The Microbiome in Reproductive Medicine

The Microbiome in Reproductive Medicine

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The microbiome of the reproductive tract and its association with reproductive outcomes is a topic of evolving interest. Alterations in the vaginal microbiome have been linked to obstetric complications including miscarriage and preterm birth.  More recent data have emerged linking the vaginal microbiome to assisted reproductive technology (ART) outcomes.

Limited information is available regarding the microbiome of the upper genital tract and its association with reproductive outcomes, particularly in the setting of ART. Studies done solely for the purpose of characterizing the upper genital tract microbiome have relied on hysterectomy specimens to assess colonization, thus precluding evaluation of any association with reproductive outcomes. Perhaps the first study to investigate the association between the microbiome of the upper reproductive tract and ART outcomes utilized culture-based technology on embryo transfer catheter tips (Selman et al JARG 2007). However, this study utilized culture-based technology, with only four major bacteria were reported. Subsequent studies have highlighted the limitations of culture-based technology, namely that it is reliant upon successful culture, often resulting in an underestimate of the diversity of organisms.

As sequencing-based technology has gained popularity and limitations of culture-based technology have become more evident, there has been an increased interest in using sequencing to characterize the microbiome. One recent study utilized next-generation sequencing (NGS) based technology on embryo transfer catheter tips to evaluate the bacteria specific 16S ribosomal gene for characterization of the upper genital tract microbiome in patients undergoing embryo transfer (Franasiak et al, JARG 2016). Although it served as proof of concept for this method of characterizing the microbiome, the limited sample size did not permit any conclusions to be drawn regarding its association with reproductive outcomes. A subsequent study utilizing sequence-based technology examined endometrial fluid and vaginal aspirate samples in 35 women in the cycle prior to IVF and found that the presence of non-Lactobacillus-dominated microbiota in the endometrium was associated with significant decreases in implantation, ongoing pregnancy and live birth (Moreno et al, AJOG 2016).

Although there is some data linking reproductive health and the microbiome of the female reproductive tract, less information exists regarding its association with the microbiome of the male reproductive tract. One cross-sectional study examining the microbial colonization of semen demonstrated an association with semen parameters (Craig et al, F&S 2015). The microbiome of the male reproductive tract warrants further investigation in this setting.

The gastrointestinal tract microbiome plays a major role in human health and disease, with many documented associations to disease states such as obesity, diabetes, and gastrointestinal disorders (Clemente et al, Cell 2012). Recent data suggests that alterations in gastrointestinal tract microbiota are associated with preterm labor. The urinary tract microbiome has been similarly studied and linked to multiple disease states such as urinary incontinence and chronic prostatitis. To date, there are no published studies that examine the association of the gastrointestinal tract microbiome or urinary microbiota with pregnancy outcomes following IVF.

The human microbiome is thought to modulate the immune system and the presence of systemic inflammation. There is a growing interest in the association of chronic systemic inflammation and reproductive disorders. A number of biomarkers that reflect chronic systemic inflammation have been identified. Interleukin-6 (IL-6) is one such biomarker that has documented associations with PCOS, endometriosis, and infertility. Such biomarkers have not yet been studied in association with pregnancy outcomes following IVF.

There is more not known about the microbiome than is known. Traditionally, we have used empiric antibiotics as a crude tool. As we learn more, the paradigm of antibiotic use to eliminate unwanted antibiotics may be eclipsed by the use of probiotics which replace desired microbiome environments. More work is needed before this can even be studied, however, the potential role of the microbiome in general reproductive health is an exciting prospect and opens the door for numerous diagnostic and therapeutic potential.

Jason M. Franasiak, MD, HCLD/ALD (ABB)

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