Butyrate modulates endometrial receptivity and decidualization to support embryo implantation

Introduction Microbial metabolites play a pivotal role in regulating endometrial function and embryo implantation, but their specific contributions remain incompletely understood. Our synthesis of published studies on the endometrial microbiota in recurrent implantation failure (RIF) revealed marked heterogeneity across cohorts, with some studies reporting altered abundance of bacterial genera with butyrate-producing capacity, providing a rationale for further investigation of butyrate. Methods In this study, we utilized human endometrial epithelial cells and stromal cells, a BeWo spheroid adhesion assay, RNA sequencing, and a lipopolysaccharide-induced mouse model of implantation impairment to evaluate the effects of butyrate, a key microbiota-derived short-chain fatty acid, on implantation-related endometrial functions. Results We found that sodium butyrate markedly increased PAEP and ITGB3 expression in human endometrial epithelial cells, promoted BeWo spheroid adhesion and spreading, and enhanced decidualization-related responses in human endometrial stromal cells. Transcriptomic analysis showed that sodium butyrate remodeled adhesion- and cell-cycle-related programs in endometrial epithelial cells, with partial overlap with clinical receptive-phase transcriptional features. In the lipopolysaccharide-induced implantation impairment model, intrauterine sodium butyrate significantly increased the number of implantation sites and improved several peri-implantation endometrial features. Discussion Together, these findings indicate that butyrate modulates multiple implantation-related endometrial states and may serve as a metabolic signal linking the local metabolic microenvironment to embryo implantation. Further studies are needed to delineate the specific molecular mechanisms underlying butyrate action, while direct measurement of intrauterine butyrate is needed to establish its physiological relevance.