurrent BV for a long time are not interested in possibly being randomized into the placebo group," says Dr. Mitchell.

The Need for Interventional Studies and Focused Microbiome Research

Although epidemiological studies of BV have been undertaken, few interventional studies have been performed to determine the impact of preventative measures in the context of the broad associations identified with various factors, including:

  • Chronic stress
  • Engagement in sexual activity at a young age
  • Having multiple sex partners (male or female)
  • Lack of condom use
  • Regular douching
  • Smoking status
  • Use of copper-containing IUDs

Dr. Mitchell emphasizes that her group does not anticipate that VMT will be a long-term solution for women with recurrent BV but rather an opportunity to identify factors that predispose such a high percentage of women to the condition.

Identifying physiological hallmarks requires an understanding of not only the vaginal microbiome but also the variations that likely exist between individuals. Despite evidence showing the vaginal microbiome's effect on outcomes related to childbirth, significantly higher susceptibility to HIV-1 infection, and HPV status, it has received a fraction of the research focus dedicated to the gut microbiome.

Furthermore, Dr. Mitchell stresses that research outcomes cannot always be translated from one biological context to another. "The prevalence of work and media attention on the microbiome tends to promote the assumption that if there are approaches capable of 'fixing' the gut microbiome, the same should be true for the vaginal microbiome. This is not the case."

Although the microbiome likely plays a role in many vaginal health issues, factors including local inflammation and a healthy immune system are also critical. And although over-the-counter kits that report the status of the vaginal microbiome are widely available, they fail to advise consumers on what to do with the information gleaned from the test. "There are no established standards for what a healthy vaginal microbiome should look like, and oral probiotics and yogurt are unlikely to be adequate solutions," says Dr. Mitchell. "I'm often the fifth or sixth doctor that some BV patients have seen for this condition, and the frustration felt by both sides with the lack of answers is universal."

Collaborating to Address Long-standing Problems

Proximity to world-class researchers and facilities in the Boston area, as well as the critical support received from her department, has allowed Dr. Mitchell to thrive as a researcher and clinician. Additionally, she acknowledges the importance of close collaborations with colleagues at Mass General.

Doug Kwon, MD, PhD, director of clinical operations at the Ragon Institute, is Dr. Mitchell's primary collaborator on the MOTIF trial. "Dr. Kwon's background in immunology research and clinical work as an infectious disease physician has been an invaluable and ideal complement to my clinical and research experience. His perspective has added immense value to the translational capacity of the trial," says Dr. Mitchell of their collaboration.

Furthermore, Dr. Mitchell is investigating complications associated with long-term treatment of autoimmunity in women as part of a clinical collaboration with John Niles, MD, director of the Vasculitis and Glomerulonephritis Center—Nephrology Division. "We shared one patient who had been admitted to the hospital with severe vaginal pain and inflammation," Dr. Mitchell describes. Further investigation revealed that some patients receiving extended administration of rituximab, a B-cell suppressor, to treat certain types of autoimmune diseases experience mucosal inflammation in different organs. Their collaboration resulted in a case study, published in BMC Womens Health, of inflammatory vaginitis following long-term rituximab treatment. "We hypothesize that this treatment dysregulates vaginal bacterial communities, resulting in a local inflammatory response. We're currently in the second year of the RituxiVag study."

Despite the research challenges, Dr. Mitchell's encounters with recurrent BV patients remain the motivating factor in her work.

Learn more about the Vincent Center for Reproductive Biology

Refer a patient to the Department of Obstetrics & Gynecology

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Lactobacillus species, which appear to protect against HIV infection and cervical cancer, are similarly abundant in vaginal samples from Black and white postmenopausal women, according to a molecular study by Caroline M. Mitchell, MD, MPH, and colleagues.


Caroline M. Mitchell, MD, director of the Vulvovaginal Disorders Program in the Department of Obstetrics & Gynecology, and colleagues have described refractory inflammatory vaginitis as a debilitating potential side effect of long-term B-cell depletion with rituximab.