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Decrease of L-cystathionine mediated by Sphingomonas echinoides contributes to the pathogenesis of hypertensive disorders of pregnancy

cardiology
gynecology-and-obstetrics

Abstract

Background: Hypertensive disorders of pregnancy (HDP) are a group of conditions that pose significant risks to both maternal and fetal health. Although the role of the uterine microbiota in the pathophysiology of non-pregnant women has been established, much less is known about its profile during pregnancy or its connection to gestational complications. This study was designed to profile the intrauterine microbiota in late pregnancy and define its relationship with HDP.

Methods: We performed full-length 16S rRNA gene sequencing and untargeted metabolomics on intrauterine swabs obtained from 49 patients with HDP and 56 normotensive late-term pregnancies. We identified key differential species and metabolites. The key microbial species were cultured under various conditions; after incubation, the supernatant was collected and subjected to HPLC-MS analysis to quantify critical metabolites, thereby validating microbial-metabolite relationships. To evaluate the functional impact of metabolites on trophoblasts, we treated HTR-8/SVneo cells with the target metabolite and assessed their invasion and migration capacities using transwell assays, wound healing assays, and Western blot analysis.

Results: Our study identified intrauterine microbiota and metabolic dysbiosis in patients with HDP. We identified three key differential species: Sphingomonas echinoides, unclassified Acinetobacter, and Burkholderia cenocepacia. Correlation analysis with ten key differential metabolites revealed a significant negative correlation between Sphingomonas echinoides and L-cystathionine. Microbial culture experiments confirmed that Sphingomonas echinoides extensively consumes L-cystathionine, while functional assays demonstrated that L-cystathionine significantly improves the invasion and migration capabilities of trophoblast cells impaired by hypoxia.

Conclusion: Our study revealed disrupted intrauterine microbial homeostasis in patients with HDP. We identified species and metabolites with differential abundance. Follow-up experiments were conducted to validate the relationship between these differential features and to assess the functional impact of key metabolites on trophoblast behavior. These findings may provide novel insights for the development of targeted therapeutic strategies.

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