A recent study published in the Best Practice & Research Clinical Obstetrics and Gynecology Journal explored the impact of obesity on vaginal microbiota and reproduction.

Study: Vaginal microbiome in obesity and its impact on reproduction. Image Credit: Mikhaylovskiy/Shutterstock.com

Background

The human microbiome is a complex of multiple microbial genomes established under varying conditions, each in its ecological niche. The vaginal microbiome has come under the radar recently, and evidence suggests its key role in reproductive outcomes.

With the onset of the obesity epidemic over the past few decades, researchers decided to examine how this condition impacts the vaginal microbiota and the eventual effect on reproduction.

Introduction

The vaginal microbiota contains bacteria, viruses, and fungi, which exist in harmony with the rest of the cells and the extracellular environment within the human body. It is relatively homogeneous compared to other microbiota in humans, dominated by Lactobacillus species.

These lactic acid producers are responsible for the acidic milieu of the vagina, which forms a barrier against infection and promotes successful reproduction.

Dysbiosis of the vaginal microbiome may contribute to or cause miscarriage, preterm birth, and cervical cancers in women with precancerous cervical changes, occur at higher rates.

Pelvic inflammatory disease (PID) may also be more common and may predispose to the higher risk of endometrial and epithelial ovarian cancers.

Mechanistically, vaginal dysbiosis may be responsible for such outcomes by directly or indirectly producing metabolites that disrupt key cellular pathways relating to DNA repair, cell proliferation, apoptosis, and the immune response.

Obesity, defined as a body mass index (BMI) of or above 30, has tripled in incidence over the last half-century and affects almost one in seven adults worldwide.

By itself, obesity poses a higher risk for type 2 diabetes, cardiovascular disease, osteoarthritis, and several common cancers such as breast, colorectal, and endometrial cancer. Moreover, pregnancy in obese women is more likely complicated by pre-eclampsia, macrosomia, and miscarriage.

An increase in BMI by one unit reduced the chances of successful implantation with assisted reproductive technologies (ART) and boosted the risk of miscarriage after embryo transfer.

While the effects of obesity may involve psychological, inflammatory, hormonal, and immunological changes in such individuals, the current paper explored the impact of obesity on the vaginal microbiota and reproduction.

What did the study show?

Vaginal dysbiosis in obesity

The scientists reviewed existing literature to identify the techniques used to achieve a more accurate picture of the vaginal microbiota, the associations of the latter with reproduction and obesity, and the mechanisms possibly underlying these effects.

Earlier methods relied on gram-staining and culture, though this excludes multiple species that do not grow under the specific conditions applied. Advances have made it possible to sequence the microbiota in terms of their nucleic acid genomes (DNA or RNA) or protein.

These approaches help outline the community’s composition using vaginal swabs as source material.

In particular, 16S RNA sequencing is the most common method of taxonomic classification of bacteria, using specific regions of the gene encoding 16S ribosomal RNA that is present in all bacteria but varies in copy number.

In addition, hierarchical clustering methods have made it possible to lay out the broad categories of microbes found in normal and abnormal states of the vaginal microbiome. Five community states are now identifiable, depending on the alpha-diversity and dominant Lactobacillus species.

With obesity, there is a marked shift in the gut microbiota, with a higher ratio of Firmicutes to Bacteroidetes, and increases in the abundance of certain species, including Lactobacillus. The resulting change in gut-derived metabolites adds to the alteration in the gut-brain crosstalk and may lead to weight gain.

Meanwhile, these women show a lower abundance of Lactobacillus in the vagina, with an especially large decrease in L. crispatus, which is dominant in healthy women. Instead, species like Dialister, Prevotella timonensis, and Anerococcus vaginalis grow abundantly, indicating increased alpha diversity.

This change has been observed in multiple studies spanning several world regions.

Again, bacterial vaginosis (BV) is more common in women with a high BMI during pregnancy and at other times. This disorder is characterized by a steep drop in Lactobacillus abundance, with strictly anerobic bacteria colonizing the vaginal mucosa.

The reverse direction of change has been observed with weight reduction and dietary changes, indicating a dynamic relationship.

Obesity in reproductive outcomes

The shift in vaginal microbiota with obesity could thus impair fertility. Obese women have lower conception rates than those with a normal BMI, perhaps through hormonal abnormalities that affect menstrual and, hence, ovarian function.

They are also more likely to have the vaginal microbiota type found in women who suffered a miscarriage.

Conception delays of over a year are six times more likely in women with morbid obesity, who also are at risk for miscarriage and are less likely to achieve pregnancy following in vitro fertilization (IVF).

The increased prevalence of BV in obesity also associates with adverse reproductive outcomes, especially if recurrent BV is identified. BV risk is over threefold higher in infertile women compared to others and in tubal infertility compared to other causes of infertility.

Women with BV are also at a higher risk for preclinical miscarriage by a factor of 2. Thus, BV may be another reason for a higher prevalence of infertility in the obese.

How does this happen?

The underlying mechanisms of vaginal dysbiosis in obesity are hypothetical at this point.

Some postulates include the effect of reduced estrogen levels in obese premenopausal women and immunological shifts following obesity-induced inflammation. Inflammation in obesity is mediated by hypoxia within hypertrophied fatty tissue and by the activity of leptin from these tissues. 

In premenopausal women with obesity, estrogen levels are reduced because the hypothalamic-pituitary-ovarian axis is disrupted; sex hormone binding globulin levels drop, causing estrogen to be cleared from the blood faster; and inhibin B synthesis by granulosa cells may be affected by obesity.

The dysbiotic gut in obesity also alters estrogen metabolism by the metabolites it generates. These may prevent estrogen deconjugation and thus reduce the levels of active estrogen in the blood.

Vaginal dysbiosis is a known risk factor for adverse reproductive outcomes. In women with recurrent pregnancy loss, the vaginal microbiota is more likely to be characterized by reduced L. crispatus and higher Gardnerella vaginalis abundance, reducing the level of protection against preterm birth.

Researchers have observed adverse effects of vaginal dysbiosis on oocyte and sperm health in women undergoing ART. Clinical pregnancy rates fell to 9% from the expected 35%, on average, in women with vaginal dysbiosis.

L. crispatus is also less abundant, and alpha-diversity increased, in obese women, suggesting that this may be another mechanism mediating reduced fertility. This type of microbiota could promote local vaginal inflammation in obese women, but this remains to be proven.

Finally, obesity in women causes increased androgen activity or functional hyperandrogenism. Oxidative stress within fatty tissues may couple with the higher levels of inflammatory adipokines, such as leptins, to promote metabolic syndrome, insulin resistance, and hyperandrogenism. The outcome is a higher risk of polycystic ovarian syndrome (PCOS).

What are the implications?

Scientists have long been exploring vaginal microbiota to identify potential pathways to improve its composition and reduce the risk of adverse reproductive outcomes.

However, there is not much evidence showing obesity acts adversely on reproduction independently of its effect on the vaginal microbiome.

Although several studies suggest a correlation between obesity, the microbiome, and reproductive fecundability, definite studies are still required.”

These should address the estrobolome, the effects of ethnicity, genetic composition, and lifestyle on the vaginal microbiome, and other mechanisms by which obesity affects reproductive outcomes.

Such evidence is necessary to develop therapeutic pathways to improve the quality of the vaginal microbiota and reduce disease incidence.