A preliminary exploration of the mechanism of endometrial cancer development induced by intestinal flora diversity and its metabolites.

BACKGROUND: Endometrial cancer (EC) is a highly prevalent gynecological malignancy increasingly affecting younger populations. While the gut microbiota significantly modulates tumor progression via organ-to-organ networks, the specific molecular mechanisms and microbial co-metabolites driving EC remain poorly understood. This study profiles gut microbiota alterations in EC patients to identify correlations between microbial lipid/bile acid metabolites and EC pathogenesis. METHODS: A clinical cohort of 41 female participants (17 patients with histologically confirmed atypical endometrial hyperplasia or endometrioid adenocarcinoma, and 24 healthy controls) was prospectively enrolled. Fecal and serum samples underwent 16S rRNA gene sequencing (Illumina MiSeq) and LC-MS-based serum metabolomics, respectively. Spearman correlation analysis explored gut microbiota-metabolite associations. RESULTS: The EC and control groups shared structural similarities, but the Bacillota / Bacteroidota (B/B) ratio was higher in the EC group (1.35) than the control group (1.19). LEfSe analysis identified Megamonas, Megasphaera, Succinivibrio, and Veillonella as the most influential genera in the EC group (LDA > 4.0). Metabolomics revealed significantly elevated levels of hypoxanthine, 2,4-dihydroxyacetophenone-5-sulfate, inosine, benzoylcholine, 20-hydroxyeicosatetraenoic acid (20-HETE), and theobromine in EC patients. KEGG enrichment analysis showed that glycerophospholipid and purine metabolism were the most significantly dysregulated pathways (P < 0.05 ), with fine-scale network dissection revealing pathological remodeling of glycerophospholipid metabolism. Spearman correlation between the top 5 differential genera and top 20 serum metabolites demonstrated functional cross-talk between specific gut microbiota and circulating lipid and porphyrin homeostasis. CONCLUSIONS: This study delineates distinct alterations in the gut microbiota and serum metabolomic profiles of EC patients, identifying Megamonas and Klebsiella as promising non-invasive predictive biomarkers. Targeting these specific taxa and their dysregulated downstream metabolites, such as protoporphyrin IX and 20-HETE, may offer novel avenues for early diagnosis and therapeutic intervention. Despite a modest sample size, these findings lay a foundation for future large-scale, mechanistic investigations into the gut-metabolism axis in EC.