Biologia Futura: endometrial microbiome affects endometrial receptivity from the perspective of the endometrial immune microenvironment

Biologia Futura (2022) 73:291–300 https://doi.org/10.1007/s42977-022-00134-3 REVIEW Biologia Futura: endometrial microbiome affects endometrial receptivity from the perspective of the endometrial immune microenvironment Wenhui Wang1 · Dingqing Feng1 · Bin Ling1 Received: 23 September 2021 / Accepted: 3 August 2022 / Published online: 26 September 2022 © The Author(s) 2022 Abstract The existence of Lactobacillus-led colonized bacteria in the endometrium of a healthy human has been reported in recent studies. Unlike the composition of the microbiome in the lower genital tract, that in the endometrium is different and closely associated with the physiological and pathological processes of gynecological diseases. For example, changing the immune microenvironment affects the receptivity of the endometrium, thereby leading to abnormal reproductive outcomes, such as embryo implantation failure and recurrent spontaneous abortion. However, the concrete functions and mechanisms of the endometrial microbiome have not been studied thoroughly. This review elaborates the research progress on the mechanisms by which the endometrial microbiome affects endometrial receptivity from the perspective of endometrial immune microenvironment regulation. Considering the lack of a unified evaluation method for the endometrial microbiome, as well as the lack of an optimal treatment protocol against recurrent spontaneous abortion, we also discussed the application of combining antibiotics with probiotics/prebiotics as precautionary measures. Keywords Endometrial microbiome · Endometrial receptivity · Lactobacillus · Embryo implantation · Spontaneous abortion · Immune microenvironment Abbreviations AMP Antimicrobial peptide APC Antigen presenting cell ART Assisted reproductive technology DC Dendritic cell ERA Endometrial receptivity array EVT Extra-villous trophoblasts HLA Human leukocyte antigen IFN-γ Interferon gamma IL Interleukin IVF In vitro fertilization NK Natural killer PAMP Pathogen-associated molecular patterns PRR Pattern recognition receptor RIF Recurrent implantation failure * Dingqing Feng * Bin Ling 1 Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China RSA Recurrent spontaneous abortion TGF-β Transforming growth factor-β Th T helper TNF-α Tumor necrosis factor alpha Tregs Regulatory T cells uNK Uterine natural killer WOI Window of implantation Introduction The human endometrium was considered sterile until some studies using next‐generation sequencing of the 16S rRNA gene revealed the existence of an endometrial microbiome represented by Lactobacillus and other bacteria (Baker et al. 2018; Moreno et al. 2020; Li et al. 2018). Despite the low biomass, the endometrial microbiome seems active (Bardos et al. 2019; Tomaiuolo et al. 2020). Recent studies have also reported the effect of the endometrial microbiome on implantation outcomes (Hashimoto and Kyono 2019; Franasiak et al. 2016; Garcia-Grau et al. 2019; Liu et al. 2018; Kitaya et al. 2019; Kyono et al. 2018, 2019; Verstraelen et al. 2016; Moreno et al. 2016; 13 Vol.:(0123456789) 292 Saxtorph et al. 2020). Furthermore, non-Lactobacillusdominated endometrial microbiome has been reported to negatively influence pregnancy outcomes (Younes et al. 2018). Nonetheless, the mechanism by which the human endometrial microbiome affects embryo implantation remains unclear (Hashimoto and Kyono 2019; Franasiak et al. 2016). The synchronization of the development of high-quality embryos and an acceptable endometrium is crucial for the success of embryo implantation (Tohma and Esin 2017). About one-third of implantation failures are caused by embryo quality, whereas the rest are due to poor endometrial receptivity (Idelevich and Vilella 2020). Pregnancy failure is also associated with repeated in vitro fertilization (IVF) cycles in many infertile women undergoing assisted reproductive technology (ART), even if the selected and transferred embryos are high-quality (Benner et al. 2018). Recent studies on the endometrial microbiome have indicated the importance of evaluating the microbial environment to better comprehend endometrial proliferation, embryo apposition/attachment/invasion, and the development of early pregnancy (Tao et al. 2017). To date, few studies have examined whether the endometrial microbiome can influence maternal intrauterine environment and thus control endometrial receptivity (Younes et al. 2018). Considering previous findings regarding chronic endometritis, vaginal or gut microbiome, and the positive influence of probiotics or prebiotics on IVF outcomes (Hashimoto and Kyono 2019; Al-Nasiry et al. 2020; Benner et al. 2018; Molina et al. 2020; Kayama et al. 2020; Zhou et al. 2018; Khalesi et al. 2019; Trush et al. 2020; Fu et al. 2020; Łaniewski et al. 2017; Pekmezovic et al. 2019; D'Ippolito et al. 2018; Xu et al. 2020), we speculate that the endometrial microbiome may play an important role in the regulation of endometrial receptivity. The human endometrium is maintained by the equilibrium of several components, including the microbiome, cellular immune response, and cytokines that affect endometrial receptivity (Hashimoto and Kyono 2019; Al-Nasiry et al. 2020; Benner et al. 2018; Molina et al. 2020; Kayama et al. 2020; Zhou et al. 2018; Khalesi et al. 2019; Trush et al. 2020; Fu et al. 2020; Łaniewski et al. 2017; Pekmezovic et al. 2019). The balance of inflammatory factors is important for the regulation of blastocyst adhesion in the epithelial endometrial wall (Bardos et al. 2019; Tohma and Esin 2017). A non-Lactobacillus-dominated endometrium status may break the balance and trigger an inflammatory response in the endometrium, which would affect endometrial receptivity (Hashimoto and Kyono 2019; Moreno and Simon 2018; Haahr et al. 2020). Nevertheless, the role and contribution of the microbiome in endometrial receptivity by regulating the immune microenvironment remain unclear (Mor et al. 2017). In this review, we summarize current research achievements regarding the mechanism by which the endometrial 13 Biologia Futura (2022) 73:291–300 microbiome affects endometrial receptivity from the perspective of immune microenvironment regulation. The composition and source of the endometrial microbiome in healthy women Many studies have investigated the composition and source of the "good" endometrial microbiome (Benner et al. 2018; Al-Nasiry et al. 2020; Franasiak and Scott 2017). However, so far, the composition and function of the endometrial microbiome remain controversial (Riganelli et al. 2020). It is generally recognized that a "healthy" female endometrium, like the vagina, is mainly colonized by Lactobacillus (Benner et al. 2018; Al-Nasiry et al. 2020; Franasiak and Scott 2017). However, some studies have expressed a different opinion. Verstraelen et al. (Winters et al. 2019) reported that three Bacteroides and one Pelomonas species were most abund (...truncated)