Microbiota and female fertility
'Microbiota' seems to be the buzzword for a few years now. It is the set of living microorganisms that coexist closely with us, especially in certain areas of the body such as mucous tissues.
Bacterial cells in the human body represent between 1 and 3% of the total body weight, that is, if we weigh 60 kilos, between 600 grams and 1.8 kilos of our weight are bacteria!
Almost the same number of cells we have in the body. Recent research has focused on understanding how different communities of bacteria in the body (eg, gut, respiratory, skin, and vaginal microbiomes) predispose to health and disease.
The mucous tissues where the different bacteria that make up the microbiota survive characterize all the 'access' areas to our body (all the orifices, so that we understand each other).
All of them have similar physiological characteristics and have very particular mechanisms to carry out a highly selective defensive function. In this defensive function, in particular, different living microorganisms participate: the microbiota.
For a long time it was called "intestinal flora" although now this term has been replaced by microbiota. The change is justified because the word "flora" refers to plant life and, however, these microorganisms are bacteria, fungi and yeasts, whose functioning has nothing to do with that of plants.
That is why the most precise and scientifically accepted name of microbiota has currently been adopted to name this microecosystem..
The importance of this lies in its ability to participate in many different physiological processes of our body.
The composition and balance between the different bacteria and microorganisms residing in the mucous membranes of the digestive and reproductive systems seem to be directly related to the reproductive health of our species. Let's see how it happens.
Microbiota and reproductive health
The interactive functions of the microbiota and the gut microbiome with their host (our body) have been extensively investigated, making it clear that our microbes are not just residents or pathogens, but are involved.
And how is this intervention?
Well, regulating, especially, the innate and adaptive immune system of the host. With this, they participate in the protection against pathogens, homeostasis and metabolism among other things.
And, as we have commented in another post, the immune system has a lot of weight in the reproductive health of women and men.
After all, the woman's body must receive a new cell, unknown to date, half "foreign" -since 50% belongs to the couple or donor, at least-, and that grows and reproduces at high speed.
Faced with this cellular dynamic, the immune system usually responds aggressively for defensive purposes. However, for implantation to take place, the woman's immune system must be "calm" enough to do a good job of investigating before attacking, and thus be able to identify the special characteristics of this new cell, so that it is respected and implantation is allowed. This discernment capacity of the immune system is directly related to the vaginal and endometrial microbiota.
vaginal microbiota
The Human Microbiome Project emerged in 2008 as an initiative of the United States National Institute of Health with the objective of identifying and characterizing the human microbiome, both in health and in disease.
Their findings demonstrate a remarkable diversity of microbial ecology within the human body.
The vaginal microbiota is unique in that in many women it is often dominated by Lactobacillus species.
However, in some women it lacks Lactobacillus and is composed of a wide range of strictly anaerobic and facultative organisms. In these cases, it is widely correlated with increased risk of infection, disease, and poor reproductive and obstetric outcomes.
Interestingly, the level of protection against infection can also vary by Lactobacillus species and strain, and some species, while dominant, are not always optimal. This influences the risk of contracting sexually transmitted infections and possibly influences the occurrence of resulting adverse reproductive outcomes, such as tubal abnormality infertility.
The vaginal microbiota should be dominated by Lactobacillus crispatus and gasseri.
Several studies corroborate this for all groups of women studied. However, the more quantity is not always the better the results. In fact, in one study it was shown that in the unexplained infertility group, the levels were the highest.
Of the three groups analysed, the group with recurrent implantation failures had a vaginal microbiota considerably less diverse, with higher levels of anaerobic bacteria such as Leptotrichia, Snethia, and Prevotella.
This type of bacteria promotes local and systemic inflammation through different inflammatory substances such as TNF-α or IL-6.
In the vaginal area, the microbiota also influences the morphology of the different tissues and determines the predisposition to suffer alterations due to irritation or micro-lesions of the same.
Furthermore, the microbiota is crucial in protecting against uterine infections, defending its niche and competing with pathogens.
This is achieved thanks to the acidic environment that bacteria generate when they are in balance. If this balance is lost, the pH of the area is modified, favoring the growth of microorganisms that are harmful to the human body.
The microbial composition of the vagina can be evaluated non-invasively, which is why it is also an accessible and economical tool. The results of this test can predict the result of natural fertility as well as assisted reproduction treatments.
Studies on vaginal microbiota and fertility
Although the data set of some studies is still too small to allow a detailed and conclusive adjusted analysis, a clear trend towards a lower clinical and biochemical pregnancy rate has been found in the group of women with an altered microbiota compared to the normal microbiota group.
Despite the shortcomings of the studies to date, the correct vaginal microbiota, dominated by Lactobacillus - specifically Lactobacillus crispatus - has been associated with a significantly higher birth rate.
Abnormal vaginal microbiota has a strong correlation with in vitro fertilization (IVF) failure, due to non-implantation or miscarriage during the first trimester. An abnormal composition of the vaginal microbiota has been shown to lead to preterm birth, miscarriage, and problems conceiving.
Studies have suggested that intestinal dysbiosis, that is, the imbalance of bacteria in the mucous membranes, reduces the successful development of the pregnancy in the first months of IVF.
Women with abnormal vaginal microbiota are approximately 1,4 times less likely to have a successful pregnancy after IVF treatment compared to women with normal microbiota. However, it is true that there are conflicting reports and that there is too much heterogeneity in the methodologies of vaginal microbiota studies during IVF, leading to poor comparability. There is still a long way to go to investigate more in detail.
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endometrial microbiota
The uterus has classically been considered a sterile cavity, that is, free of bacteria and other microorganisms. But today, this vision has changed and it has been shown that it is not so.
Not only is it colonized by a group of microorganisms, but its receptive capacity is crucial for fertility. In addition to the correct implantation process, it is also vital for the subsequent formation of the placenta, since the initiation of the placenta depends to a large extent on the interaction with immune cells.
The study of the endometrial microbiota is a factor to take into account given the increase in implantation failures, recurrent losses and other pathologies of the endometrium and placenta, such as preeclampsia, which are increasingly common.
More robust studies are needed to investigate uterine colonization. Based on the current data, future research should include the uterine microbiome as a relevant factor to understand the players required for a healthy pregnancy.
Endometrial fluid can be easily analyzed in search of information about the microbiota in the area. In total, some 190 different strains are currently known, although the endometrial microbiota is believed to be highly stable and mainly composed of Lactobacillus-like strains.
The presence of a microbiota not dominated by these Lactobacillus in a receptive endometrium has been associated with poor reproductive outcomes for patients undergoing in vitro fertilization treatment, and significant decreases in implantation rates, pregnancy rates, ongoing pregnancies, and of the number of children born alive.
gut microbiota
At a more systemic level, there are also studies that relate the state of the intestinal microbiota with reproductive success. The diversity of gut bacteria among groups of infertile women, compared to control groups, is generally less diverse.
In addition, women with fertility problems (recurrent implantation failure) had, according to one study, an unphysiological bacterial composition, where gram-positive bacteria abounded, mainly from the Firmicutes phylum.
In contrast, gram-negative bacteria were relatively more abundant in the idiopathic or unexplained infertility group.
In addition, genera of mucus-producing bacteria such as Prevotella and Sutterella decreased in all groups experiencing infertility.
And, curiously, in these groups there was evidence of a significant increase in the genus Hungatella, associated with the production of Trimethylamine N-oxide (TMAO), better known for causing coagulation disorders, capable of altering embryo implantation.
Finally, this study offered one last curiosity. Vaginal dysbiosis did not usually coexist with intestinal dysbiosis. Either there is vaginal dysbiosis (alteration), or there is intestinal dysbiosis.
So, given all this evidence, in case of difficulty in achieving natural or assisted fertility, a study of the microbiota, both vaginal, uterine and intestinal, is recommended.
References:
- Moreno, I. Codoner, FM. Vilella, F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. American Journal of Obstetrics & Gynecology DECEMBER 2016
- Haahr, T. et al. Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Human Reproduction, Vol.31, No.4 pp. 795–803, 2016
- Skafte-Holm, A. et al. The Association between Vaginal Dysbiosis and Reproductive Outcomes in Sub-Fertile Women Undergoing IVF-Treatment: A Systematic PRISMA Review and Meta-Analysis. Pathogens 2021, 10, 295.
- Singer, M. et al. The relationship of the vaginal microbiota to early pregnancy development during in vitro fertilization treatment. A meta-analysis. Journal of Gynecology Obstetrics and Human Reproduction 48 (2019) 223–229 f.
- Schoenmakersa, S. Laven, J. The vaginal microbiome as a tool to predict IVF success fertility, IVF and reproductive genetics. 2020 Wolters Kluwer Health, Inc.