The Microbiome and Women’s Health
by Diana Price 2/2021
If you’ve eaten a yogurt and noticed the note on the label promoting the “live cultures” in the product, you’re likely aware of the promotion of these “good bacteria,” or probiotics, as nutritional supplements.
And it’s not just marketing hype. Laboratory research in mice has shown that the probiotics in yogurt, which ferment the milk, are beneficial for bone health.[i] In a study published in Osteoporosis International, Swiss researchers examined yogurt consumption in healthy men and women who were recruited at the age of 65.[ii] This study included 733 healthy postmenopausal women who underwent a bone mineral density (DXA, or dual-energy X-ray absorptiometry) scan at baseline and again three years later. At the beginning of the study, women who consumed yogurt had higher bone density and were thinner than women who did not consume yogurt.
At the follow-up assessment three years later, women who ate at least one serving of yogurt per day had less bone loss than those who did not eat yogurt. These findings were independent of any other factors that could account for differences in bone density, such as physical activity, protein consumption, and total calcium intake. Also, the number of fractures trended toward a lower rate: 19 percent among yogurt consumers versus 29 percent for non-consumers.
While awareness of the beneficial effects of probiotics has become widespread, the study of bacteria and other microorganisms in the body has expanded considerably in recent years. Researchers are learning much more about how bacteria and other microbes in and on our bodies affect our health—from understanding how the microbiome might predict risk for certain conditions and diseases to how it can affect a person’s response to treatment for diseases like cancer.
What is the Microbiome?
Our bodies serve as hosts for trillions of microbes, or tiny organisms, roughly equal to the number of cells in the human body.[iii] These microorganisms, or microbiota, living in and on our body include bacteria, viruses, fungi, and protozoa; together, they make up the human microbiome.[iv]
While you may have heard of the “gut microbiome,” which refers to the microbes that live in our intestines, Ami Bhatt, MD, PhD, Assistant Professor of medicine and of genetics at Stanford University School of Medicine, notes that, “it’s important to understand that we have many microbiomes in and on our bodies,” which include the reproductive microbiome, the skin microbiome, and the oral microbiome, all of which host a vast array of microorganisms.
Each person has a unique microbiome, which initially develops during birth, when an infant exchanges microbiota with his or her mother while passing through the birth canal and via breastfeeding thereafter.[v] The microbiome continues to develop throughout the first few years of life, and the composition will shape digestive health, and immune and cognitive function.[vi] While we develop our individual microbiome at this early stage, unlike our DNA, the microbiome can change over the course of our life.
Marina Walther-Antonio, PhD, who studies the role of the human microbiome in women's health, at Mayo Clinic, says “genetic elements, immune system function, age, sex, and overall health and disease status” of a person are all factors in how our microbiome is ultimately composed. In addition, she notes, “environmental factors, including exposure to environmental microbes, diet, and medication use, particularly those with antimicrobial activity such as antibiotics” also impact the microbiome.
How Does the Microbiome Affect Our Health?
In a healthy microbiome, the “good” and “bad” bacteria coexist in balance. However, if that balance is disrupted—through environmental factors, introduction of too much bad bacteria, or medications like antibiotics, for instance—that imbalance, or dysbiosis, can lead to health problems.
Research is ongoing to understand how dysbiosis and other aspects of microbiome composition are connected to specific conditions and diseases.
Dr. Walther-Antonio says that the capacity of microbes to interfere with human cell functioning is substantial. “Microbes can produce compounds that have carcinogenic properties, such as oxidating agents, and the presence of particular microbes can also generate chronic inflammatory responses, interfering with immune surveillance and their ability to remove human cells that are defective.” In addition, she notes, “Microbes can also directly disrupt host cell functions by producing compounds that alter cellular cycling, both outside and inside the host cells.”
Research has revealed significant definitive findings describing direct connections between the microbiome and disease risk. For instance, Dr. Bhatt she says, “we know that having a microbiome that is depleted in diversity can increase an individual's risk for certain types of infections, such as Clostridium difficile, or C. diff, associated diarrhea.” And, she adds, “there are suggestions that an individual's microbiome may be connected to risk of diseases ranging from heart disease to inflammatory bowel disease to cancer, but the research in these areas is still pretty preliminary, so we need to learn more before we understand the implications of these associations.”
The potential for research into the microbiome to impact our health on such large scale is exciting, and the following expert insights and small sample of current studies offer a glimpse into this dynamic field.
One active area of current research is the connection between the microbiome and cancer risk. Dr. Walther-Antonio and a research team at Mayo Clinic have been investigating endometrial cancer through this lens.
“We’ve been exploring the possibility that particular microbes associated with endometrial cancer and endometrial hyperplasia (pre-cancer) generate environmentally induced genetic modifications (methylation, which is an epigenetic modification) that alter the cellular functioning,” she says. “We are also exploring the possibility that metabolites produced by a particular microbe (Porphyromonas somerae) disrupt the cellular cycling of the host endometrial cell.”
Dr. Walther-Antonio and colleagues have now conducted two studies to identify differences in the uterine microbiome between patients with and without endometrial cancer. The studies verified the main known risk factors for endometrial cancer (postmenopausal status and obesity) and identified high vaginal pH as an additional factor associated with patients with endometrial cancer, which led to the development of a vaginal swab screening used for endometrial cancer.[vii]
Of the research results, Dr. Walther-Antonio says, “If the microbiome does play a role in endometrial cancer, beyond being a marker for it, this could have important implications for endometrial cancer prevention.” [viii]
Johns Hopkins Kimmel Cancer Center researchers recently released results of laboratory research revealing that a microbe found in the colon and commonly associated with the development of colitis and colon cancer may also play a role in the development of some breast cancers.[ix] In the study, published in Cancer Discovery, when the toxin enterotoxigenic Bacteroides fragilis (ETBF) was introduced to the guts or breast ducts of mice, it always induced growth and metastatic progression of tumor cells.[x]
“Despite multiple established risk factors for breast cancer, such as age, genetic changes, radiation therapy, and family history, a large number of breast cancers arise in women harboring none of these, indicating the need to look beyond,” says senior study author Dipali Sharma, MS, PhD. “Our study suggests another risk factor, which is the microbiome. If your microbiome is perturbed, or if you harbor toxigenic microbes with oncogenic function, that could be considered an additional risk factor for breast cancer.”[xi]
One area of extensive microbiome research has been the role of the microbiome in inflammatory conditions connected to the gut microbiome. David Borenstein, MD, MACP, MACR, Clinical Professor of Medicine, Division of Rheumatology at The George Washington University Medical Center in Washington, DC, and Executive Editor of The Spine Community, says that “gut bacteria are constantly interacting with the immune system that resides in the gastrointestinal tract. In most circumstances, our normal microbiome protects against foreign bacteria and the maintenance of the normal gut immunity.”
However, he says, “When abnormal organisms gain access to the gut, immune responses can occur that may cause local inflammation, which can cause Inflammatory Bowel Disease (IBD), for instance, or systemic inflammation, which might result in conditions like ankylosing spondylitis (an inflammatory spinal disease).
IBD, in particular, which includes two sub-types—Crohn’s disease and ulcerative colitis—has been the subject of microbiome research. Studies have shown that the gut microbiome of people with IBD differs from healthy people, and research is ongoing to understand how the gut microbiome in IBD patients could be modified to lessen severity of symptoms or provide a cure.[xii]
Research is also underway to understand how modifying the gut microbiome may benefit patients diagnosed with ankylosing spondylitis. While studies have investigated the role of diet modifications, including the Mediterranean diet, polyunsaturated oils, and limited animal proteins, and some benefit has been reported, Dr. Borenstein notes that trial results have not been consistent. “In regard to [the role of] probiotics, benefits in decreased immune activation may be associated with the use of Bacteroides fragilis,” he says.[xiii] “However, the benefits require the use of probiotics indefinitely.”
Ultimately, Dr. Borenstein says, it’s good to keep in mind that, “our understanding of the microbiome is in its infancy. The potential to benefit human disease by modification of the microbiome does exist. What modifications, for which disease, by specific mechanisms remains to be determined.”
One area of research emerging in the wake of the COVID-19 pandemic, is the relationship between the microbiome and this virus. Dr. Bhatt says that “Researchers have speculated that one's microbiome may be connected to the severity of symptoms when they get diseases such as COVID-19.”[xiv] If these links are identified, she says, “modifying the microbiome of patients to try and decrease their symptoms or even prevent them from having severe COVID-19 disease” might be possible. But she cautions, “at present, the findings that have been presented on these topics are limited and early. Hopefully with more research, we can answer these questions better.”
Treatment and Manipulating the Microbiome
In addition to studies exploring the connection of the microbiome to disease risk, research is ongoing into how an individual’s microbiome may affect the way their body responds to various medications and treatments. It may be possible, studies suggest, that in addition to curing some conditions, manipulating the microbiome may improve a person’s response to certain therapies.
Dr. Walther-Antonio explains that, “the microbiome as a whole has a broader capacity to metabolize compounds, including drugs, than human cells do. Depending on a person’s microbiome, he or she may be exposed to a lower or higher dosage than another individual with a different microbiome.” She adds, “the microbiome can also shield host cells from drug actions by metabolizing it. One example was the finding of microbiome shielding the actions of the chemotherapy drug gemcitabine in pancreatic tumors, which prevented the drug from reaching the tumors at the intended dosage.[xv]
As we learn more about how the microbiome may influence a response to treatment, the role of Fecal Microbiota Transplantation (FMT), or stool transplant, continues to expand. In FMT, fecal microbes are transferred from one individual to another to modify the gut microbiome. This intervention is used to cure some conditions, like C. diff, by taking fecal microbes from a healthy individual and introducing them into the intestines of the patient. When used to treat Irritable Bowel Syndrome (IBS), FMT has been shown to reduce symptoms in some patients with abdominal bloating.[xvi]
Recently, FMT is also being explored as a means of manipulating the gut microbiome of patients who are not responding to specific therapies. A study conducted by researchers at the National Cancer Institute (NCI) Center for Cancer Research in collaboration with investigators from UPMC Hillman Cancer Center at the University of Pittsburgh, found that “some patients with advanced melanoma who initially did not respond to treatment with an immune checkpoint inhibitor, a type of immunotherapy, did respond to the drug after receiving a transplant of fecal microbiota from a patient who had responded to the drug.”[xvii] The results, published in Science,
“suggest that introducing certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells.”[xviii][xix]
While FMT represents an extreme intervention—an overhaul—to modulate the gut microbiome, Dr. Bhatt notes that “treatments with probiotics or with prebiotics (fiber present in certain foods), are also being explored for the treatment of a wide range of diseases.”
Moving forward, Dr. Bhatt says, there is opportunity to learn much more about the role that the microbiome can play in the treatment of disease: “I'm particularly excited about research focused on digging into the details of the microbiome. If we can identify molecules that microbes make that ‘signal’ to human cells to change human biology, we can develop new treatments based on these signals.” This area of research, she says, could lead to “microbiome-inspired treatments and interventions, which could improve symptoms and outcomes of diseases, but also improve general health.”
Given the wide range of research interests related to the microbiome, it seems clear that it will remain a rich field of study. As Dr. Bhatt notes, the preliminary studies to date have offered valuable insight into the connection of the microbiome to various conditions, but there’s still a lot to learn. “While we know that the microbiome is altered in many diseases, in many cases we don't know whether the change in the microbiome causes the disease, is a contributor to the disease, or is simply an ‘effect’ of having the disease.”
[i] Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, Bäckhed F, Ohlsson C. The gut microbiota regulates bone mass in mice. J Bone Miner Res. 2012 Jun;27(6):1357-67. doi: 10.1002/jbmr.1588. PMID: 22407806; PMCID: PMC3415623.
[ii] Biver E, Durosier-Izart C, Merminod F, et al. Fermented dairy products consumption is associated with attenuated cortical bone loss independently of total calcium, protein, and energy intakes in healthy postmenopausal women. Osteoporos Int. 2018 Aug;29(8):1771-1782. doi: 10.1007/s00198-018-4535-4. Epub 2018 May 3. PMID: 29725715.
[iii]Abbot, A. Scientists bust myth that our bodies have more bacteria than human cells. January 8, 2016. Available at: . Accessed February 15, 2021.
Scientists bust myth that our bodies have more bacteria than human cells
Decades-old assumption about microbiota revisited.
[iv] Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13(4):260-270. Published 2012 Mar 13. doi:10.1038/nrg3182
[v] Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med. 2015;21(2):109-117. doi:10.1016/j.molmed.2014.12.002
[vi] Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 2012;70 Suppl 1(Suppl 1):S38-S44. doi:10.1111/j.1753-4887.2012.00493.x
[vii] Walther-António, M.R.S., Chen, J., Multinu, F. et al. Potential contribution of the uterine microbiome in the development of endometrial cancer. Genome Med 8, 122 (2016). https://doi.org/10.1186/s13073-016-0368-y
Potential contribution of the uterine microbiome in the development of endometrial cancer
Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. We set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer. We undertook a study of the microbiome in samples taken from different locations along the female reproductive tract in patients with endometrial cancer (n = 17), patients with endometrial hyperplasia (endometrial cancer precursor, n = 4), and patients afflicted with benign uterine conditions (n = 10). Vaginal, cervical, Fallopian, ovarian, peritoneal, and urine samples were collected aseptically both in the operating room and the pathology laboratory. DNA extraction was followed by amplification and high-throughput next generation sequencing (MiSeq) of the 16S rDNA V3-V5 region to identify the microbiota present. Microbiota data were summarized using both α-diversity to reflect species richness and evenness within bacterial populations and β-diversity to reflect the shared diversity between bacterial populations. Statistical significance was determined through the use of multiple testing, including the generalized mixed-effects model. The microbiome sequencing (16S rDNA V3-V5 region) revealed that the microbiomes of all organs (vagina, cervix, Fallopian tubes, and ovaries) are significantly correlated (p < 0.001) and that there is a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases (p = 0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes (Anaerostipes, ph2, Dialister, Peptoniphilus, 1–68, Ruminococcus, and Anaerotruncus), Spirochaetes (Treponema), Actinobacteria (Atopobium), Bacteroidetes (Bacteroides and Porphyromonas), and Proteobacteria (Arthrospira). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99 % match to P. somerae) were found to be associated with disease status, especially if combined with a high vaginal pH (>4.5). Our results suggest that the detection of A. vaginae and the identified Porphyromonas sp. in the gynecologic tract combined with a high vaginal pH is statistically associated with the presence of endometrial cancer. Given the documented association of the identified microorganisms with other pathologies, these findings raise the possibility of a microbiome role in the manifestation, etiology, or progression of endometrial cancer that should be further investigated.
Postmenopause as a key factor in the composition of the Endometrial Cancer Microbiome (ECbiome)
Incidence rates for endometrial cancer (EC) are rising, particularly in postmenopausal and obese women. Previously, we showed that the uterine and vaginal microbiome distinguishes patients with EC from those without. Here, we sought to examine the impact of patient factors (such as menopause status, body mass index, and vaginal pH) in the microbiome in the absence of EC and how these might contribute to the microbiome signature in EC. We find that each factor independently alters the microbiome and identified postmenopausal status as the main driver of a polymicrobial network associated with EC (ECbiome). We identified Porphyromas somerae presence as the most predictive microbial marker of EC and we confirm this using targeted qPCR, which could be of use in detecting EC in high-risk, asymptomatic women. Given the established pathogenic behavior of P. somerae and accompanying network in tissue infections and ulcers, future investigation into their role in EC is warranted.
[ix] Parida S, Wu S, Siddharth S, et al. A pro-carcinogenic colon microbe promotes breast tumorigenesis and metastatic progression and concomitantly activates Notch and βcatenin axes. Cancer Discovery. January 6, 2021 DOI: 10.1158/2159-8290.CD-20-0537.
[x]Gut Microbe May Promote Breast Cancers [news release]. Johns Hopkins Medicine website. Available at: . Accessed February 15, 2021.
Gut Microbe May Promote Breast Cancers
Short-term exposure to B. fragilis toxin leaves lasting impression in cells, increasing the risk for cancer
[xi] Gut Microbe May Promote Breast Cancers [news release]. Johns Hopkins Medicine website. Available at: . Accessed February 15, 2021.
Gut Microbe May Promote Breast Cancers
Short-term exposure to B. fragilis toxin leaves lasting impression in cells, increasing the risk for cancer
[xii] Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol. 2020 Jan;145(1):16-27. doi: 10.1016/j.jaci.2019.11.003. PMID: 31910984.
[xiii] Stebbings SM et al. The immune response to autologous bacteroides in ankylosing spondylitis is characterized by reduced interleukin 10 production. J Rheumatol 2009;36:797-800.
[xiv] Olaimat, A.N., Aolymat, I., Al-Holy, M. et al. The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19. npj Sci Food 4, 17 (2020). https://doi.org/10.1038/s41538-020-00078-9
The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19
COVID-19 is a pandemic disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This new viral infection was first identified in China in December 2019, and it has subsequently spread globally. The lack of a vaccine or curative treatment for COVID-19 necessitates a focus on other strategies to prevent and treat the infection. Probiotics consist of single or mixed cultures of live microorganisms that can beneficially affect the host by maintaining the intestinal or lung microbiota that play a major role in human health. At present, good scientific evidence exists to support the ability of probiotics to boost human immunity, thereby preventing colonization by pathogens and reducing the incidence and severity of infections. Herein, we present clinical studies of the use of probiotic supplementation to prevent or treat respiratory tract infections. These data lead to promising benefits of probiotics in reducing the risk of COVID-19. Further studies should be conducted to assess the ability of probiotics to combat COVID-19.
Intra-tumour bacteria promote gemcitabine resistance in pancreatic adenocarcinoma
[xvi] Holvoet T, Joossens M, Vázquez-Castellanos JF, Christiaens E, Heyerick L, Boelens J, Verhasselt B, van Vlierberghe H, De Vos M, Raes J, De Looze D. Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial. Gastroenterology. 2021 Jan;160(1):145-157.e8. doi: 10.1053/j.gastro.2020.07.013. Epub 2020 Jul 15. PMID: 32681922.
[xvii] Fecal microbiota transplants help patients with advanced melanoma respond to immunotherapy. National Cancer Institute website. Available at: https://www.cancer.gov/news-events/press-releases/2021/fecal-transplants-cancer-immunotherapy. Accessed February 15, 2021https://www.cancer.gov/news-events/press-releases/2021/fecal-transplants-cancer-immunotherapy.
[xviii] [xviii] Fecal microbiota transplants help patients with advanced melanoma respond to immunotherapy. National Cancer Institute website. Available at: https://www.cancer.gov/news-events/press-releases/2021/fecal-transplants-cancer-immunotherapy. Accessed February 15, 2021https://www.cancer.gov/news-events/press-releases/2021/fecal-transplants-cancer-immunotherapy.
[xix] Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021 Feb 5;371(6529):595-602. doi: 10.1126/science.abf3363. PMID: 33542131.