Marilen Benner

CHAPTER 6 166 narrow down the window in which a certain microbe-associated effect on pregnancy takes place. In the future, robust evidence for a uterine microbiome might also fuel novel options for intervention concerning fertility and prevention of preterm birth risk in women with a history of BV. Chicken or egg It is possible that the state of inflammation is a sign of dysregulated immunity, rather than only a result of the presence of pathogenic, bacterial colonization. Chronic endometritis, the persistent inflammation of the endometrial lining, is associated with RIF (201) and successful antibiotic treatment of endometritis could clear the condition (as characterized by accumulation of plasma cells in biopsy samples), but clearance did not improve the chance of implantation. In this case, a certain microbial profile might not represent the cause but, instead, the effect of an immune state that is unfavorable for pregnancy. Interestingly, bacteria found in the endometrium causing the inflammation were not found in the vagina, suggesting that they are commensals in a dysbiotic state, rather than pathogenic intruders (36). However, at present, we cannot exclude an active effect of microbiota on the physiological changes needed for a receptive endometrium. Functional studies are needed to understand the host-microbe interaction in the uterus. More robust information on the species involved in uterine colonization will allow further functional assessment using in vitro endometrial models (202). Next to this, the association of bacterial metabolites as a cause or consequence of certain microbial colonization and the state of fertility needs to be examined. Yeoman et al. (2013) evaluated metabolomic profiling as a fast and cost-effective diagnostic tool for BV (203). It remains to be elucidated whether uterine metabolites can be a proxy for the infertility related to dysbiosis. Also, since naturally occurring microbes continuously breach the endothelial barrier and are a part of homeostasis, microbes will continuously shape the immune environment. How this impacts the tightly regulated immunological processes involved from endometrium preparation towards a healthy pregnancy is yet to be discovered. Dynamic bugs Recently, the importance of the microbiome for regulation of rhythmic biological changes has been stated (204). Fluctuating microbial community structures might direct hormonal changes (205). It is tempting to speculate that similar dynamics are involved in the female cycle. Moreno and colleagues observed differences in the microbiota detected in the pre-receptive versus receptive phase in the endometrium (19). The extent of this effect varied. However, also for the vaginal microbiota it was shown that while in some women low constancy and high species turnover is observed, the extent of these changes can be very small for others (206). Until now, sample size prohibits conclusions on putative characteristic changes of the endometrial microbiota associated with the induction of the WOI. More in-depth studies on changes in the endometrial microbiome are needed to assess whether microbiota play a role in orchestrating