Modulation of Intrauterine Adhesion Fibrosis by Lactobacillus delbrueckii: Insights from ERK1/2 Pathway Inhibition and Multi-omics Analyses

BackgroundIntrauterine adhesion (IUA) is an important cause of infertility and menstrual disorders, substantially reducing quality of life and increasing healthcare costs. Current treatments, including hysteroscopic adhesiolysis and hormonal therapy, show limited efficacy and high recurrence, highlighting the need for new therapeutic strategies. MethodsWe evaluated the antifibrotic effects of Lactobacillus delbrueckii in IUA, with a focus on ERK1/2 signaling inhibition. A multimodal framework integrating clinical outcomes, cellular and animal experiments, uterine microbiome profiling (16S rRNA sequencing), transcriptomics, and metabolomics was used to characterize host-microbe-metabolite interactions relevant to fibrosis. ResultsClinically, patients receiving L. delbrueckii showed lower adhesion formation scores(AFS) and reduced recurrence. Microbiome profiling demonstrated increased uterine microbial diversity and altered community composition in treated patients, accompanied by reduced expression of fibrosis-associated markers. In both cellular and mouse models, L. delbrueckii decreased fibrotic marker expression and reduced ERK1/2 phosphorylation. Metabolomics identified elevated 3-hydroxyanthranilic acid (3-HAA) in treated groups, suggesting a potential role in immune and inflammatory modulation. ConclusionL. delbrueckii attenuates IUA-associated fibrosis, at least in part, by suppressing ERK1/2 phosphorylation and increasing the abundance of the metabolite 3-HAA. These findings support the therapeutic potential of L. delbrueckii for improving uterine repair and reproductive outcomes. Future studies should validate efficacy and safety in larger, diverse cohorts and assess long-term outcomes.