Frontiers in immunology · 2025
Unraveling the gut microbiota-SCFAs-cathepsin C pathway in preeclampsia: a novel therapeutic target.
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Lu Fan, Lei Houkang, Xiao Xiang, Yu Luzhu
Аннотация
INTRODUCTION: Preeclampsia (PE) is a severe obstetric syndrome linked to impaired maternal-fetal immune tolerance, placental insufficiency, and systemic inflammatory activation. Emerging studies suggest that gut microbiota and its metabolites, especially short-chain fatty acids (SCFAs), play a pivotal role in the pathogenesis of PE. However, the precise molecular mechanisms through which SCFAs influence maternal-fetal immune interactions remain poorly understood.
METHODS: This study combined clinical data and experimental models to explore the role of SCFAs in regulating cathepsin C expression, a key protease involved in immune modulation, and its impact on immune disturbances in PE. We analyzed the gut microbiota composition and serum SCFA levels in PE patients, and used an L-NAME-induced rat model of PE to assess the effects of SCFA supplementation. Additionally, forced cathepsin C overexpression in rats was performed to establish causality.
RESULTS: Our findings revealed significant gut microbiota alterations in PE patients, with a reduction in SCFA-producing bacteria and an increase in inflammatory microbes. Clinically, SCFA levels were inversely correlated with cathepsin C expression, which was associated with hypertension and proteinuria. In rats, SCFA supplementation significantly reduced cathepsin C levels and alleviated PE symptoms, including hypertension, proteinuria, and fetal growth restriction. Furthermore, overexpression of cathepsin C negated the beneficial effects of SCFAs, exacerbating PE progression. Mechanistically, SCFAs modulated macrophage polarization by inhibiting cathepsin C, promoting the shift to an anti-inflammatory M2 phenotype.
DISCUSSION: This study elucidates the "gut microbiota-SCFAs-cathepsin C-macrophage polarization" pathway as a crucial mechanism in the development of PE. SCFAs promote immune tolerance at the maternal-fetal interface by downregulating cathepsin C and driving M2 macrophage polarization. These findings offer new insights into potential therapeutic strategies for PE, including interventions aimed at modulating the gut microbiota to prevent or mitigate the disease.
METHODS: This study combined clinical data and experimental models to explore the role of SCFAs in regulating cathepsin C expression, a key protease involved in immune modulation, and its impact on immune disturbances in PE. We analyzed the gut microbiota composition and serum SCFA levels in PE patients, and used an L-NAME-induced rat model of PE to assess the effects of SCFA supplementation. Additionally, forced cathepsin C overexpression in rats was performed to establish causality.
RESULTS: Our findings revealed significant gut microbiota alterations in PE patients, with a reduction in SCFA-producing bacteria and an increase in inflammatory microbes. Clinically, SCFA levels were inversely correlated with cathepsin C expression, which was associated with hypertension and proteinuria. In rats, SCFA supplementation significantly reduced cathepsin C levels and alleviated PE symptoms, including hypertension, proteinuria, and fetal growth restriction. Furthermore, overexpression of cathepsin C negated the beneficial effects of SCFAs, exacerbating PE progression. Mechanistically, SCFAs modulated macrophage polarization by inhibiting cathepsin C, promoting the shift to an anti-inflammatory M2 phenotype.
DISCUSSION: This study elucidates the "gut microbiota-SCFAs-cathepsin C-macrophage polarization" pathway as a crucial mechanism in the development of PE. SCFAs promote immune tolerance at the maternal-fetal interface by downregulating cathepsin C and driving M2 macrophage polarization. These findings offer new insights into potential therapeutic strategies for PE, including interventions aimed at modulating the gut microbiota to prevent or mitigate the disease.