What is the microbiome, and who are EMMA and ALICE?

Most people are familiar with the fact that our gastrointestinal systems are colonized by bacteria. All the way from the mouth to the anus, the long tube known as the “gut” is full of bugs! Your skin is also covered. In fact, it has been estimated that there are more than 10 times as many microbes that live in/on our bodies than our bodies’ own cells. Gross, right?

The microbiome is the environment within our bodies comprised of trillions of other living organisms (and BTW, it’s not just bacteria). Eubiosis is the condition of harmony with our microscopic friends; dysbiosis is an imbalance of the microbiome with an overabundance of unwelcome guests.*

It has become apparent that a proper balance is not only important to prevent infections and maintain healthy digestion but can also influence the immune system and even neurological diseases like Parkinson’s syndrome. Click here for an interesting review on the topic. If you want to dive deeper into the geeky rabbit-hole, read about the concept of the hologenome. It’s fascinating!

We also know that the vagina hosts a variety of normal flora. Lactobacillus is the dominant species, named for its production of lactic acid that maintains a healthy pH, defending against pathogenic microbes. Yeast infections and bacterial vaginosis occur when the balance of normal bacteria is disrupted. Furthermore, vaginal dysbiosis increases risks for sexually transmitted infections, pelvic inflammatory disease, and even gynecological cancers. During pregnancy, dysbiosis can cause miscarriage and preterm labor. In addition, a mother’s microbiome can potentially have long-term health effects for her offspring [1].

On a related note, we have long since appreciated that infections in the reproductive tract can cause infertility. For example, sexually transmitted infections like chlamydia can destroy fallopian tubes; tuberculosis (luckily not common in our part of the world) can irreversibly damage the endometrium. Pathological bacteria secrete toxins and create a biofilm that is hostile to sperm, eggs, and embryos (not to mention your overall health!). In turn, the immune system is activated to fend off the attackers, but the inflammatory state causes collateral damage to the tissues.

It turns out that a healthy uterus doesn’t just require the absence of bad, it also needs the presence of good: the uterus has its own microbiome. Once again, lactobacillus is the good stuff, although in a much lower density than the vagina. A study with IVF patients demonstrated that patients with >90% lactobacillus concentration in their microbiomes had significantly higher implantation and live birth rates than those who were non-lactobacillus dominated [2].

A trickier condition is chronic endometritis (CE): a low-level infection that does not usually cause any noticeable symptoms.  One study demonstrated that up to 42% of women with recurrent implantation failure after IVF had CE [3].  Unfortunately, diagnosing CE has also been traditionally challenging since it relies on the microscopic identification of plasma cells with H&E staining and cell culture, both of which are plagued with inaccuracy, often leading to misdiagnosis. Hysteroscopy is helpful but also of limited value since we simply can’t see all infections [4]. Carpet-bombing with antibiotics to try to kill the bad bacteria has been proposed but is problematic for obvious reasons.

Fortunately, we have new way to assess the uterine microbiome: EMMA (Endometrial Microbiome Metagenomic Analysis) and ALICE (Analysis of Infectious Chronic Endometritis). Cute names aside, these tests leverage a high-tech approach called metagenomic sequencing to comprehensively evaluate bacterial diversity. This technique identifies organisms that can not be studied with conventional tests.  

Sometimes the results will reveal low biomass: a reduced concentration of the healthy bacteria, which can then be overrun by the troublemakers. Occasionally, a specific infection will be revealed. The results will determine if treatment with probiotics, antibiotics, or both/neither are justified.

To perform the test, an endometrial biopsy is required. For our IVF patients, we will usually combine the ALICE & EMMA with the ERA (read about it here), for the hattrick cleverly named EndomeTRIO. Like the ERA, there are downsides: 1) a month is required to perform the tests, and occasionally another month is necessary to verify adequate treatment, 2) the biopsy can be uncomfortable, 3) there is a financial cost.

Has it made a difference for our patients yet? Too early to say. We have been offering ALICE & EMMA for about 1 year (in contrast we have been using ERA for more than 5 years), and we are still gathering data. In my humble opinion, I believe that there is an ample body of evidence supporting the significance of chronic infections and dysbiosis as they relate to infertility, and ALICE & EMMA appear to be better ways to diagnoses these conditions.

What about just loading up on probiotics? That seems reasonable, but 1) the probiotics should contain only lactobacillus species, 2) they should be administered vaginally, so as not to disturb the gut microbiome, and 3) maybe it’s possible to have too much of a good thing. To be honest, there is no evidence to support that just prescribing probiotics to all-comers will make a difference for fertility outcomes, but it seems like there is little downside. We will have to wait and see…

 

*Bonus- a gut busting joke as a reward for making it to the end of this extra-long post:

Q: What’s the opposite of dysbiosis?

A: Datbiosis!

 

References:

[1]       R. Tomaiuolo, I. Veneruso, F. Cariati, and V. D’argenio, “Microbiota and human reproduction: The case of female infertility,” High-Throughput, vol. 9, no. 2. MDPI AG, 01-Jun-2020.

[2]       I. Moreno et al., “Evidence that the endometrial microbiota has an effect on implantation success or failure,” in American Journal of Obstetrics and Gynecology, 2016, vol. 215, no. 6, pp. 684–703.

[3]       R. Romero, J. Espinoza, and M. Mazor, “Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization?,” Fertil. Steril., vol. 82, no. 4, pp. 799–804, 2004.

[4]       I. Moreno et al., “The diagnosis of chronic endometritis in infertile asymptomatic women: a comparative study of histology, microbial cultures, hysteroscopy, and molecular microbiology,” Am. J. Obstet. Gynecol., vol. 218, no. 6, pp. 602.e1-602.e16, Jun. 2018.