Marilen Benner

CHAPTER 6 162 bile acids (177). Another contribution by commensals is continuous receptor stimulation leading to TLR upregulation; needed to sense potentially dangerous bacteria (178). Mice and humans treated with antibiotics, diminishing the intestinal microbiota, are highly susceptible to antibiotic- resistant strains because of a reduced expression of antimicrobial defense mechanisms (179). In the female reproductive tract, inhibition of gonococci ( Neisseria gonorrhoeae ) adherence is observed in the presence of Lactobacilli when using an in vitro model of endometrial epithelial cells (180). In an endocervical epithelial cell model, TLR agonists, as a surrogate for microbial products, were shown to stimulate antimicrobial products and mucins (181). Maintaining commensal colonization within the endometrium may likely offer a similar means of effective protection against uterine infections. Tissue adaptation In addition to lymphocytes, epithelial cells play a crucial role in co-existence with commensal colonization. An intact epithelium allows for safe colonization without extensive (pathogenic) barrier breach, through a physical barrier and reaction of the epithelial cells towards bacterial ligands. On the other hand, bacteria also contribute to a healthy barrier development. Increasing evidence highlights the importance of microbiota for gut development and morphogenesis. Known adaptations of microbiota-implicated tissue adaptations include intestinal epithelial cell differentiation (182), support of epithelial cell regeneration (183), modulation of epithelial cell permeability (184), and vascularization (185). In the uterus, commensal bacteria might contribute to the remodeling needed for a receptive state of the endometrium. The genus Bacteroides , constituting 30% of the endometrial community in 90% of women, is known to be tightly involved in intestinal tissue development by influencing epithelial cell maturation and maintenance (186, 187). Hooper and colleagues showed that B. thetaiotaomicron induced gene expression of proteins involved in nutrient absorption, angiogenesis, intestinal maturation, and mucosal barrier reinforcement (188). Bacteroides was shown to be essential for intestinal vascularization through signaling mediated by Paneth cells, the main type of epithelial cell in the intestine secreting anti- microbial compounds (189). Further studies using endometrial epithelial cells are warranted to ascribe similar physiological functions to the uterine microbiome during endometrial remodeling. The continuous reparative processes following the secretory phase might benefit from microbial support mechanisms. Dysbiosis in this critical period of preparing for blastocyst invasion might be one of the unrevealed causes leading to recurrent implantation failure due to failed remodeling. Another interesting tissue adaptation involved in the peri-implantation period is the change in barrier function of the endometrial epithelium. Features of tight junctions, such as area of whole junction and the area enclosed by junctional strands, decrease from day 13 to day 22 of the menstrual cycle, which could be beneficial for implantation (190). Redistribution of adherens junctions and desmosomes during the WOI may also prepare for trophoblast invasion (191). The tight junctional barrier function is regulated by nutrients and cytokines (192). As a side effect