Bacteria were among the first forms of life on earth, and while some strains cause infection or spoil food, others are essential to providing nutrients to plants, fermenting foods, and supporting our gut and reproductive health. Dr. Melissa Herbst-Kralovetz, associate professor of basic medical sciences, as well as obstetrics and gynecology at the College of Medicine – Phoenix, explains how the delicate balance between “good” and “bad” bacteria effect the health of the female reproductive tract. She shares how her research will ultimately help to develop better diagnostics, preventatives and treatments for sexually transmitted infections, gynecological cancer, and more.
Dr. Herbst-Kralovetz’s recent publication: https://healthsciences.arizona.edu/newsroom/news-releases/2021/bacteria-are-key-vaginal-health-uarizona-health-sciences-researchers-say
Bacteria often gets a bad rap, especially when they find out that bacteria live inside of us. Explain the delicate balance between good and bad bacteria, particularly how it relates to your work with the female reproductive tract.
Most people hear “bacteria,” and they think “bad” - let's kill it with antibiotics. That's worked well for us for a while, but now we're gaining a better appreciation for the good bacteria that contribute to our overall health and wellbeing.
We've known since the 1800s that the Lactobacillus species contribute to women's health and the female reproductive tract, but now we're gaining a further appreciation for this.
These bacteria are found in the gut as well, but they come in different flavors in the female reproductive tract. Like in the gut, they contribute to health and homeostasis within the female reproductive tract. If you deplete these bacteria or if they become destroyed by particular compounds, that's an opportunity for the “bad bacteria” to overgrow and contribute to a whole host of adverse women's health outcomes.
Where do these microbes come from? Are we born with them? How do they get inside of us?
The jury is still out – it’s actually a controversial topic.
We know that the lactobacilli population changes across a women's lifespan. When you're born, you have lactobacilli that are supported by the estrogen you get from your mom. During adolescence, you have more anaerobic organisms and not as many lactobacilli, but as you enter menarche, your estrogen feeds the glycogen in our epithelium, and we therefore have more lactobacilli.
Lactobacilli dominance is again associated with overall vaginal health during menopause. When that estrogen is depleted, those glycogen levels go down, so the epithelium may change, and we may not have as much lactobacilli dominance during that time, which can cause a lot of issues. If we give hormone replacement therapy, then we can get back that food source for those bacteria, and we have more lactobacilli dominance again.
Overall, this lactobacilli dominance really contributes to health and homeostasis throughout our lifespan.
The presence of certain strains of bacteria like lactobacilli can be a sign of good reproductive tract health. How does losing that type of bacteria potentially increase susceptibility to infection or disease?
As I mentioned, there are different factors that drive lactobacilli depletion, and so when that happens, you have an overgrowth of bad bacteria - anaerobic organisms – leading to a condition we call bacterial vaginosis (BV), or vaginal dysbiosis.
BV is an enigma. It's a very complex, polymicrobial condition, meaning it's not one single ideologic agent or pathogen that we're studying. I got hooked on studying BV because it is linked to so many adverse women’s health outcomes.
We initially took a reductionist approach to this complex condition because we didn't know what any of those bugs were doing. No one had started to dissect the mechanisms of the bacteria that make up this polymicrobial consortium.
We're now learning that there are early colonizers – bacteria that come in at an early stage – who might contribute to the biofilm in the female reproductive tract. The secondary colonizers come in later after the biofilm has been established, and they have different mechanisms of action. Those are the bugs that are driving things like inflammation and adverse health outcomes.
By understanding the interactions between different microbes and our bodies, how can your work help to inform prevention of treatment strategies for different diseases of the female reproductive tract?
We are really focused on understanding the functional roles of these individual organisms because if we want to target them, we need to better understand the key bacteria that are driving this dysbiosis. We want to know if we can disassemble the biofilm by targeting some of these bacteria that contribute to it, as well as by blocking secondary colonizers to inhibit inflammation.
The other aspect is that if we know that there's a microbial signature through immunoproteomics and metabolomics analysis, we could potentially use those as markers for diagnostics for some of these conditions as well.
We're in the early stages, but we ultimately want to see this translated back to the clinic so we can impact women's health in a positive way.
Where did your passion for doing this type of research stem from?
My undergraduate research experience in Colorado sparked my interest in infectious diseases. I started doing an undergraduate research project where we were working on a number of viruses. I originally wanted to go to medical school but that undergraduate research project got me hooked on infectious diseases.
I was working on a virus that infects but doesn’t cause disease in deer mice, though it does cause disease in humans. That differential host response and trying to understand the hosts factors or immunologic mechanisms that caused these pathogens to manifest disease in different ways was my entry into pathogen-host interactions.
Since then, I’ve been intrigued by all these pathogens. I may not stay in my lane and work on one pathogen my entire life because I'm just so intrigued by how each of these pathogens work differently. It really feeds into this whole question of BV and it being a polymicrobial condition because I don't have to study just one single pathogen.
We've had two BIO5 post-docs - Dr. Robert Jackson in Dr. Koenraad Van Doorslaer’s lab, and Dr. Kate Rhodes from Dr. Maggie So's lab - on our podcast. Both are collaborating with you using your novel 3D bioreactor technology to make lifelike representations of the female reproductive track to enhance their research. How have the connections that you've made through BIO5 enabled you to make scientific advancements and discoveries that might not have otherwise been possible?
Bacterial vaginosis and the associated dysbiosis lead to several poor women's health outcomes, and one of those is an increased risk for all sexually transmitted infections (STIs), making BV a huge public health problem. We want to understand the mechanism and know what about the microenvironment might be creating more of a favorable STI favorable environment.
Both Dr. Jackson and Dr. Rhodes study highly relevant, sexually transmitted infections – human papillomavirus and Neisseria gonorrhea, respectively. With their collaborations, we're able to start to better understand the factors that are driving that increased risk of infection, as well as growth and persistence of those organisms. We can use our human three-dimensional models to study those interactions.
We're really excited about these opportunities to partner with these BIO5 members to extend our findings and to make more of an impact on the understanding of risk factors associated with those other infections.
You're the director of the Women's Health Microbiome Initiative. Tell us more about this initiative and how it’s helping to advance women's health.
The initiative aims to bring together clinical collaborators and scientists. Bacteriologists, biologists, immunologists, biostatisticians, and bioinformatics gurus look at the microbiome to search for changes in the microenvironment that might be setting up for all these adverse disease outcomes. Being able to partner at this larger level, have access to clinical specimens, and to perform translational research allows us to tackle some of these incredibly complex women's health questions.
We're really interested in studying cervical cancer and endometrial cancer, as well as cancer health disparities that are disproportionately impacting women here in Arizona, like our Latina and indigenous populations.
You’re incredibly busy and successful in your work at the university, but I'm curious how you spend your time outside of lab. What are your favorite hobbies, and how do they help benefit your career and your personal life?
We can't just be in the lab all the time, but I’d say I’m a recovering workaholic.
It’s important that we spend that time rejuvenating and recharging. The way that I do that is with my family. I have two boys, a 10-year-old and a 13-year-old, and they like to get dirty. We love camping as a family and doing outdoor activities. I think it's so important to reconnect with nature so that we can be recharged, and when we come back to the lab, we have new questions and feel to make these scientific discoveries and breakthroughs.
About the University of Arizona BIO5 Institute
The BIO5 Institute at the University of Arizona connects and mobilizes top researchers in agriculture, engineering, medicine, pharmacy, data and computational science, and basic science to find creative solutions to humanity’s most pressing health and environmental challenges. Since 2001, this interdisciplinary approach has been an international model of how to conduct collaborative research, and has resulted in disease prevention strategies, innovative diagnostics and devices, promising new therapies, and improved food sustainability. Learn more at BIO5.ORG.
LAND ACKNOWLEDGEMENT We respectfully acknowledge the University of Arizona is on the land and territories of Indigenous peoples. Today, Arizona is home to 22 federally recognized tribes, with Tucson being home to the O’odham and the Yaqui. Committed to diversity and inclusion, the University strives to build sustainable relationships with sovereign Native Nations and Indigenous communities through education offerings, partnerships, and community service.