by Lewis Chang, PhD
Not all heroes are muscle-bound and wear capes. There is a tiny, almost invisible, hero that lives in our gut and promotes our health and wellbeing. Its name, Akkermansia muciniphila, may be a mouthful, but it’s time to get to know this hero better, as its health-promoting effects have earned it the reputation as a next-generation beneficial bacteria.1

​Gut health is intricately connected to human health in ways that surprise us. Our gut is home to trillions of bacteria, fungi, and other microorganisms that form a complex ecosystem known as the gut microbiome. A healthy gut microbiome promotes proper digestion, strengthens our immune system to fight off infections and diseases, helps regulate our metabolism and weight, and influences our mood and brain function. On the other hand, an imbalance in the gut microbiome can lead to various health issues, including digestive problems like bloating, diarrhea, and constipation. It can also weaken our immune system, making us more susceptible to infections and inflammation.2 Additionally, an imbalanced gut microbiome has been linked to conditions such as obesity, metabolic disorders, mental health disorders, and autoimmune diseases.

Enter Akkermansia muciniphila and why it’s a guardian of our gut
The layer of mucus in our gut acts as a natural defence barrier, crucial for keeping our intestines healthy. Akkermansia muciniphila, unlike many of the known probiotic species in the gut, is unique for living inside the mucus layer, where it can interact closely with intestinal epithelial and immune cells. It feeds on mucins (key components of mucus) and produces beneficial substances called short-chain fatty acids (SCFAs), which have anti-inflammatory and antioxidant properties, improve insulin sensitivity, and help regulate appetite.3 Numerous studies have uncovered actions of Akkermansia muciniphila in the gut. For example:

• It enhances mucin production by increasing the number and density of goblet cells (mucin-producing cells), which helps restore the thickness of the mucus layer.4
• It enhances the integrity of the intestinal lining by boosting the expression of proteins that strengthen the tight junctions between cells.5
• One of its membrane proteins, Amuc_1100, interacts with toll-like receptor 2 (TLR2), triggering anti-inflammatory pathways and preventing the passage of harmful substances (such as lipopolysaccharides (LPS)).6
• The short-chain fatty acid (SCFA) acetate produced by Akkermansia muciniphila supports the growth of other beneficial bacteria, such as Faecalibacterium prausnitzii, which is known for producing another beneficial SCFA, butyrate.7 

It is believed that through reinforcing gut barrier function, Akkermansia muciniphila supports various bodily functions, such as energy, lipid and glucose metabolism, as well as immune responses.1

The connection between Akkermansia muciniphila and metabolic health
Akkermansia muciniphilia, has garnered significant attention due to its relative abundance.  The reason behind this growing interest lies in the compelling links observed between low levels of this species and various health conditions, including obesity, type 2 diabetes, high blood pressure, and liver diseases.9-14

Conversely, when Akkermansia muciniphila is more abundant in the gut, it tends to be associated with a healthier body weight, less body fat, and better insulin sensitivity.9,15 Furthermore, animal studies have shown Akkermansia muciniphila reverses metabolic disorders, weight gain caused by a high-fat diet, metabolic endotoxemia, inflammation in fat tissues, and insulin resistance.8

Given the correlation between abundance of Akkermansia muciniphila and health status, efforts have been made to restore and promote abundance of Akkermansia muciniphila, such as increasing intake of polyphenol-rich foods (e.g., EGCG),16,17 supplementing selected probiotic strains,18,19 and exercise.20 This unique species is now available in supplemental form, allowing a direct route to augment Akkermansia muciniphila abundance.

In a clinical study conducted by Patrice Cani, PhD, Willam de Vos, PhD and their colleagues, they examined the health-promoting potential of this microbe in people who were overweight or obese and had insulin-resistance.21 Thirty-two volunteers received either placebo (inactive medicine), live Akkermansia muciniphila (10 billion CFU/day), or pasteurized Akkermansia muciniphila (30 billion total fluorescent unit (TFU)/day) for three months and were asked not to change their diet and exercise habits. At the end of study, researchers found supplementation with Akkermansia muciniphila to be safe and well-tolerated and demonstrated improvements in metabolic syndrome risk factors, such as total cholesterol and insulin resistance, as well as body weight, fat mass, and hip circumference. Importantly, the pasteurized (heat-inactivated) form of Akkermansia muciniphila, not the live form, improved insulin resistance and reduced insulinemia and total cholesterol, as well as parameters elevated in obesity and glucose intolerance (i.e., white blood cell counts) and inflammation (i.e., LPS). These findings suggest the pasteurized form of Akkermansia muciniphila is more effective for addressing metabolic syndrome risk factors.21

Who can benefit from Akkermansia muciniphila supplementation?
The unique attributes of this tiny hero, Akkermansia muciniphila, has gained its recognition as a valuable player in gut and metabolic health.1 While a balanced diet and regular exercise are the cornerstones for maintaining healthy weight and minimizing metabolic syndrome risks, this next-generation bacteria, pasteurized Akkermansia muciniphila, offers a novel solution to support metabolic health in those who are overweight or obese.

Citations

1. Cani PD et al. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol. 2022;19:625-637.
2. Cani PD. Gut microbiota – at the intersection of everything? Nat Rev Gastroenterol Hepatol. 2017;14(6):321-322.
3. Derrien M et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004;54(Pt 5):1469-1476.
4. Zhu L et al. Akkermansia muciniphila protects intestinal mucosa from damage caused by S. pullorum by initiating proliferation of intestinal epithelium. Vet Res. 2020;51(1):34.
5. Ottman N et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One. 2017;12(3):e0173004.
6. Plovier H et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017;23(1):107-113.
7. Lopez-Siles M et al. Alterations in the abundance and co-occurrence of Akkermansia muciniphila and Faecalibacterium prausnitzii in the colonic mucosa of inflammatory bowel disease subjects. Front Cell Infect Microbiol. 2018;8:281.
8. Everard A et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066-9071.
9. Dao MC et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-436.
10. Yassour M et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med. 2016;8(1):17.
11. Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.
12. Li J et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017;5(1):14.
13. Grander C et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut. 2018;67(5):891-901.
14. Png CW et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420-2428.
15. Fruge AD et al. Fecal Akkermansia muciniphila is associated with body composition and microbiota diversity in overweight and obese women with breast cancer participating in a presurgical weight loss trial. J Acad Nutr Diet. 2020;120(4):650-659.
16. Zhu L et al. Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe(-/-) mice. Atherosclerosis. 2018;268:117-126.
17. Jeong HW et al. Green tea encourages growth of Akkermansia muciniphila. J Med Food. 2020;23(8):841-851.
18. Ryan JJ et al. Short-term tolerability, safety, and gut microbial composition responses to a multi-strain probiotic supplement: an open-label study in healthy adults. Integr Med (Encinitas). 2021;20(1):24-34.
19. Hibberd AA et al. Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults. Benef Microbes. 2018:1-16.
20. Munukka E et al. Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women. Front Microbiol. 2018;9:2323.
21. Depommier C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019;25(7):1096-1103.

by Noelle Patno, PhD

Introduction

Recent findings show that not only respiratory disease but also hypertension and diabetes are prevalent comorbidities associated with COVID-19 infection.1 In fact, multiple meta-analyses indicate that individuals with high blood pressure, diabetes, or cardiovascular diseases have a higher risk for the COVID-19 disease.2–4 Metabolic disease and the immune response to infections are closely tied together in the gut, from which digestion and defense originate, as the oral route into the intestine is one major way that the body encounters food and foreign substances through the intestine. Key microbial species in the intestinal microbiome have been associated with both metabolic disorders and immunological responses.

One key popular species, Akkermansia muciniphila, has been observed at higher levels in the intestinal microbiome to be associated with better metabolic health as well as being related to inflammatory and immune mechanisms for overall immune health. The species is reduced in microbiomes of the obese5,6 and those with glucose regulation impairment,7 type 2 diabetes,5,6 as well as high blood pressure.8 In addition, A. muciniphila levels are significantly lower in samples from inflammatory bowel disease (IBD) patients9,10 and are protective in preclinical models against progression of colitis,11 including the promotion of wound healing in the intestinal mucosa,12 which is needed to heal ulcerated tissue in IBD. Thus, A. muciniphila may be a key species for microbiome therapy to support intestinal metabolic and immune responses.

What does research suggest?
Research suggests that A. muciniphila participates in mechanisms that improve immune response related to metabolism. Higher endotoxin levels and the serum inflammatory marker high-sensitivity C-reactive protein (hs-CRP) are associated with significantly lower levels of A. muciniphila in nonalcoholic steatohepatitis patients.13 Animal models have shown how A. muciniphila affects glucose metabolism through underlying inflammatory response modulation, specifically, the immune system cytokine interferon gamma (IFN-y).14 Recently, A. muciniphila has been shown to induce the intestinal immune response specifically through T cell responses in mice.15 Glucose metabolism and inflammation become dysregulated during cancer as well, another situation in which A. muciniphila levels are relevant. Specifically, A. muciniphila increases the response against tumor growth during anti-PD-1 immunotherapy in cancer patients.16 Multiple studies now have shown that higher A. muciniphila is associated with beneficial response during cancer treatment.17

In an in vitro study with peripheral blood mononuclear cells (PBMCs), components from A. muciniphila modulated the cytokine response,18 suggesting that it could balance the gut ecosystem, which may be involved in how the host would respond to cytokine storm, an uncontrolled release of proinflammatory cytokines.19 Compared to other bacteria in the study, A. muciniphila’s induction was shown to be lower in inflammatory potential compared to other studied microbes.18 Many other in vitro and preclinical studies have demonstrated that the bacteria also induces anti- or proinflammatory responses depending on the context of the situation, and overall, A. muciniphila shows a protective role in intestinal immunity.20 One key preclinical study21 suggested that a certain threshold of A. muciniphila was likely protective for these intestinal barrier effects to support intestinal immune responses.

To therapeutically increase A. muciniphila in the intestine, dietary modifications have demonstrated some efficacy. A healthy lifestyle approach, including dietary modification and fiber increases, has been beneficial.22 Metformin treatment in diabetes has resulted in an increase in A. muciniphila.23,24  Multiple supplementary strategies have been explored in preclinical research to increase A. muciniphila.20 Use of probiotics to modulate A. muciniphila is an emerging area of research. One clinical trial showed that daily consumption of 10 billion CFU of probiotic Bifidobacterium lactis B420 resulted in higher levels of A. muciniphila in the gut in a large scale, randomized, placebo-controlled trial.25 In that same probiotic supplementation trial, probiotic B420 consumption was associated with a reduction in caloric intake, maintenance of body weight, and a reduction in waist circumference, while the placebo group gained weight during the six-month trial.26 Thus, the B. lactis B420 probiotic supplementation trial associated A. muciniphila increases with beneficial metabolic effects as well.  

Conclusion
Higher levels of A. muciniphila in stool samples are associated with better metabolic profiles as well as underlying immune mechanisms, while lower levels are associated with metabolic diseases and inflammatory bowel diseases. Thus, increasing this beneficial bacteria may be an approach to reduce the risk of negative health outcomes in diabetic, obese, and hypertensive patients who are also more susceptible to immunological insults.
Citations

1. Yang J et al. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis. International Journal of Infectious Diseases. 2020;94:91-95.
2. Wang B et al. Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis. Aging (Albany NY). 2020;12(7):6049-6057.
3. Emami A et al. Prevalence of underlying diseases in hospitalized patients with COVID-19: a systematic review and meta-analysis. Arch Acad Emerg Med. 2020;8(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096724/. Accessed April 27, 2020.
4. Li B et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020:1-8.
5. Dao MC et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-436.
6. Yassour M et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med. 2016;8.
7. Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.
8. Sun S et al. Gut microbiota composition and blood pressure. Hypertension. 2019;73(5):998-1006.
9. Png CW et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420-2428.
10. Rajilić-Stojanović M et al. Phylogenetic analysis of dysbiosis in ulcerative colitis during remission. Inflamm Bowel Dis. 2013;19(3):481-488.
11. Kang C et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One. 2013;8(10):e76520.
12. Alam A et al. The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol. 2016;1:15021.
13. Ozkul C et al. Determination of certain bacterial groups in gut microbiota and endotoxin levels in patients with nonalcoholic steatohepatitis. Turk J Gastroenterol. 2017;28(5):361-369.
14. Greer RL et al. Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism. Nat Commun. 2016;7:13329.
15. Ansaldo E et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science. 2019;364(6446):1179-1184.
16. Routy B et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.
17. Zhang T et al. Akkermansia muciniphila is a promising probiotic. Microb Biotechnol. 2019;12(6):1109-1125.
18. Ottman N et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One. 2017;12(3):e0173004.
19. Tisoncik JR et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16-32.
20. Xu Y et al. Function of Akkermansia muciniphila in obesity: Interactions with lipid metabolism, immune response and gut systems. Front Microbiol. 2020;11:219.
21. Schneeberger M et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015;5:16643.
22. Verhoog S et al. Dietary factors and modulation of bacteria strains of Akkermansia muciniphila and Faecalibacterium prausnitzii: A systematic review. Nutrients. 2019;11(7):1565.
23. de la Cuesta-Zuluaga J et al. Metformin is associated with higher relative abundance of mucin-degrading akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40(1):54-62.
24. Lee H et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2018;9(2):155-165.
25. Hibberd AA et al. Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults. Benef Microbes. 2019;10(2):121-135.
26. Stenman LK et al. Probiotic with or without fiber controls body fat mass, associated with serum zonulin, in overweight and obese adults—randomized controlled trial. EBioMedicine. 2016;13:190-200.

By Monazza Ahmad, B.Pharm, MSc

In the fascinating world of our microbiome, there is one bacterium that has been making waves, and that is Akkermansia muciniphila. 
Among the trillions of bacteria residing in our body (yes, that's 10 times more than our own cells!), this particular species has caught the attention of researchers and health enthusiasts alike. Discovered about 20 years ago, A. muciniphila has been continuously showing promising results in promoting healthier gut lining and overall wellbeing.1*
You might wonder, don't all good bacteria do that? What sets A. muciniphila apart? Let's explore the unique attributes of this remarkable bacterium and discover how you can increase its levels to unlock its outstanding health benefits.* 

Uncovering Akkermansia muciniphila and the secret to its success
A. muciniphila is quite a unique character on the stage of the bacterial world. It thrives in areas with limited oxygen supply, making it particularly adept at flourishing even in tissues that have less oxygen supply.2

A. muciniphila does not follow the same dietary rules as its bacterial counterparts. While many bacteria rely on fiber for growth, A. muciniphila doesn't need it to survive. It can thrive on its own, without the need for any additional nutrients to reproduce.

Originating from Greek, muciniphila translates to “mucin-loving.” And true to its name, this bacterium resides in the mucus lining of our intestines, where it finds its energy source—mucin. By feasting on mucin, it encourages our epithelial cells to produce even more of it. What's so special about mucin? Mucin is a molecule that lubricates the gut lining, playing a crucial role in strengthening the walls of our gut against allergens and debris.*

Unveiling the impact of A. muciniphila on the microbial community
Here is another interesting fact about Akkermansia muciniphila: It turns mucin into something incredibly beneficial for our gut health—short-chain fatty acids (SCFAs), such as butyrate, which can be used as food by other friendly bacteria in our body. This quality makes A. muciniphila a “cross-feeder.” It makes up about 3-4% of the gut lining in healthy people, populating our gastrointestinal tract within the first year of life through breast milk but gradually decreasing as we age. Hence, it’s critical to give it lifelong care to maintain a thriving gut environment.3*

Unraveling the importance of Akkermansia in improving health
Research on the effects of A. muciniphila on human health is ongoing, but some studies have shown encouraging results, indicating that A. muciniphila may offer potential benefits for various aspects of health:

Excess weight: Overweight individuals are mostly found to have lower levels of A. muciniphila alongside other beneficial bacteria as compared to their lean counterparts. By increasing the thickness of the protective mucus layer in the intestines and enhancing gut barrier function, this microbe blocks bacteria and other substances from entering our bloodstream. The result? Our metabolic health gets a boost! From blood sugar and cholesterol to blood pressure and waist circumference, A. muciniphila helps keep them all in check.4,5*

Glucose regulation: Did you know that a thinner mucus layer is associated with health risks? This is why, if you have an adequate amount of A. muciniphila in your body, it will boost healthy gut mucus lining and improve glucose metabolism. By degrading the mucus layer in the intestines, A. municiphila can increase the production of SCFAs, which keeps the glucose regulated and produces energy in your body.6*
Therefore, supplementation with A. muciniphila can lead to reduced fat mass, improved insulin metabolism, and better blood sugar control—factors that are essential in tackling blood sugar health.7*

Cardiovascular health: There are several cardiovascular markers shown to improve with the presence of Akkermansia in the body. This bacterium works wonders helping to promote healthy arteries and healthy blood pressure. How does it support our hearts? By producing the superstar butyrate!8-13*

Understanding the difference between live vs. pasteurized forms
One more thing to consider is the live and pasteurized forms of Akkermansia. Although the difference in their effects is still inconclusive, most studies found the pasteurized form to be more effective than the live form.14,15*

Nurturing the growth of Akkermansia for optimal health
There are many ways to naturally enhance the production of this beneficial bacteria in your body.

Foods that help16,17

• Dietary fiber: Adopt a diet rich in fiber from fruits, vegetables, whole grains, legumes, and nuts, such as a Mediterranean diet, that encourages the growth of A. muciniphila.*
• Prebiotics: Incorporate prebiotic-rich foods into your diet. Prebiotics are nondigestible fibers that support the growth and activity of beneficial gut bacteria.* Foods like onions, garlic, leeks, asparagus, yacon root, and bananas are good sources of prebiotics.
• Polyphenol-rich foods: Foods rich in polyphenols, such as berries (especially cranberries), cocoa, green tea, and red wine (in moderation), may have a positive impact on your gut health and promote the growth of A. muciniphila.*
• Probiotics and fermented foods: While A. muciniphila itself is not commonly available as a probiotic supplement, consuming other probiotics and fermented foods (e.g., yogurt, kefir, sauerkraut, kimchi) may help create a gut environment that supports A. muciniphila growth.*
• Omega-3 fatty acids: Fatty fish such as salmon, mackerel, sardines, etc. as well as flaxseeds and chia seeds are a good source of fish oils to boost Akkermansia production.*

Lifestyle that helps6,16

• Avoid high-fat diets and alcohol: High-fat diets, especially those rich in unhealthy fats, as well as alcohol may negatively impact the gut microbiome. Strive for a balanced diet with healthy fats, stay away from fast food, and limit alcohol consumption.16

• Regular exercise: Regular physical activity has been associated with a more diverse and beneficial gut microbiome, which may also promote the growth of A. muciniphila.18

• Stress management: Chronic stress can negatively affect gut health. Engaging in stress-reducing activities such as meditation, yoga, or spending time in nature may be beneficial.19

Remember that individual responses to dietary and lifestyle changes can vary, and it's important to make these adjustments as part of an overall healthy lifestyle. So don’t forget to consult with your healthcare provider before making significant changes to your diet or lifestyle!

Navigating the caveats: potential risks of overabundance of Akkermansia
Just like anything out of balance in life, the overabundance of this bacteria may bring some risks as well. For example, excess Akkermansia in the body may upset the intestinal barrier due to overconsumption of mucin that makes up the epithelial lining to prevent the passage of bacteria.20*

There are other emerging studies on the possible association of the abundance of A. muciniphila with certain health parameters. Whether it’s detrimental or supportive is yet to be concluded.21-24

Remember, moderation is the key! Just like any other supplements, make sure to avoid overconsumption and always consult with your healthcare practitioner before starting supplementation. 

​References:
1. Zitong L et al. Front Microbiol. 2022;13:1037708.
2. Rodrigues CF et al. Front Immunol. 2022;13:934695.
3. Zhang T et al. Microb Biotechnol. 2019;12(6):1109-1125.
4. Mayorga-Ramos A et al. Front Nutr. 2022(9).
5. Xu Y et al. Front Micriobiol. 2020;11:219.
6. Suriano F et al. Front Immunol. 2022;13:953196.
7. Hasani A et al. J Med Microbiol. 2021;70(10).
8. Li J et al. Circulation. 2016;133(24:2434-2446.
9. Wassenaar TM et al. Eur J Microbiol (Bp). 2018;8(3):64-69.
10. Mohammad S et al. Front Immunol. 2020;11:594150.
11. Luo X et al. Int J Mol Sci. 2023;24(5):4955.
12. Tilves C et al. JAHA. 2022;11(13).
13. Yan J et al. Gut Microbes. 2021;13(1):1984104.
14. Choi Y et al. Microorganisms. 2021;9(10):2039.
15. Ashrafian F et al. Scientific Reports. 2021;11:17898.
16. Zhou K. J Funct Foods. 2017;33:194-201.
17. Anonye BO. Front Immunol. 2017;8.
18. Hintikka JE et al. Scientific Reports. 2023;13:11228. 
19. Madison A et al. Curr Opin Behav Sci. 2019;28:105-110.
20. Qu S et al. Front Microbiol. 2023;14:1111911.
21. Wang K et al. Front Microbiol. 2022;13:932047. 
22. Nishiwaki H et al. NPJ Parkinsons Dis. 2022;8:65.
23. Fang X et al. Curr Med Sci. 2021;41(6):1172-1177.
24. Floch N. Science Direct. 2017. 

by Ashley Jordan Ferira, PhD, RDN

Recent research from three well-known cohorts, The Nurses’ Health Study (NHS), NHS2 and Health Professionals’ Follow-Up Study (HPFS), reveals that higher magnesium intake is associated with lower risk of type 2 diabetes (T2D), particularly in diets with poor carbohydrate quality.1

Green leafy vegetables, unrefined whole grains, and nuts are richest in magnesium, while meats and milk contain a moderate amount.2 Refined foods, like carbohydrates (carb), are poor sources of magnesium. Diets with poor carb quality are characterized by higher glycemic index (GI), higher glycemic load (GL), and lower fiber intake. These poor carbs require a higher insulin demand.

The typical American diet is low in vegetables and whole grains, resulting in reduced magnesium intake.

The Recommended Daily Allowance (RDA) for magnesium is 310-320 mg/day for adult women and 400-420 mg/day for adult men.3 Half of the US population fails to meet their daily magnesium needs, and hypomagnesemia exists in 1/3 of adults.4-5 Magnesium is needed for normal insulin signaling; current research has linked insufficient magnesium intake to prediabetes, insulin resistance and T2D.4 Increased magnesium intake has been inversely associated with T2D risk in observational studies.6

​Collaborators from Tufts University, Harvard University, and Brigham and Women’s Hospital, sought to investigate the impact of magnesium intake, from both dietary and supplemental sources, on the risk of developing T2D in subjects who had diets with poor carb quality and raised GI, GL, or low fiber intake.1 They followed three large prospective cohorts, NHS, NHS2 and HPFS (totaling over 202,700 participants). Dietary intake was quantified by validated food frequency questionnaires (FFQ) every 4 years, and T2D cases were captured via questionnaires. Over 28 years of follow-up, there were 17,130 cases of T2D.

Major study findings included:1

• Increased magnesium intake (390-470 mg/day) was associated with a 15% lower risk of developing T2D compared to lower magnesium intake (229-280 mg/day)
• Risk of T2D was reduced by 4% with each additional 50 mg/day of magnesium intake
• In diets with poor carb quality, magnesium was more strongly, and inversely, associated with T2D

Consuming a poor carb quality diet over the long-term may increase the demand on pancreatic beta cells, contributing to beta cell exhaustion and failure, resulting in increased risk for diabetes. Magnesium may help mitigate this process. Low magnesium may not only be a cause of diabetes, but also a consequence. 

Similar to the US population estimates, 40-50% of study participants had inadequate magnesium intake. A healthful, varied diet and supplemental magnesium (especially in diets that restrict or exclude carbohydrates, dairy or meat) are essential to ensure sufficient daily magnesium intake.

Why is this Clinically Relevant?

• Magnesium is an essential macromineral that is under-consumed by at least ½ of the US population
• Magnesium is required for normal insulin signaling and action
• Poor carbohydrate diet quality is characterized by higher GI and GL as well as lower fiber intake leading to increased insulin demand
• Inadequate magnesium intake and status are inversely associated with diabetes risk
• HCPs can help patients achieve magnesium sufficiency through a healthful diet of unrefined whole grains, green leafy vegetables, legumes, meats, and dairy
• If dietary input and/or blood level of magnesium are found to be insufficient, a magnesium supplementation regimen should be considered

Link to Abstract

Citations

1. Hruby A, Guash-Ferré M, Bhupathiraju SN, Manson JE, Willett WC, McKeown NM, Hu FB. Magnesium intake, quality of carbohydrates, and risk of type 2 diabetes: results from three U.S. cohorts. Diab Care. 2017;40(12):1695-1702.
2. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Magnesium. https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/. Accessed December 6, 2017.
3. Institute of Medicine (IOM). Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC: National Academy Press, 1997.
4. U.S. Department of Health and Human Services and U.S. Department of Agriculture. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Advisory Report to the Secretary of Health and Human Services and the Secretary of Agriculture. 2015. https://health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.pdf. Accessed November 9, 2017,
5. Hruby A, McKeown NM. Magnesium deficiency: what is our status? Nutr Today.2016;51:121-128.
6. Gommers LMM, Hoenderop JGJ. Hypomagnesemia in type 2 diabetes: a vicious circle? Diabetes 2016;65:3-13.

Urinary Tract Infections (UTIs) aren't just a health inconvenience; they're a global epidemic, affecting millions worldwide, with Africa bearing a particularly heavy burden of 150 million cases annually. However, amidst this alarming statistic, there's a glimmer of hope: the potential of natural solutions in tackling this pervasive issue.

The UTI Epidemic:

UTIs, primarily instigated by the bacterium E. coli, pose a significant health challenge, especially for women, with half experiencing at least one UTI in their lifetime. The recurring nature of UTIs complicates treatment, often rendering conventional approaches inadequate.

Harnessing Nature's Arsenal:

Natural ingredients offer promising avenues in UTI management:

D-Mannose: A naturally occurring monosaccharide, D-mannose emerges as a formidable weapon against UTIs. Its mechanism involves binding to E. coli bacteria, impeding their attachment to bladder walls, and facilitating their expulsion via urine. Studies highlight its superiority over antibiotics in preventing recurrent UTIs.

Cranberry: Famed for its anti-adhesion properties, cranberry contains proanthocyanidins that deter E. coli attachment to urinary epithelial cells, thus diminishing infection risk. Moreover, cranberry's proanthocyanidins disrupt biofilm formation, further hindering bacterial colonization.

Quercetin: This potent flavonoid boasts antioxidant and anti-inflammatory prowess, making it a valuable ally in UTI combat. Its antibacterial action, particularly against E. coli, coupled with biofilm inhibition, enhances efficacy in UTI management.

Vitamin C: Beyond bolstering the immune system, vitamin C wields antibacterial effects, bolstering the body's defense against UTIs.

2’-Fucosyllactose: Derived from human milk, 2’-Fucosyllactose acts as a decoy for pathogens, thwarting their colonization and adhesion to epithelial cells in the gut—a pivotal aspect of UTI prevention.

The Proof in Research:
Pilot studies featuring women with UTIs showcase significant symptom and quality of life enhancements with D-mannose supplementation.
Combining D-mannose and cranberry with antibiotics elevates cure rates by a remarkable 53%, underscoring the ingredients' synergistic effects.
Comparative investigations between D-mannose and antibiotics for recurrent UTI prevention highlight D-mannose's superiority, offering renewed hope to recurrent infection sufferers.
In Conclusion:

Despite the daunting prevalence of UTIs, natural remedies offer a beacon of hope. By harnessing the potency of nature's arsenal, UTI management transcends conventional limitations. Bid adieu to UTI discomfort and embrace a journey toward wellness with nature's nurturing touch—a journey powered by D-mannose, cranberry, quercetin, vitamin C, and 2’-Fucosyllactose.

References:

1. Sihra N, et al. Nonantibiotic prevention and man-agement of recurrent urinary tract infection. Nature. 2018;15:750-776.
   
2. Mwang'onde BJ, Mchami JI. The aetiology and prevalence of urinary tract infections in Sub-Saharan Africa: a Systematic Review. J Health Biol Sci. 2022;10(1):1-7. doi:10.12662/2317-3206jhbs. v10i1.4501.p1-7.2022. Available from: https://fi-admin.bvsalud.org/document/view/mww44
   
3. Wagenlehner F, et al. Why d-Mannose May Be as Efficient as Antibiotics in the Treatment of Acute Uncomplicated Lower Urinary Tract Infec-tions-Preliminary Considerations and Conclusions from a Non-Interventional Study. Antibiotics (Basel). 2022;11(3):314. Published 2022 Feb 25. doi:10.3390/antibiotics11030314
4. Rădulescu D, et al. Combination of cranberry extract and D-mannose - possible enhancer of uropathogen sensitivity to antibiotics in acute therapy of urinary tract infections: Results of a pilot study. Exp Ther Med. 2020;20(4):3399-3406. doi:10.3892/etm.2020.8970
5. Reygaert W, et al. Green tea as an effective antimicrobial for urinary tract infections caused by Escherichia coli. Front Microbiol. 2013 Jun 18;4:162.
   
6. Friedman M. Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol Nutr Food Res. 2007 Jan.
   
7. Memariani H, et al. An overview on anti-biofilm properties of quercetin against bacterial pathogens. World J Microbiol Biotechnol. 2019 Sep 6;35(9):143.
   
8. Rodriguez-Pérez C, et al. Antibacterial activity of isolated phenolic compounds from cranberry (Vaccinium macrocarpon) against Escherichia coli. Food Funct. 2016 Mar;7(3):1564-1573.
   
9. Pinzón-Arango PA, et al. Role of cranberry on bacterial adhesion forces and implica-tions for Escherichia coli-uroepithelial cell attachment. J Med Food. 2009 Apr;12(2):259-270.
   
10. Carlsson S, et al. Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide. 2001;5(6):580-586. doi:10.1006/niox.2001.037.
    
11. Mydock-McGrane LK, et al. Rational design strategies for Fim H antagonists: new drugs on the horizon for urinary tract infection and Crohn's disease. Expert Opin Drug Discov. 2017 Jul;12(7):711-731.
12. 12. Kranjčec B, et al. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014 Feb;32(1):79-84\
    
13. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9(11):1211. Published 2017 Nov 3. doi:10.3390/nu9111211
    
14. Vazquez E, et al. Major human milk oligosaccharides are absorbed into the systemic circulation after oral administration in rats. Br J Nutr. 2017;117(2):237-247. doi:10.1017/S0007114516004554
    
15. Lin AE, et al. Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J Infect Dis. 2014;209(3):389-398. doi:10.1093/infdis/jit464
    
16. Triantis V, et al. Immunological Effects of Human Milk Oligosaccharides. Front Pediatr. 2018;6:190. Published 2018 Jul 2. doi:10.3389/fped.2018.00190
    
17. Mann R, et al. Metabolic Adaptations of Uropathogenic E. coli in the Urinary Tract. Front Cell Infect Microbiol. 2017;7:241. Published 2017 Jun 8. doi:10.3389/fcimb.2017.00241
    
18. Bae JY, et al. Antibacterial activities of polyphenols against foodborne pathogens and their application as antibacterial agents. Food Sci Biotechnol. 2022;31(8):985-997. Published 2022 Mar 7. doi:10.1007/s10068-022-01058-3
19. Cooper TE, et al. D‐mannose for preventing and treating urinary tract infections. Cochrane Database of Systematic Reviews 2022, Issue 8. Art. No.: CD013608. DOI: 10.1002/14651858. CD013608.pub2. Accessed 15 March 2024.
20. González de Llano D, et al. Anti-Adhesive Activity of Cranberry Phenolic Compounds and Their Microbial-Derived Metabolites against Uropathogenic Escherichia coli in Bladder Epithelial Cell Cultures. International Journal of Molecular Sciences. 2015; 16(6):12119-12130. https://doi. org/10.3390/ijms16061211

by Bianca Garilli, ND
For women, the pre- and post-menopausal years represent a time of major change in many aspects of life including spiritual, emotional, and physical. From a physical perspective, shifting levels of sex hormones such as dehydroepiandrosterone (DHEA), testosterone, and estrogen play critical roles in the transition in and through menopause. It’s during this chapter of a woman’s life that the number of ovarian follicles begin to decline. Their eventual depletion cause the ovaries to no longer respond to FSH and LH from the pituitary, resulting in cessation of estrogen and progesterone production from the ovaries.1 Declining estrogen levels typically begin several years before the final menstrual period (FMP)- which is defined as the cessation of the menstrual period for at least 1 year- and stabilize around two years after the FMP.2

In a similar fashion, testosterone levels change in women during the menopausal timeframe, although this sex hormone does not seem to experience as dramatic of a decline as estrogen. Frequently this results in a higher ratio of testosterone to estrogen in the post-menopausal timeframe.3 This higher testosterone level as compared to estrogen level has been associated with higher risk factors for cardiovascular disease (CVD) in women, although the impact on incident events of CVD, coronary heart disease (CHD), and heart failure (HF) in response to this sex hormone ratio is less clear.4

A study published in the Journal of the American College of Cardiology studied 2,834 post-menopausal women from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, with a mean age of 64.9 years and without CVD at baseline.4 Levels of testosterone, estradiol, DHEA, and sex hormone-binding globulin (SHBG) were assessed at the beginning of the study; participants were followed for an average of 12.1 years.4 Levels of sex hormones were evaluated for association with incident CVD, CHD, and HF. Adjustments were made for relevant variables including demographics, CVD risk factors, and hormone therapy use.4

The study found no associations between DHEA nor SHBG levels with incident CVD, CHD, and HF outcomes.4 However, an elevated risk for incident CVD, CHD, and HF events was found to be associated with a higher testosterone/estradiol ratio, with higher testosterone levels associated with higher CVD and CHD.4 Conversely, higher estradiol levels were associated with a lower CHD risk, leading the authors of this study to conclude that “sex hormone levels after menopause are associated with women’s increased CVD risk later in life”.4

Why is this Clinically Relevant?

• Hormone levels and their ratios are important biomarkers to review pre- and post-menopause
• It’s important to support balanced testosterone/estradiol ratios in post-menopausal women
• Women experiencing risk factors for CVD disease should discuss testing for sex hormone levels to mitigate additional risk through an imbalance of testosterone/estradiol levels

View the abstract
Citations

1. Dalal PK, Agarwal M. Postmenopausal syndrome. Indian J Psychiatry. 2015;57(Suppl 2):S222–S232.
2. Santoro N, Randolph JF Jr. Reproductive hormones and the menopause transition. Obstet Gynecol Clin North Am. 2011;38(3):455–466.
3. Kim C, Harlow SD, Zheng H, McConnell DS, Randolph JF Jr. Changes in androstenedione, dehydroepiandrosterone, testosterone, estradiol, and estrone over the menopausal transition. Womens Midlife Health. 2017;3:9.
4. Zhao D, Guallar E, Ouyang P, et al. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. J Am Coll Cardiol 2018;71(22)2555-2566. 

by Bianca Garilli, ND
The demarcations of a woman’s physiological stages of life are often delineated by the various, unique phases and cycles associated with fertility, reproduction, and the hormones at work behind the scenes. These stages include:1

• Signaling of possible fertility at menarche
• Rhythm of monthly menstrual cycles controlled by the peaks and valleys of estrogen and progesterone
• Miraculous growth of new life during pregnancy
• Production of irreplicable nutrition for baby via breastmilk
• Rebalancing dance of hormones during postpartum period
• Eventual decline and shift of hormonal production during perimenopause
• Menopause signals the end of the fertile phase of a woman’s life and, in many women, imparts a sense of liberation and movement into new areas of spiritual and physical health and wellbeing

All of these phases are controlled by and linked to one another through changes in hormones, mostly estrogen, progesterone, FSH, LH, and testosterone.1,2 These natural cycles of a woman’s hormones, however, are not always carefree nor symptom-free. In particular, the transition time between regular menstrual cycles and menopause, known as perimenopause, is a phase frequently marked by changes in a woman’s physical, mental, and emotional health. Some of the more common symptoms experienced during perimenopause include:2 irregular periods, mood changes, vaginal and bladder concerns, decreased fertility, sexual desire changes, bone loss, headaches, changes in cholesterol levels, and commonly, hot flashes and sleep problems.

For many women, after many years of sleep deprivation during the child-bearing and rearing years, a good night’s rest is welcomed. Unfortunately, perimenopause, which typically begins sometime in a woman’s mid-to-late 40s and can last anywhere from 2-10 years, may create a whole new set of sleep challenges.2,3

Prevalence of sleep problems during perimenopause
Compared to men, sleep complaints are approximately twice as prevalent in women of all ages, with a prevalence during perimenopause ranging from 39-47%, underscoring the importance of investigating sleep problems in a female-centric way.3
To this end, sleep duration and quality of a nationally representative sample of women 40-59 years of age were studied by the CDC and broken down categorically by menstrual cycle/menopausal phase; sleep data during the perimenopausal phase revealed that:4

• 56% of perimenopausal women sleep < 7 hours/night, on average. A lower prevalence of postmenopausal and premenopausal women reported sleeping < 7 hours/night (40.5% and 32.5%, respectively)
• 24.8% of perimenopausal women say they have trouble falling asleep ≥ 4x per week
  • 30.8% of perimenopausal women have difficulty staying asleep at least 4 nights per week
• 49.9% of perimenopausal women wake up in the morning feeling tired ≥ 4 days per week

Hormones are at play
Sex hormones
So what is happening during perimenopause that so dramatically and negatively impacts sleep patterns? For starters, the decline in levels of sex hormones (in particular estrogen, progesterone, and testosterone) during the perimenopausal years lead to an array of symptoms, most of which can adversely affect sleep habits. These include: hot flashes, migraines, sleep apnea, circadian rhythm abnormalities, restless legs syndrome, lifestyle factors, as well as mood disturbances such as anxiety.2,4,5

Interestingly, in an analysis reviewing sleep concerns in various stages of menses/menopause, it was found that vasomotor symptoms (hot flashes) and sleep disturbances may work bidirectionally.6 In other words, hot flashes may increase difficulties obtaining appropriate duration and quality of sleep, while sleep problems may worsen vasomotor symptoms,6 a circuitous “what came first?- chicken or egg,” kind of hormonal dance.

The types of sleep disturbances most often noted by perimenopausal women include difficulties with initiating and/or maintaining sleep, as well as frequent nocturnal and/or early morning awakenings.5 It’s well known that during perimenopause, estrogen levels drop sharply, corresponding to many of the symptoms associated with this transition period. However, less well known is another hormone whose levels decline and no doubt, play a key role in sleep dysfunction. That hormone is melatonin, which decreases during perimenopause, although the decline in melatonin is more gradual than that of estrogen.7

Melatonin
Melatonin secretion from the pineal gland drops as individuals hit their mid-life years, coinciding with the perimenopausal phase in women.7 An article published in the Journal of Sleep Disorders and Therapy indicates that exogenous use of melatonin may improve some of these sleep challenges, including the nocturnal awakenings observed during perimenopause.5 Further research indicates that the use of slow-release melatonin preparations increase total sleep time and sleep efficiency, as well as reducing sleep latency in patients with insomnia.5

Interestingly, melatonin may also play a role in the modulation of many symptoms and conditions associated with menopause, including reduction in bone density, mood disorders, fibromyalgia, and potentially even neurodegenerative diseases.7 Assuredly, much more research is needed in the area of sleep disorders, perimenopause, and related hormonal fluctuations.

Sociodemographic factors
Sociodemographic variables can also contribute to perimenopausal sleep disturbances:

• Race/ethnicity: Prevalence of sleep difficulties is lowest in Japanese women (28.2%), followed by Chinese women (31.6%), African American women (35.5%), Hispanic women (38%), and Caucasian women (40.3%)8
• Socioeconomic status: One study found that lower income and higher financial stress increase the risk of experiencing sleep disturbances during perimenopausal years9
• Social/partnership health: Improved sleep quality has been associated with marital happiness: “Analysis of women’s relationship histories over the 6–8 years prior to the sleep study showed advantages in sleep for women who were consistently partnered versus women who were unpartnered throughout this interval, or those who had lost or gained a partner over that time course.”10,11

It’s easy to see there are myriad factors that can affect sleep health during perimenopause. It’s also important to understand that effective and individualized solutions are critical, as poor sleep quality and quantity are associated with an increased risk for chronic health conditions such as cardiovascular disease and diabetes.4
Women who are experiencing sleep concerns should work with a healthcare practitioner trained to 1) take a deep dive into the various aspects of lifestyle that may be affecting sleep health and 2) identify and address any deleterious health consequences from inadequate sleep. These areas should encompass the full spectrum of her individual health and wellness, from a focused cardiovascular and metabolic exam, to an in-depth look into the social and emotional aspects of her life. Each of these areas is important to consider and address to effectively and safely treat sleep challenges during the perimenopausal years and beyond.
 Citations

1. Merck Manual. Female Reproductive Endocrinology. https://www.merckmanuals.com/professional/gynecology-and-obstetrics/female-reproductive-endocrinology/female-reproductive-endocrinology. Accessed January 24, 2019.
2. Mayo Clinic. Perimenopause. https://www.mayoclinic.org/diseases-conditions/perimenopause/symptoms-causes/syc-20354666. Accessed January 24, 2019.
3. Kravitz H et al. Sleep during the perimenopause: a SWAN story. Obstet Gynecol Clin North Am. 2011;38(3):567–586.
4. CDC. Sleep duration and quality among women aged 40-59, by menopausal state. https://www.cdc.gov/nchs/products/databriefs/db286.htm. Accessed January 25, 2019.
5. Jehan S et al. Sleep disorders in postmenopausal women. J Sleep Disord Ther. 2015;4(5):1000212.
6. Thurston RC et al. Beyond frequency: Who is most bothered by vasomotor symptoms? Menopause. 2008;15:841–847.
7. Jehan S et al. Sleep, melatonin, and the menopausal transition: what are the links? Sleep Sci. 2017;10(1):11–18.
8. Sowers MF et al. SWAN: a multicenter, multiethnic, community-based cohort study of women and the menopausal transition. In: Menopause: biology and pathobiology.Orlando, Fla: Academic Press Inc. 2000:175–188.
9. Hall M et al. Socioeconomic status as a correlate of sleep in African-American and Caucasian women. Ann N Y Acad Sci. 1999;896:427-430.
10. Troxel WM et al. Marital happiness and sleep disturbances in a multi-ethnic sample of middle-aged women. Behav Sleep Med. 2009;7(1):2-19.
11. Troxel WM et al. Marital/cohabitation status and history in relation to sleep in midlife women. Sleep. 2010;33(7):973-981.

Angela Kelly, MA and Michael Stanclift, ND
This is the last installment of a three-part series on bacterial vaginosis (BV). In part one, we discussed a healthy vaginal microbiome, symptoms, and diagnostic criteria. In part two , we highlighted the risk factors that contribute to BV, the health impacts it can cause, and conventional antimicrobial treatments, along with their propensity for resistance.

As we saw in part two , conventional antimicrobials often only temporarily resolve BV, and contribute to antibiotic resistance. For this reason, many patients turn to alternative treatments. In addition, new therapeutics are appearing and some show great promise. It is important to note that treatments such as boric acid, prebiotics, garlic, vaginal microbiome transplantation, Zataria Multiflora cream, vitamin C, antiseptics, and seaweed extracts have limited clinical data to support their use.  However, multiple clinical trials can be found supporting the use of probiotics for the treatment of BV.

Boric acid
Though toxic if taken orally, boric acid administered intravaginally has been used to treat vaginal infections for over 100 years.1 It can lower the rate of BV recurrences when used as a complementary therapy to antimicrobials.2 A recent study shows the potential for boric acid as a standalone treatment for BV.3 Side effects are uncommon (< 10% of cases) but include watery discharge during treatment, vaginal burning sensations, and vaginal erythema.4

Prebiotics
Prebiotics feed beneficial microorganisms. In a randomized double-blind study from 2012, a prebiotic gel containing prebiotics from the glucooligosaccharides (GOS) family was shown to quickly restore the vaginal microbiota.5 Additionally a clinical study from 2017 showed that prebiotic gels may also improve the success of BV treatments.6

Garlic
A 2013 study comparing garlic tablets to oral metronidazole found that garlic tablets were as effective as metronidazole with far fewer reported side effects.7 Side effects of garlic tablets were more tolerable than metronidazole and included heartburn and nausea.7

Vaginal microbiome transplantation
Vaginal microbiome transplantation (VMT) involves seeding a recipient’s vaginal microbiome with the bacteria from a healthy donor. A 2019 study of VMT successfully treated four out of five participants with intractable and recurrent BV.8 In some cases, multiple VMT treatments may be necessary.8

Zataria multiflora cream
Also known as Shirazian thyme, Zataria multiflora is a plant native to Iran, Afghanistan, and Pakistan. The plant’s essential oil contains thymol and carvacrol, which have antibacterial properties.9 A 2008 clinical trial revealed Zataria multiflora vaginal cream to be as effective in treating BV as metronidazole vaginal cream.9 Adverse side effects of treatment included nausea, vaginal dryness, and burning.

Vitamin C
In a 2011 clinical trial it was shown that when administered intravaginally, silicon-coated vitamin C tablets were as effective as metronidazole gel in treating BV and were beneficial in preventing recurrences.10 However, not all participants were able to tolerate treatment due to itching, burning, and pain.10

Antiseptics
In a study of patients with recurrent BV, Octenidine showed high initial cure rates over 87%; however, the development of bacterial resistance to Octenidine was very high with 37.5% of patients showing complete resistance at three treatments/one-year follow-ups.11 At six months the relapse rate of patients included in this study were as high as 66.6%.11

Seaweed extracts
Preclinical research found that ethanol extract of green seaweed (U. Pertusa) possesses robust antimicrobial activity against G. vaginalis, which may have potential as a future treatment for BV.12

Probiotics: Lactobacillus reuteri RC-14 and Lactobaciullus rhamnosus GR-1
Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”13 Currently, probiotics are not recommended as a standalone treatment for BV. However, supplementation with probiotics appears to be beneficial in managing BV, regardless of concurrent antimicrobial treatment.14
Probiotics are a promising complementary therapy to antimicrobials for the treatment of BV.15-20  Studies have shown that when taken orally, lactobacillus probiotics are safe and can improve the vaginal microbiota.16,21 Lactobacillus reuteri RC-14, which was first isolated from a healthy woman’s urogenital tract, can displace G. vaginalis biofilms in vitro.22Studies combining L. reuteri RC-14 and L. rhamnosus GR-1 show success in colonizing and rebalancing the vaginal microflora.16,21,23 Women treated with a combination of metronidazole, L. rhamnosus GR-1, and L. reuteri RC-14 were more than twice as likely to achieve cure than withantimicrobials alone (88% vs. 40%).15 Another study showed using tinidazole for treating BV was improved when combined with L. rhamnosus GR-1 and L. reuteri RC-14.24 In that study, researchers showed an 87.5% cure rate in probiotic group vs. 50% cure rate in the antibiotic/placebo group.24

​A randomized, double-blind, placebo-controlled trial (RCT) in postmenopausal women with L. rhamnosus GR-1 and L. reuteri RC-14 as a standalone preventative therapy resulted in a shift from “indeterminate” to “normal” vaginal microbiota in 60% of the women in the probiotic group vs. 16% of women in the control group.25 Another RCT revealed that L. rhamnosus GR-1 and L. reuteri RC-14 may prevent BV infections in women with HIV.26
So how do these probiotics, which are taken orally, work to help the vaginal microbiome? L. rhamnosus GR-1 and L. reuteri RC-14 can colonize the vagina from the intestinal tract via the perineum.16,27 Lactobacilli weaken biofilms by producing lactic acid, hydrogen peroxide, bacteriocins, and antiadhesive biosurfactants.20 Biosurfactants produced by L. rhamnosus GR-1 and L. reuteri RC-14 work to disrupt the biofilms created by Gardnerella and residing multispecies anaerobes.20 This disruption allows probiotic strains to displace/crowd out pathogenic bacteria.20 L. rhamnosus GR-1 may also positively impact mucosal immunity, allowing the host to defend against pathogenic bacteria through colonization of the gut or vagina or both.16
With the low long-term cure rate of antibiotics in treating BV and the growing threat of antibiotic resistance, the use of probiotics in treating BV should continue to be explored further.

Final thoughts
BV infections can result in devastating physical, reproductive, and emotional health consequences for women and their partners. The high rate of recurrence underlines the need to improve the current standard of care. Finding personalized, effective, long-term solutions to BV requires ingenuity and tenacity. Emerging BV treatments offer clinicians better solutions to help patients stop the revolving door of BV. Liberating women from a cycle of recurring BV is well worth the endeavor.
Citations

1. Zeron Mullins M et al. BASIC study: is intravaginal boric acid non-inferior to metronidazole in symptomatic bacterial vaginosis? Study protocol for a randomized controlled trial. 2015;16(315).
2. Reichman O et al. Boric acid addition to suppressive antimicrobial therapy for recurrent bacterial vaginosis. Sex Transm Dis. 2009;36:732–734.
3. Marrazzo JM et al. Safety and efficacy of a novel vaginal anti-infective, TOL-463, in the treatment of bacterial vaginosis and vulvovaginal candidiasis: a randomized, single-blind, phase 2, controlled trial. Clin Infect Dis. 2019;68(5):803-809.
4. Iavazzo C et al. Boric acid for recurrent vulvovaginal candidiasis: the clinical J Womens Health. 2011;20:1245–1255.
5. Coste I et al. Safety and efficacy of an intravaginal prebiotic gel in the prevention of recurrent bacterial vaginosis: a randomized double-blind study. Obstet Gynecol Int. 2012;2012:147867.
6. Hakimi S et al. The effect of prebiotic vaginal gel with adjuvant oral metronidazole tablets on treatment and recurrence of bacterial vaginosis: a triple-blind randomized controlled study. Arch Gyn Obstet. 2017;297(1):109-116.
7. Mohammadzadeh F et al. Comparing the therapeutic effects of garlic tablet and oral metronidazole on bacterial vaginosis: a randomized controlled clinical trial. Iran Red Crescent Med J. 2014;16(7):e
8. Lev-Sagie et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat Med. 2019;25(10):1500-1504.
9. Simbar M et al. A comparative study of the therapeutic effects of the Zataria multiflora vaginal cream and metronidazole vaginal gel on bacterial vaginosis. Phytomedicine. 2008;15(12):1025-1031.
10. Petersen EE et al. Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomised, double blind, placebo controlled clinical trial. Arzneimittelforschung. 2011;61(4):260-265.
11. Swidsinski A et al. Polymicrobial Gardnerella biofilm resists repeated intravaginal antiseptic treatment in a subset of women with bacterial vaginosis: a preliminary report. Arch Gynecol Obstet. 2015;291(3):605-609.
12. Ha YM et al. Inhibitory effects of seaweed extracts on the growth of the vaginal bacterium Gardnerella vaginalis. J Environ Biol. 2014;35(3):537-542.
13. FAO/WHO. Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. http://www.fao.org/es/ESN/Probio/probio.htm. Accessed March 10, 2022.
14. Joseph RJ et al. Finding a balance in the vaginal microbiome: how do we treat and prevent the occurrence of bacterial vaginosis?. Antibiotics (Basel). 2021;10(6):719.
15. Anukam K et al. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo-controlled trial. Microbes Infect. 2006;8(6):1450-1454.
16. Reid G et al. Use of Lactobacillus rhamnosus GR-1 and fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol. 2003;35:131–134.
17. Petricevic L et al. Randomized, double-blind, placebo-controlled study of oral Lactobacilli to improve the vaginal flora of postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2008;141(1):54-57.
18. Martinez et al. Improved cure of bacterial vaginosis with single dose of tinidazole (2 g), Lactobacillus rhamnosus GR-1, and Lactobacillus reuteri RC-14: a randomized, double-blind, placebo-controlled trial. Can J Microbiol. 55(2):133-138.
19. Hummelen R et al. Deep sequencing of the vaginal microbiota of women with HIV. PLoS One. 2010;58:12078.
20. McMillan et al. Disruption of urogenital biofilms by lactobacilli. Colloids Surf B Biointerfaces. 2011;86(1):58-64.
21. Liu CM et al. Penile microbiota and female partner bacterial vaginosis in Rakai, Uganda. 2015;6:e00589.
22. Saunders S et al. Effect of Lactobacillus challenge on Gardnerella vaginalis biofilms. Colloids Surf B Biointerfaces. 2007;55(2):138-142.
23. Reid G. The scientific basis for probiotic strains of Lactobacillus. Appl Environ Microbiol. 1999;65:3763-766.
24. Martinez et al. Improved cure of bacterial vaginosis with single dose of tinidazole (2 g), Lactobacillus rhamnosus GR-1, and Lactobacillus reuteri RC-14: a randomized, double-blind, placebo-controlled trial. Can J Microbiol. 55(2):133-138.
25. Petricevic L et al. Randomized, double-blind, placebo-controlled study of oral Lactobacilli to improve the vaginal flora of postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2008;141(1):54-57.
26. Hummelen R et al. Deep sequencing of the vaginal microbiota of women with HIV. PLoS One. 2010;58:12078.
27. Yang S et al. Effect of oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on the vaginal microbiota, cytokines and chemokines in pregnant women. Nutrients. 2020;12(2):368.

Angela Kelly, MA and Michael Stanclift, ND
This is part two in a three-part series about bacterial vaginosis (BV). In part one we discussed a healthy vaginal microbiome, BV’s characteristics, and diagnostic criteria. In this section, we’ll explore risk factors for developing BV, the health impacts of it, and current conventional therapies.

BV risk factors
While the precise causes of BV are still being investigated, researchers have discovered the following risk factors that can contribute to its development:

• Having a sexual partner with a history of BV1
• Douching2-3
• Smoking4-5
• Recent antibiotic use5-6
• Being a Black or Mexican-American woman1,3,7-9
• Menstruation2,5,10-11
• Pregnancy5,12
• Having an IUD (especially copper)13
• New sexual partner(s)—result in a 2.5-fold increased risk1,4
• Uncircumcised sexual partner(s)4,14
• Inconsistent condom use4
• Previous STI diagnosis15-16Having female sexual partners or both female and male sexual partners1,4,17
• Becoming sexually active at 14 years of age or younger18
• Socioeconomic status5,19
• Chronic stress20-21
• Obesity22

Health impact of BV
Although most cases of BV are asymptomatic, BV can still have devastating health consequences. Even without symptoms, BV can cause:

• Genital inflammation23
• Increased risk of contracting and passing STIs, including a 60% increase in the acquisition of HIV23-30
• Impaired healing of the epithelial barrier11,31
• Increased risk of HPV infection and resulting cervical cancer11,32
• Infertility33-35
• Increased risk of pelvic inflammatory disease (PID)36-38
• Failure of in vitro fertilization39
• Miscarriage12,39,40
• Amniotic fluid infection41
• Preterm birth42-44,45-46
• Postsurgical infections47

Beyond the raised physical health risks, BV is associated with a significant negative impact on self-esteem, sexual relationships, and quality of life.48 Women report feelings of shame, stress, anxiety over loss of control over recurrent infections, and fear of others’ detection of odor or discharge. With approximately 29% of women in the US suffering from BV, more effective and lasting treatments are needed to reduce the health and economic burden of bacterial vaginosis.22

Current antimicrobial therapeutics and resistance
Current antimicrobial therapeutics often provide only temporary relief and ultimately contribute to antibiotic resistance. BV is usually treated with metronidazole, clindamycin, or a combination of oral and intravaginal antibiotic therapies.49Occasionally other antibiotics such as rifaximin, secnidazole, and tinidazole are prescribed.49-51 A 2020 in vitro study showed clindamycin had greater initial effectiveness against G. vaginalis than metronidazole; however, clindamycin is strongly associated with antibiotic resistance.52-53 In a randomized clinical trial 17% of cases had baseline clindamycin resistance, and 53% showed resistance to it after therapy.53 Also of consideration, clindamycin has been linked to Clostridioides difficile (C. diff) colonization and pseudomembranous colitis.13,50,54 Studies demonstrate G. vaginalis and A. vaginae also show resistance to metronidazole, although to a lesser extent than clindamycin.52,55 When metronidazole is used to treat BV, it can break up the biofilm created by G. vaginalis and A. Vaginae; however, live cells can persist within the biofilm, allowing for recurrences.56 Microbial profiling shows metronidazole temporarily reduces vaginal microbial diversity, and the reestablished microbiota rarely returns to a balanced lactobacilli-dominant state.57 Treatment with metronidazole frequently causes the adverse effects of nausea, vomiting, GI disturbances, and metallic taste.54,58 Occasionally metronidazole may also cause seizures, peripheral neuropathy, transient neutropenia, and allergic reactions, including anaphylaxis.58

These findings highlight that effective and lasting treatments for BV are urgently needed. The pipeline of antibiotics continues to dwindle, and bacteria grow more resistant with the antibiotic treatment of each episode.59 The treatment of protracted or recurring cases of BV often results in a revolving door of relapses for patients.59 Identifying lasting treatments for BV that rely less on antibiotics is of the utmost urgency.60,61

BV recurrence after antimicrobials
The recurrence rate following treatment of BV with antibiotics is high, with a study revealing that 58% of participants experienced a recurrence within a year and 69% returned to abnormal vaginal profiles.50,58  The high rate of recurrence appears to be multifaceted, linked to biofilms created by G. vaginalis and A. vaginae, impaired immune system response, antibiotic resistance, hygiene practices, and, according to some researchers, sexual transmission and reinfection by a woman’s sexual partner(s).60-63 Although there are variations in studies, a recent study showed improved BV recurrence rates when male partners were treated with oral and topical antibiotics. More research on the efficacy of treating sexual partners is needed.64 Having an untreated sexual partner is linked to a raised risk of recurrence of BV, although more research is needed.63,65
We can see the contributing factors for BV are multifactorial and that simple antimicrobial therapies are failing the majority of women they are prescribed to help. In our next and final installment in this series  we’ll explore alternative and emerging treatments for BV, including the role of probiotics. We’ll see how a problem characterized by microbial overgrowth may ultimately need more microbes to see its resolution.
Citations

1. Plummer EL et al. Combined oral and topical antimicrobial therapy for male partners of women with bacterial vaginosis: acceptability, tolerability and impact on the genital microbiota of couples – a pilot study. PLoS One. 2018;13(1):e
2. Borges S et al. The role of lactobacilli and probiotics in maintaining vaginal health. Arch Gynecol Obstet. 2014;289:479-489.
3. Ness S et al. Can known risk factors explain racial differences in the occurrence of bacterial vaginosis? J Natl Med Assoc. 2003;95:201-212.
4. Bradshaw CS et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006;193:1478–1489.
5. Amabebe E et al. Mechanistic insights into immune suppression and evasion in bacterial vaginosis. Curr microbiol. 2022;79(3):84.
6. Wilks M et al. Identification and H(2)O(2) production of vaginal lactobacilli from pregnant women at high risk of preterm birth and relation with outcome. J Clin Microbiol. 2004;42(2):713-717.
7. Peebles K et al. High global burden and costs of bacterial vaginosis: a systematic review and meta-analysis. Sex Transm Dis. 2019;46(5):304-311.
8. https://www.cdc.gov/std/bv/stats.htm. Accessed September 19, 2022.
9. Hensel KJ et al. Pregnancy-specific association of vitamin D deficiency and bacterial vaginosis. Am J Obstet Gynecol. 2011;204(1):e1-41.e419.
10. Reid G et al. Use of Lactobacillus rhamnosus GR-1 and fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol. 2003;35:131–134.
11. Coudray MS et al. Bacterial vaginosis-a brief synopsis of the literature. Eur J Obstet Gynecol Reprod Biol. 2020;245:143-148.
12. Nelson DB et al. Bacterial vaginosis in pregnancy: current findings and future directions. Epidemiol Rev. 2002;24(2):102-108.
13. Joseph RJ et al. Finding a balance in the vaginal microbiome: how do we treat and prevent the occurrence of bacterial vaginosis?. Antibiotics (Basel). 2021;10(6):719.
14. Plummer EL et al. Lactic acid-containing products for bacterial vaginosis and their impact on the vaginal microbiota: A systematic review. PloS One. 2021;16(2):e0246953-e0246953.
15. Nelson DB et al. Bacterial vaginosis in pregnancy: current findings and future directions. Epidemiol Rev. 2002;24(2):102-108.
16. Moi H. Prevalence of bacterial vaginosis and its association with genital infections, inflammation and contraceptive methods in women attending sexually transmitted disease and primary health clinics. Int J STD AIDS. 1990;1:86–94.
17. Marrazzo JM et al. Safety and efficacy of a novel vaginal anti-infective, TOL-463, in the treatment of bacterial vaginosis and vulvovaginal candidiasis: a randomized, single-blind, phase 2, controlled trial. Clin Infect Dis. 2019;68(5):803-809.
18. Hensel KJ et al. Pregnancy-specific association of vitamin D deficiency and bacterial vaginosis. Am J Obstet Gynecol. 2011;204(1):e1-41.e419.
19. Allsworth JE et al. Severity of bacterial vaginosis and the risk of sexually transmitted infection. Am J Obstet Gynecol. 2011;205(2):113.e1-113.e1136.
20. Culhane JF et al. Maternal stress is associated with bacterial vaginosis in human pregnancy. Matern Child Health J. 2001;5(2):127-134.
21. Amabebe E et al. The vaginal microenvironment: the physiologic role of lactobacilli. Front Med (Lausanne). 2018;5:181.
22. Koumans EH et al. The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis. 2007;34(11):864-869.
23. McKinnon et al. The evolving facets of bacterial vaginosis: implications for HIV transmission. AIDS Res Hum Retrovir. 2019;35(3):219-228.
24. Cherpes et al. Association between acquisition of herpes simplex virus type 2 in women and bacterial vaginosis. Clin Infect Dis. 2003;37:319–325.
25. Wiesenfeld et al. Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia trachomatis infection. Clin Infect Dis. 2003;36:663–668.
26. Dareng EO et al. Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women. Epidemiol Infect. 2015:1–15.
27. Atashili J et al. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. 2008;22(12):1493–1501.
28. Sharami SH et al. Urinary tract infections in pregnant women with bacterial vaginosis. J Obstet Gynaecol. 2007;27(3):252-254.
29. Afrakhteh M et al. Relationship between bacterial vaginosis and urinary tract infection. J Zanjan Univ Med Sci H Serv. 2003;42:37–42.
30. Harmanli OH et al. Urinary tract infections in women with bacterial vaginosis. Obstet Gynecol (NY 1953). 2000;95(5):710-712.
31. Zevin AS et al. Microbiome composition and function drives wound-healing impairment in the female genital tract. PLoS Pathog. 2016;12(9):e1005889-e1005889.
32. Suehiro TT et al. Association of human papillomavirus and bacterial vaginosis with increased risk of high-grade squamous intraepithelial cervical lesions. Int J Gynecol Cancer. 2019;29(2):242-249.
33. Ravel J et al. Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. Am J Obstet Gynecol. 2021;224(3):251-257.
34. Damke E et al. Male partners of infertile couples with seminal positivity for markers of bacterial vaginosis have impaired fertility. Am J Mens Health. 2018;12(6):2104-2115.
35. He Y et al. Evaluation of the inhibitory effects of Lactobacillus gasseri and Lactobacillus crispatus on the adhesion of seven common lower genital tract infection-causing pathogens to vaginal epithelial cells. Front Med (Lausanne). 2020;7:284.
36. Wiesenfeld et al. Lower genital tract infection and endometritis: insight into subclinical pelvic inflammatory disease. Am J Obstet Gynecol. 2002;100(3):456-463.
37. Soper DE et al. Observations concerning the microbial etiology of acute salpingitis. Am J Obstet Gynecol. 1994;170:1008–1014.
38. Hillier SL et al. Role of bacterial vaginosis-associated microorganisms in endometritis. Am J Obstet Gynecol. 1996;175:435– 441.
39. Moreno I et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016;215(6):684-703.
40. Ralph et al. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ. 1999;319:220-223.
41. Silver HM et al. Evidence relating bacterial vaginosis to intraamniotic infection. Am J Obstet Gynecol. 1989;161:808–812.
42. Kurki T et al. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol. 1992;80:173–177.
43. Hillier SL et al. Association between bacterial vaginosis and preterm delivery of a low- birth-weight infant. N Engl J Med.1995;333:1737–1742.
44. Gratocos E et al. Spontaneous recovery of bacterial vaginosis during pregnancy is not associated with an improved perinatal outcome. Acta Obstet Gynecol Scand. 1998;77:37–40.
45. Meis PJ et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol. 1995;173:1231–1235.
46. Goldenberg RL et al. The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection. Obstet Gynecol. 1996;87:656–660.
47. Persson E et al. Infections after hysterectomy. A prospective nation-wide Swedish study. The Study Group on Infectious Diseases in Obstetrics and Gynecology within the Swedish Society of Obstetrics and Gynecology. Acta Obstet Gynecol Scand. 1996;75(8):757-761.
48. Bilardi J et al. Women’s management of recurrent bacterial vaginosis and experiences of clinical care: a qualitative study. PLoS One. 2016;11(3): e0151794.
49. Muzny CA et al. The role of antimicrobial resistance in refractory and recurrent bacterial vaginosis and current recommendations for treatment. Antibiotics (Basel). 2022;11(4):500.
50. Bradshaw CS et al. Current treatment of bacterial vaginosis-limitations and need for innovation. J Infect Dis. 2016;214:S14-S20.
51. Ravel J et al. Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. Am J Obstet Gynecol. 2021;224(3):251-257.
52. Li T et al. Antimicrobial susceptibility testing of metronidazole and clindamycin against gardnerella vaginalis in planktonic and biofilm formation. Can J Infect Dis Med Microbio. 2020;2020:1361825-1361827.
53. Beigi RH et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am J Obstet Gynecol. 2004;191(4):1124-1129.
54. Bagnall P et al. Bacterial vaginosis: a practical review. JAAPA. 2017;30(12):15-21.
55. Nagaraja P et al. Antibiotic resistance of Gardnerella vaginalis in recurrent bacterial vaginosis. Indian J Med Microbiol. 2008;26(2):155-157.
56. McMillan et al. Disruption of urogenital biofilms by lactobacilli. Colloids Surf B Biointerfaces. 2011;86(1):58-64.
57. Hummelen R et al. Deep sequencing of the vaginal microbiota of women with HIV. PLoS One. 2010;58:12078.
58. Sobel R et al. Metronidazole for the treatment of vaginal infections. Expert Opin Pharmacother. 2015;16(7):1109-1115.
59. Bannatyne RM et al. Recurrent bacterial vaginosis and metronidazole resistance in Gardnerella vaginalis. Sex Transm Infect. 1998;74:455–456.
60. Swidsinski A et al. Polymicrobial Gardnerella biofilm resists repeated intravaginal antiseptic treatment in a subset of women with bacterial vaginosis: a preliminary report. Arch Gynecol Obstet. 2015;291(3):605-609.
61. Eschenbach DA. Bacterial vaginosis: resistance, recurrence, and/or reinfection? Clin Infect Dis. 2007;44:220–221.
62. Klebanoff MA et al. Personal hygienic behaviors and bacterial vaginosis. Sex Transm Dis. 2010;37(2):94-99.
63. Plummer EL et al. A prospective, open-label pilot study of concurrent male partner treatment for bacterial vaginosis. MBio. 2021;12(5):e
64. Plummer EL et al. Combined oral and topical antimicrobial therapy for male partners of women with bacterial vaginosis: Acceptability, tolerability and impact on the genital microbiota of couples – a pilot study. PloS One. 2018;13(1):e0190199-e0190199.
65. Amaya-Guio J et al. Antibiotic treatment for the sexual partners of women with bacterial vaginosis. Cochrane Database Syst Rev. 2016;10(10):CD011701.

Angela Kelly, MA and Michael Stanclift, ND
In part one of this three-part series, we’ll discuss a healthy vaginal microbiome, symptoms, and the diagnostic criteria of bacterial vaginosis (BV).

A healthy vaginal microbiome
The vaginal microbiome is the lesser-known heroine of the body’s microbiomes and the first line of defense against pathogens that can cause infections.1-5 Like the gut microbiome, the vaginal microbiome is seeded from mother to daughter and the surrounding environment within 24 hours of birth.6-7Hormonal fluctuations related to puberty, the menstrual cycle, pregnancy, and menopause each contribute to the constantly changing landscape of the vaginal microbiome.8

During the reproductive years, the vaginal vault is populated by 90–95% lactobacilli in a balanced, healthy state. 9-10 Vaginal epithelial cells deposit glycogen, and the “friendly” lactobacilli ferment the polysaccharide, producing lactic acid.11 This fermentation process serves to lower vaginal pH, inhibit potentially harmful anaerobes’ growth, and discourage pathogens’ attachment to the vaginal epithelium.11 Additionally, lactobacilli produce antimicrobials such as hydrogen peroxide and bacteriocins, which deter biofilms and keep pathogenic anaerobes dormant.11 But what happens when the bacterial balance of the vagina is thrown out of whack?

Bacterial vaginosis characteristics
Bacterial vaginosis (BV) is the often silent, sometimes maddening, and quite common vaginal microbiome dysbiosis that affects 29.2% of women of reproductive age in the United States.12 The dysbiosis of BV is characterized by decreased “friendly” lactobacilli and an overgrowth of potentially pathogenic bacteria that may multiply to 1,000-10,000 times normal levels.13 Many studies suggest asymptomatic BV poses serious threats to reproductive and urogenital health and increases the risk of contracting and transmitting STIs.9,14-15 While the exact cause of BV is still under debate, the initial disruption of the vaginal microbiome is likely due to sexual transmission.16-17 Although with significantly lower frequency, females who have never been sexually active can also develop BV.18

BV is found globally, with higher incidences in certain countries and ethnicities.9 In the United States, Black and Mexican-American women are more likely to be affected by BV.9,19-20 Despite being the most common vaginal dysbiosis, women’s awareness of BV prior to their first infection is very low.21

Symptoms of bacterial vaginosis and diagnostic criteria
While most BV cases occur asymptomatically, the CDC describes the following common symptoms that may occur:12,22

• A thin white or gray vaginal discharge
• Pain, itching, or burning in the vagina
• A strong fish-like odor, especially after sex
• Burning when peeing
• Itching around the outside of the vagina

BV can be diagnosed using Amsel’s criteria or the Nugent scoring system.

Amsel’s criteria for the diagnosis of BV are met when 3 out of 4 of the following clinical signs are present:23

1. Abnormal vaginal discharge
2. Amine (fish-like) odor when vaginal fluid is exposed to 10% potassium hydroxide (KOH)
3. Clue cells on wet mount
4. Vaginal pH > 4.5

Alternatively, the Nugent scoring system can be used to diagnose BV using a Gram stain, microscope, and a 0-10 score based on the amounts of the following microorganisms seen per high-powered field:24

• Curved rods (Mobiluncus species morphotypes)
• Gram variable rods (Garderella vaginalis morphotypes)
• Lactobacillus morphotypes

So now that we have some of the basic background knowledge of the vaginal microbiome and how to detect BV in our patients, part two of this series will look at causes and risk factors, health impacts, and current conventional therapies for BV. In part three, we’ll look at alternative and emerging treatments, the role of probiotics, and discuss the mechanisms behind these approaches.

Citations

1. Brotman RM. Vaginal microbiome and sexually transmitted infections: An epidemiologic perspective. J Clin Invest. 2011;121(12):4610-4617.
2. Graver MA et al. The role of acidification in the inhibition of Neisseria gonorrhoeae by vaginal lactobacilli during anaerobic growth. Ann Clin Micro Antimicrob. 2011;10(1):8-8.
3. O’Hanlon DE et al. In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Inf Dis. 2011;11(1):200.
4. Gong Z et al. Lactobacilli inactivate Chlamydia trachomatis through lactic acid but not H2O2. PloS One. 2014;9(9):e107758-e107758.
5. Nunn KL et al. Enhanced trapping of HIV-1 by human cervicovaginal mucus is associated with Lactobacillus crispatus-dominant microbiota. MBio. 2015;6(5):1-9.
6. Rotimi VO et al. The development of the bacterial flora in normal neonates. J Med Microbiol. 1981;14:51-62.
7. Borges S et al. The role of lactobacilli and probiotics in maintaining vaginal health. Arch Gynecol Obstet. 2014;289(3):479–895.
8. Joseph RJ et al. Finding a balance in the vaginal microbiome: how do we treat and prevent the occurrence of bacterial vaginosis? Antibiotics (Basel). 2021;10(6):719.
9. Coudray MS et al. Bacterial vaginosis-a brief synopsis of the literature. Eur J Obstet Gynecol Reprod Biol. 2020;245:143-148.
10. Bautista CT et al. Association of bacterial vaginosis with chlamydia and gonorrhea among women in the U.S. army. Am J Prev Med. 2017;52(5):632-639.
11. Amabebe E et al. The vaginal microenvironment: the physiologic role of lactobacilli. Front Med (Lausanne). 2018;5:181.
12. Koumans EH et al. The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis. 2007;34(11):864-869.
13. Larsson PG et al. Diagnosis of bacterial vaginosis: need for validation of microscopic image area used for scoring bacterial morphotypes. Sex Transm Infect. 2004;80(1):63-67.
14. McKinnon et al. The evolving facets of bacterial vaginosis: implications for HIV transmission. AIDS Res Hum Retrovir. 2019;35(3):219-228.
15. Allsworth JE et al. Severity of bacterial vaginosis and the risk of sexually transmitted infection. Am J Obstet Gynecol. 2011;205(2):113.e1-113.e1136.
16. Zozaya M et al. Bacterial communities in penile skin, male urethra, and vaginas of heterosexual couples with and without bacterial vaginosis. Microbiome. 2016;4(16):16.
17. Liu CM et al. Penile microbiota and female partner bacterial vaginosis in Rakai, Uganda. 2015;6:e00589.
18. Yen S et al. Bacterial vaginosis in sexually experienced and non-sexually experienced young women entering the military. Obstet Gynecol. 2003;102:927–933.
19. Ness S et al. Can known risk factors explain racial differences in the occurrence of bacterial vaginosis? J Natl Med Assoc. 2003;95:201-212.
20. https://www.cdc.gov/std/bv/stats.htm. Accessed September 19, 2022.
21. Bilardi J et al. Women’s management of recurrent bacterial vaginosis and experiences of clinical care: a qualitative study. PLoS One. 2016;11(3):
22. https://www.cdc.gov/std/bv/stdfact-bacterial-vaginosis.htm. Accessed September 19, 2022.
23. Amsel R et al. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiological associations. Am J Med. 1983;74:14-22.
24. Udayalaxmi J et al. Comparison of the methods of diagnosis of bacterial vaginosis. J Clin Diag Res. 2011;5(3):498–501.