Metronidazole Shrinks Endometriosis Via Microbiota (in Mice)

Marlene Busko

May 07, 2019

In a study in mice, metronidazole unexpectedly slowed endometriotic lesion growth by altering as yet unknown bacteria in the gut, researchers report.

"Our findings suggest that gut bacteria promote endometriosis progression in mice," Sangappa B. Chadchan, PhD, post-doc research associate at the Center for Reproductive Health Sciences, Washington University, St Louis, Missouri, and colleagues write in their article, published online last week in Human Reproduction.

"This finding, if translated to humans, could aid in the development of improved diagnostic tools and personalized treatment strategies," they conclude.

However, senior author Ramakrishna Kommagani, PhD, assistant professor of obstetrics and gynecology at the Center for Reproductive Health Sciences, Washington University, stressed to Medscape Medical News that "this research is in a very early stage." It is a "long process" from finding promising therapies in animal studies to getting approval for diseases in humans.

However, Kommagani continued, the preclinical study suggests that "if we somehow manage the microbiota in the gut, then we could potentially alleviate the disease burden" of endometriosis.

"I'm not saying we could cure [it]," he cautioned, but if subsequent studies pan out, "it really would help a lot of women with their pain and probably other issues such as infertility."

Surprising Finding With Common Antibiotic

The investigators were surprised that of four broad-spectrum antibiotics they tested in the mice — vancomycin, neomycin, ampicillin, and metronidazole — only the latter, a widely used antibiotic that suppresses growth of certain gram-negative bacteria, reduced the size of the endometriotic lesions.

Further research is needed, Kommagani said, since "we don’t have a full picture of what specific bacteria metronidazole might be affecting that leads to this suppressive activity."

As a next step, the team plans to conduct a small pilot trial in humans at their center and a couple of other centers.

"Our initial goal was to understand how these gut bacteria, or microbiota, might be connected to endometriosis," Kommagani summarized in a statement by the university. "But in the process, we may have found a cost-effective treatment."

"This study is exciting as it opens new frontiers in identifying bacterial candidates that can promote endometriosis in reproductive-age women,” added co-author Indira Mysorekar, PhD, professor of pathology and immunology and director of the Center for Reproductive Health Sciences, Washington University.

“And it enables us to conduct future studies aimed at developing simpler ways to diagnose endometriosis."

Endometriosis Is Poorly Understood

Endometriosis, in which cells migrate from the uterus and form lesions elsewhere, affects up to 10% of women aged 25 to 40, but is poorly understood, the researchers write, and current treatment with hormone therapy and surgery have significant side effects.

Previous studies have shown that inflammatory bowel disease is associated with endometriosis, and the gut microbiota seems to somehow be involved, Kommagani noted.  

So the researchers aimed to see how endometriotic lesions grew in mice that did not have gut bacteria. Starting 24 hours after endometriosis-induction surgery, the animals were given drinking water for 21 days that contained four broad-spectrum antibiotics — vancomycin, neomycin, metronidazole, and ampicillin — and aspartame to mask the taste, to completely wipe out their bacteria.

Control mice received water with aspartame.  

At 21 days, the endometriotic lesions were about fivefold smaller in the antibiotic-treated mice than in controls (P < .01).

Further testing showed that only metronidazole, and not the other three antibiotics, reduced lesion size.

Next, the researchers reintroduced bacteria to the mice that had no bacteria.

That is, they gave fecal samples (from mice with internal bacteria) by mouth to the mice with no bacteria.

If the lesions began to grow again, it would suggest gut bacteria somehow play a role in increasing the size of endometriotic lesions. In fact, this is what the research showed.

Overall, the experiments showed that "metronidazole alone inhibits the [endometriotic] lesion growth, but if you put back bacteria by giving the fecal samples through an oral route, then the lesions come back," Kommagani summarized.

"That pretty much suggests that [gut] bacteria have a role in endometriosis."

The study was funded by grants from the National Institutes of Health (NIH)/National Institute of Child Health and Human Development. Kommagani has received start-up funds from the Washington University School of Medicine and an Endometriosis Foundation of America Research Award. The Genome Technology Access Center is supported by grants from the National Cancer Institute and NIH National Center for Advancing Translational Sciences. The authors have disclosed no relevant financial relationships.

Hum Reprod. Published online April 30, 2019. Abstract

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