Prevotella disiens Disrupts Endometrial Function via p38 MAPK-Mediated WNT Inhibition and Tryptophan Metabolism Dysregulation

Background: Recurrent implantation failure poses a challenge in assisted reproductive technology, often linked to an imbalance in the endometrial microbiome. Prevotella disiens, a bacterium found in the reproductive tract, is associated with reduced implantation success, but its effects on the endometrium are not well understood. This study uses hormone-responsive endometrial organoids to explore how Prevotella disiens alters endometrial function at a molecular level, aiming to uncover mechanisms contributing to implantation failure. Results: Endometrial organoids exposed to Prevotella disiens showed structural damage and significant changes in gene expression, unlike those treated with Lactobacillus species. Key findings include activation of the p38 MAPK pathway, suppression of WNT signaling, and increased expression of tryptophan metabolism genes. Metabolomic analysis revealed elevated kynurenine pathway metabolites in these organoids. Additionally, higher p38 MAPK and kynurenine pathway gene expression, and lower WNT pathway gene expression were observed in endometrial biopsies from patients with Prevotella disiens colonization. Blocking p38 MAPK in endometrial organoids reversed WNT suppression and normalized tryptophan metabolites. Conclusions: Prevotella disiens disrupts endometrial function by activating p38 MAPK, which inhibits WNT signaling and alters tryptophan metabolism, potentially hindering embryo implantation. These findings highlight the endometrial microbiome’s influence on reproductive success and point to p38 MAPK as a possible target for improving outcomes in assisted reproductive technology.