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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295682 | GEO | 2026/04/25

REPOSITORIES: GEO

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Project description:Background: Recurrent implantation failure (RIF) remains a major barrier to successful assisted reproductive technology, given the lack of effective, mechanism-informed interventions to enhance endometrial receptivity. Jiawei Shoutai Wan (pills) (JWSTW), a modified formulation of the classic Shoutai Pill (STP) used in reproductive medicine, has not been systematically evaluated in the treatment of RIF, and its bioactive components and molecular targets remain largely unclear. Purpose: To determine whether JWSTW improves implantation competence and to identify the pathways associated with its effects. Materials and methods: A mifepristone-induced embryo implantation dysfunction (EID) rat model was established to evaluate implantation outcomes, uterine histology, and markers of endometrial receptivity and vascular perfusion. Bulk uterine transcriptomics and peripheral blood serum untargeted metabolomics were integrated with liquid chromatography-tandem mass spectrometry (LC-MS) based component profiling, network pharmacology, multi-omics correlation analysis, uterine cavity microbiota profiling and structure-based computational analyses. Key pathway molecules were further assessed using targeted molecular experiments. A retrospective cohort of RIF patients undergoing assisted reproduction was analyzed for ultrasound-derived endometrial receptivity parameters before and after treatment. Results: JWSTW administration improved implantation outcomes in EID rats, characterized by the upregulation of multiple receptivity- and perfusion-associated tissue markers. Integrated multi-omics analyses identified peroxisome proliferator-activated receptor (PPAR) signaling and lipid metabolism as significantly enriched pathways, supported by corresponding gene-metabolite correlations. JWSTW was also associated with structured changes in the uterine cavity microbiota, with enriched taxa and predicted functions aligned with lipid metabolism related pathways. LC-MS/MS characterization identified sweroside and loganic acid as major circulating constituents, while computational analyses prioritized a PPAR-centered target network with favorable binding affinity and structural stability. In the retrospective RIF cohort (n = 100), JWSTW was associated with increased endometrial thickness and improved Doppler-derived perfusion indices. Conclusion: These findings support JWSTW as a mechanism-informed candidate to improve endometrial receptivity in implantation failure via a PPAR-lipid metabolism axis.

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

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