Cervical Cancer May Be Driven by Imbalance in Vaginal Bacteria

Originally published June 4, 2018, by the University of Arizona Cancer Center.

This story was picked up by several media sources, including KJZZ 91.5 FM Phoenix.

Melissa Herbst-Kralovetz, PhD

PHOENIX – Virtually all cervical cancers are caused by HPV, or human papillomavirus, dubbed the “common cold” of sexually transmitted infections because nearly every sexually active person catches it. Fortunately, the immune system vanquishes the majority of HPV infections, with only a small percentage progressing to precancer and, ultimately, cancer. But why do some people clear the infection while others are unable to fight it?

To answer that question, a team led by the University of Arizona Cancer Center’s Melissa M. Herbst-Kralovetz, PhD, associate professor at the UA College of Medicine – Phoenix, studied 100 premenopausal women to find links between vaginal bacteria and cervical cancer. Her team found that women without cervical abnormalities are hosts to different communities of vaginal bacteria than women with cervical cancer and precancer, a discrepancy that reveals a direct relationship between “good” bacteria and cervical health, and “bad” bacteria and increased cancer risk. The results were published online May 15 in the open-access Nature publication Scientific Reports.

Bacterial friends and foes

The microbiome is the community of microbes that take up residence in the body. Some species of bacteria have been found to promote a healthy vaginal environment. For example, previous research has shown that women with Lactobacillus gasseri-dominant vaginal microbiomes are more likely to clear HPV infections. Good bacteria also can hold territory to keep bad bacteria from moving in. Sometimes, however, they lose this turf war.

“In cancer and precancer patients, lactobacilli — good bacteria — are replaced by a mixture of bad bacteria,” said Dr. Herbst-Kralovetz. The study found that, as Lactobacillus populations dwindled, cervical abnormalities became more severe. On the other hand, “bad” bacteria, called Sneathia, were linked to HPV infection, precancer and cervical cancer.

Graphic: Gaius J. Augustus

Sneathia are rod-shaped bacteria that can grow into fibrous chains. They have been associated with other gynecological conditions, including bacterial vaginosis, miscarriage, preterm labor, HPV infection and cervical precancer. Dr. Herbst-Kralovetz’s study is the first to find that a substantial Sneathia population is associated with all stages of the HPV-to-cancer continuum, from initial HPV infection to precancer to invasive cervical cancer.

Endometrial cells colonized with “good” bacteria called Lactobacillus crispatus (colored purple). Image: Herbst-Kralovetz Lab

What’s unknown is whether Sneathia species actively promote HPV infection or cancer formation, or if they’re just along for the ride. The current study offers only a snapshot of women at one point in time. To establish a cause-and-effect relationship, future studies must follow women over time.

“There’s really not a lot in the literature about how Sneathia functions in the reproductive tract,” said Dr. Herbst-Kralovetz. “How Sneathia may be impacting the hallmarks of cancer is an active area of investigation in our lab.”

Promoting an acidic environment

The bacteria that make up the vaginal microbiome are inextricably linked to the acidity of the vaginal environment. A vagina with a pH of 4.5 or below defends against harmful bacteria that are unable to survive in such an acidic environment. When pH is elevated, harmful bacteria gain the opportunity to move in, disrupting the vaginal ecosystem.

“High pH is a great reflection of the vaginal microbiome composition,” said Dr. Herbst-Kralovetz. “Lactobacilli produce lactic acid that directly lowers the pH. If you have high levels of lactobacilli you’re going to have a lower vaginal pH, and that’s associated with health.”

Dr. Herbst-Kralovetz’s team found that, as the vaginal environment loses acidity, cervical abnormalities become more severe. The team is the first to show a relationship between elevated pH and advanced cervical abnormalities.

The bacteria that dominate women on the HPV-to-cancer continuum tend to be those that are associated with bacterial vaginosis, a common gynecological infection that is characterized by elevated pH and an imbalance in vaginal bacteria. The team also identified bacteria types that hadn’t previously been associated with HPV infection or cervical cancer.

“We don’t know a lot about what they do in the reproductive tract,” Dr. Herbst-Kralovetz said of these novel bacteria. “Our next step is to take these bacteria and determine their impact on the epithelium.”

Probiotics for prevention?

The presence of bad bacteria cannot cause cervical cancer on its own — only HPV can do that. But investigating how certain bacteria work hand in hand with HPV to trigger cancer progression might provide a basis for preventive strategies. Antibiotics might do the trick, but Dr. Herbst-Kralovetz cautions that antibiotics are best when they are very specific to one type of bacteria so as not to disturb the rest of the body’s fragile bacterial ecosystem.

But what if instead of focusing on eliminating bad bacteria, we focused on nurturing the good vaginal bacteria that have been found to be protective against cervical cancer? Many consumers hope to ward off disease with store-bought probiotics (beneficial bacteria) or prebiotics (supplements thought to nourish beneficial bacteria).

Yogurt is a familiar source of probiotics, but its gynecological health benefits are dubious. Image licensed under the Creative Commons Attribution-Share Alike 2.0 Generic license

Yogurt, for example, is often touted as a home remedy for yeast infections and other gynecological conditions, based on the idea that the lactobacilli in yogurt will be able to populate the vagina after traveling through the gastrointestinal tract.

“In your yogurt, you have the gut lactobacilli,” said Dr. Herbst-Kralovetz. “The vaginal lactobacilli species are very different than what you would find in your gut — or in yogurt.”

To introduce the appropriate species of beneficial bacteria into the vaginal microbiome, yogurt probably wouldn’t do the trick. Although it’s popular and easily accessible, there’s a huge gap between what’s commercially available and what is backed by science.

“We need more randomized, controlled trials to show efficacy of the probiotics,” Dr. Herbst-Kralovetz said. “I think it would be more effective to vaginally apply a probiotic of a vaginal lactobacilli.”

Fighting health disparities

Roughly half of the patients studied were Hispanic, while the other half were of non-Hispanic origin. Hispanic women have the highest incidence of cervical cancer of all racial and ethnic groups. Studies assessing factors such as race and ethnicity in cancer risk are important for understanding why some populations are disproportionately affected by cancer.

“I wanted to truly reflect the Arizona population in our study,” said Dr. Herbst-Kralovetz. “Latinas are at a higher risk of cervical cancer. A long-term goal of mine is to help address that health disparity.”

The team found that Hispanic women were more likely to have decreased Lactobacillus populations and increased Sneathia populations. Perhaps differences in the vaginal microbiome is one factor behind Hispanic women’s increased risk for cervical cancer.

“One of our duties at the UA Cancer Center is to improve the health of Arizonans,” said William Cance, MD, deputy director of the UA Cancer Center at Dignity Health St. Joseph’s Hospital and Medical Center. Referring to the UA’s recent designation as a Hispanic Serving Institution by the U.S. Department of Education, Dr. Cance added, “Studies such as those being led by Dr. Herbst-Kralovetz show our commitment to supporting not just the education of Hispanics in Arizona, but also their health.”

“This was a highly collaborative group, performing a multi-site study here in the Phoenix area,” concluded Dr. Herbst-Kralovetz. “This work serves as the foundation for a lot of other studies. It creates many hypotheses and future directions for us in the lab, and also allows us to address some of these health disparities here in Arizona.”

This study was supported by the Flinn Foundation Grant No. 1917 and partially by the National Institutes of Health NIAID Grant 1R15AI113457-01A1 and the National Institutes of Health NCI Grant P30 CA023074. The study was conducted at the UA Cancer Center at Dignity Health St. Joseph’s Medical Center and Maricopa Integrated Health Systems.