Marilen Benner

MICROBIOTA AND ENDOMETRIAL HEALTH 167 6 the cyclic endometrial changes and establishing a receptive endometrium. Studies examining 16S rRNA from endometrium alongside first trimester and term placental samples are needed to show if, and how far, the microbes of the fetal-maternal interface relate to the pre-pregnancy state. Origin The origin of the endometrial, and especially the placental, microbiome is highly discussed. Different routes of colonization have been suggested, including the gut, vagina, or oral cavity. We believe that with placental development originating from decidualized endometrium, it would be highly unlikely that the endometrial and placental microbiome are completely independent. In the intimate relationship of endometrium/decidua and placenta, the trophoblast cells invading the uterine mucosal tissue have to be in contact with the residential microbiota. Systematically comparing the healthy, pre-pregnancy endometrium to placental samples will help to elucidate whether the placental colonization results from the bacteria already present in the uterus. A vaginal origin is one of the suggested routes of uterine colonization, as a number of species seem to be residents of both body sites. Transfer of labeled macrospheres by a “uterine peristaltic pump” activity from vagina to uterus has been shown (207, 208). Evidence from mouse studies points out that a change in TLRs and antimicrobial peptide expression and function allows the passage of vaginal bacteria through the cervix into the uterus upon cervical infection. Remarkably, in nonpregnant mice, bacteria could travel from the lower reproductive tract into the uterus, but this was prohibited during pregnancy. These findings suggest that a healthy, uninfected cervix, regulates the ascents of vaginal bacteria (209). This theory is supported by earlier findings of differences in biochemical and chemical properties of the cervix depending on the pregnancy state (210, 211). In line with theories on oral transmission of bacteria into the uterus, an association of periodontal disease and pregnancy complications is highly discussed (212). Indeed, bacteria such as Lactobacillus or A.vaginae that were found in the 16S assessment of the endometrial microbiome, are associated with caries, but not healthy plaques (213, 214). Interestingly, the placental microbiome resembles that of the oral cavity more than that of gut or even vagina (24). Several studies also show an association of cytokines and bacteria from amniotic fluid with oral microbiota (215, 216). It remains to be seen whether bacteria of the oral cavity can indeed travel via the circulatory system to selectively colonize the uterus before or during pregnancy (217). Jimenez and colleagues elegantly showed that in utero bacterial colonization of the fetus takes place, which can be influenced by maternal oral uptake of microbiota (218). Pregnant mice were fed with a genetically labeled E. fecium strain isolated from human breast milk, and the bacteria could be detected in pups delivered by C-section. The authors point out that next to the possible oral route, APCs of the gut might sense and actively harvest intestinal bacteria, facilitating their