Marilen Benner

SUMMARY AND DISCUSSION 227 8 to systemic immunity (69-74). In Chapter 6 , we studied the available evidence regarding the possible impact of microbiota on endometrial immunology and fertility. With the chance to analyze microbial composition through measuring 16S rRNA rather than culturing methods, even rare species, and low biomass colonization, can be assessed. The discussion on the contribution of a local microbiome for healthy pregnancy lifted off with the exposure of a possible placental microbiome in 2014 (75). At the same time, bacteria were also observed within cells of the placenta, without signs of inflammation such as accumulation of immune cells in the proximity (76, 77). As outlined throughout this thesis, the placenta evolves from, and depends on, a healthy endometrium. Therefore, we assume that in theory, the placental microbiome stems from microbiota of the endometrium, but both may differ to a large extent in composition. The microbiome is known to adapt due to gestation (78, 79). For example, when pregnant, 70% of women present with increased fractions of gut microbiota that are associated with inflammation (80). It has been suggested, that this compositional shift is dictated by pregnancy hormones (81). The same hormones also reach the uterine cavity, and can thus impact the local microbiome. In Chapter 6 , we focus on the endometrial microbiome as a contributor to setting the stage for conception . We extrapolate known contributions of gut microbiota to possible mechanisms at play within the uterus. Even though only limited endometrial profiles of healthy women were available at the time point of the study, we conclude that, if bacteria are present within the uterus, a physiological role for maintenance of uterine adaptation and immunity is inevitable. THE STERILE WOMB PARADIGM Based on the hypothesis that newborns acquire their initial bacterial colonization through birth, rather than in the uterus, the dogma of the “sterile womb” was manifested by French pediatrician Henry Tissier (82). This concept has proven persistent; whether the uterus harbors a microbiome, or whether this is merely an artefact of sampling or detection, is still under heavy debate; research has not reached consensus regarding when the baby is initially colonized by bacteria (83-85). An overview of arguments supporting and refuting antenatal microbial exposure exceeds the scope of this thesis. It remains to be established how the neonatal microbiome relates to a gestational uterine microbiome, and might consequently disrupted upon microbial modulation during pregnancy. In Chapter 6 , we stress how controlling for contamination, and a standardized approach to detect 16S rRNA can support a worthwhile search to find consensus on uterine microbiota. In the years following publication of this chapter, a rapid increase in studies, that support a shift in perspective on the microbiome and the uterus, could be observed (86-89). Even now, species composition of the healthy endometrium is yet to be determined. Contrary to the well-studied, and well-defined, mucosal microbiome of the gut or the vagina, the uterine cavity contains only a very low biomass of microbiota (90). Low biomass does not equal sterility;