Endometrial microbiota-dimethylglycine-Treg cell axis affects endometrial receptivity in recurrent implantation failure

Recurrent implantation failure (RIF) poses a substantial challenge in assisted reproductive technologies, causing serious psychological burden and economic pressure to patients with infertility. However, the pathogenesis of RIF remains unclear; therefore, in-depth research on RIF is crucial for guiding clinical treatment. Recent studies have indicated that reproductive tract microbiota imbalance is closely related to RIF, making it a new and promising research direction to explore. The present study shows that during the secretory phase, alpha diversity of the endometrial microbiota (EnM) significantly differed (P=0.022) between the RIF and control groups. Moreover, beta diversity analysis found significant differences in both the EnM and uterine lavage fluid microbiota (UfM) (both P0.05). Further comparing the endometrial tissue metabolites of the RIF and control groups in the secretory phase, 34 metabolites were significantly increased, while 19 others, such as dimethylglycine (DMG), were significantly decreased in the RIF group. Correlation analysis revealed significant correlations between differentially abundant microbiota and metabolites in the endometrium. Furthermore, transplantation of EnM from the RIF group into the uterine cavity of SD rats significantly altered the microecological environment of the uterine cavity, decreasing Hoxa-10 and Lif and reducing embryonic implantation sites. Further exploration of the mechanism revealed that this transplantation decreased the proportion of uterine regulatory T (Treg) cells and the expression of DMG. Additionally, DMG supplementation is expected to mitigate the reduction in Treg and the impairment of endometrial receptivity caused by endometrial tissue microbiota disorders. Therefore, alterations in EnM in patients with RIF may alter endometrial metabolites, decrease Treg-cell proportions, affect endometrial receptivity, and ultimately induce recurrent implantation failure.