Role of microbial metabolites in the pathogenesis of hypertensive disorders of pregnancy: From short‑chain fatty acids to tryptophan metabolites (Review).

Abstract

Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and perinatal morbidity worldwide, and their pathogenesis involves complex interactions among vascular dysfunction, placental ischemia and immune dysregulation. The gut microbiota has been highlighted as a key upstream modulator, with microbial metabolites serving as key functional mediators rather than microbial composition alone. The present review focused on the roles of short‑chain fatty acids (SCFAs) and tryptophan metabolites in HDP pathogenesis. SCFAs and tryptophan‑derived metabolites modulate vascular function, immune tolerance and placental development via G protein‑coupled receptors, histone deacetylase inhibition and aryl hydrocarbon receptor (AhR) signaling. Their crosstalk underscores integrated regulatory networks at the maternal‑fetal interface. For example, butyrate promotes regulatory T cell differentiation via histone deacetylase inhibition, while indole‑3‑lactic acid activates the AhR; these pathways may synergistically enhance immune tolerance, yet competition for AhR binding between different tryptophan metabolites could produce antagonistic effects. Despite key progress, notable challenges remain regarding causal inference, methodological standardization and translational barriers. The present review aimed to synthesize current mechanistic insights and evaluate the clinical translation potential of targeting microbial metabolites for HDP prevention and management.