Marilen Benner

MICROBIOTA AND ENDOMETRIAL HEALTH 157 6 seen from the secretory phase towards early pregnancy (121). More recently, regulatory T (Treg) cells and Th17 cells have been included in the discussion (122, 123). Increasing evidence on the shaping of T cell subsets by microbiota based on studies of the gut is emerging (124). Like in the endometrium, mucosal immunity of the intestines depends on an interplay of IFN- γ producing Th1 cells, Th17 cells that secrete IL-17 and IL-22, and innate lymphoid cells with Th2-cytokine secreting functions, and suppressive Foxp3 + Treg cells. Differentiation of various T cell subsets is impaired in mice with disrupted gut microbiota (125, 126). Commensal segmented filamentous bacteria were shown to be important for Th17-mediated mucosal protection (127). A detailed understanding of the mechanisms underlying bacteria-mediated T cell induction is not yet available. One of the few examples in which the link between microbe and host is known, is polysaccharide A (PSA) originating from the capsule of Bacteroides fragilis (127). Bacteroides, found in a number of the endometrial studies analyzing 16S rRNA, tunes the Th17 response of intestinal T cells, and causes a systemic increase of circulating CD4+ T and Th1 cells (128-130). Other microbiota are known to induce and cause accumulation of Treg cells, essential in maintaining tolerance and known to be important for pregnancy (131). In the gut, Treg mediated IL-10 production is thought to be critical to maintain intestinal microbial homeostasis by limiting continuous activation of Th1 and Th17 cells. Commensal microbiota promote de novo generation and activation of mucosal Treg cells (132) as shown by mice colonized with altered Schaedler flora species ( Lactobaillus, Bacteroides, species of Flexistipes phylum and gram-positive bacteria of the Firmicutes, Bacillus-Clostridium group) (132, 133). Focusing on specific strains, colonization of mice with Clostridia strains was shown to induce expansion of Treg cells locally in the lamina propria and systemically, resulting in increased resistance to colitis and IgE responses in adult mice (134). These intestinally induced Treg were shown to express a T-cell receptor repertoire specific for bacteria of the luminal content of colonized mice, allowing tolerance towards individual species (135). Similar generation and activation of immune cell types by endometrial microbiota could be essential for correct homeostasis regarding maintenance of a microbiome and programming the local immunity within the uterus. The majority of work on microbiota and immunity focuses on T cell homeostasis, but especially cells of the innate arm of the immune system are involved in the peri-implantation period. Cytokines and chemokines belong to the soluble factors known to be associatedwith reproductive health. Induced by either endometrial cells or immune cells recruited upon blastocyst encounter, the implantation period is characterized by an increase in pro-inflammatory Th1 cytokines, such as IL-6, IL-8, LIF, and TNF- α , with implications for immune cell recruitment and activation of the endometrium, as reviewed previously (136, 137). Throughout the female cycle, healthy endometrial stromal cells constitutively secrete the chemokine CCL2, also known as monocyte