Prathi Selvapathi

Background: Preeclampsia is a hypertensive disorder of pregnancy associated with maternal endothelial dysfunction, placental abnormalities, fetal growth restriction, and increased maternal-fetal morbidity and mortality. Although current management strategies primarily focus on symptom control and delivery, disease-modifying therapies remain limited. Recent studies have demonstrated that gut microbiota composition is significantly altered in patients with preeclampsia, suggesting that microbiota dysbiosis may contribute to disease progression through inflammatory and vascular pathways.1-5 Gut microbiota-derived metabolites, including trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), have emerged as potential mechanistic mediators of endothelial dysfunction, placental injury, and systemic inflammation in preeclampsia. Understanding these pathways may provide novel diagnostic and therapeutic targets for future clinical management.

Objective: In this narrative review, we explored the role of gut microbiota-derived metabolites in the pathogenesis of preeclampsia and evaluated their potential clinical applications as therapeutic targets and diagnostic biomarkers.

Search Methods: An online literature search was conducted using the PubMed database for studies published between 2020 and 2026. Search terms included “preeclampsia,” “gut microbiota,” “trimethylamine N-oxide,” “TMAO,” “short-chain fatty acids,” “SCFA,” “FMO3,” “metabolites,” “vascular dysfunction,” and “inflammation.” Primary experimental studies, mechanistic animal models, and human metabolomic studies evaluating gut microbiota-derived metabolites in preeclampsia were reviewed.

Results: Multiple studies demonstrated that gut microbiota dysbiosis contributes to preeclampsia-like features through inflammatory and vascular mechanisms. Fecal microbiota transplantation from patients with preeclampsia into antibiotic-treated mice induced hypertension, proteinuria, placental abnormalities, fetal growth restriction, and systemic inflammation, supporting a causal role for microbiota imbalance in disease progression.^1,3 Elevated circulating TMAO levels were associated with increased blood pressure and adverse pregnancy outcomes in patients with preeclampsia.¹ Mechanistic studies showed that TMAO promotes oxidative stress and inflammatory signaling in endothelial and trophoblast cells, impairing placental vascular function and trophoblast invasion.¹ Increased expression of flavin-containing monooxygenase 3 (FMO3), the enzyme responsible for converting trimethylamine into TMAO, was also associated with inflammatory cytokine production and worsened maternal-fetal outcomes in animal models.² Partial suppression of FMO3 improved blood pressure, inflammation, and placental outcomes.² In contrast, SCFAs, particularly butyrate, demonstrated protective effects. Sodium butyrate supplementation significantly reduced hypertension and proteinuria while improving placental and fetal growth in rat models of preeclampsia.⁴ Human metabolomic studies additionally demonstrated altered SCFA profiles in patients with preeclampsia, with several metabolites correlating with disease severity and demonstrating strong diagnostic accuracy.⁵

Conclusions: Current evidence suggests that gut microbiota-derived metabolites play a significant mechanistic role in the development of preeclampsia through promotion of inflammatory signaling, endothelial dysfunction, and placental injury. Targeting harmful metabolites such as TMAO, restoring protective metabolites such as butyrate, and utilizing metabolite profiles as biomarkers may provide novel approaches for the diagnosis and treatment of preeclampsia. However, most evidence currently remains preclinical, and further human studies are needed to determine the safety, efficacy, and translational potential of microbiota-targeted therapies in clinical practice.

Works Cited

1. Wang J, Gao Y, Ren S, et al. Gut microbiota-derived trimethylamine N-oxide: a novel target for the treatment of preeclampsia. Gut Microbes. 2024;16(1):2311888. doi:10.1080/19490976.2024.2311888
2. Xu X, Zhang Y, Zu Y, et al. The role of gut microbiota imbalance in preeclampsia pathogenesis: insights into FMO3-mediated inflammatory mechanisms. Front Microbiol. 2025;16:1682007. doi:10.3389/fmicb.2025.1682007
3. Chen X, Li P, Liu M, et al. Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation. Gut. 2020;69(3):513-522. doi:10.1136/gutjnl-2019-319101
4. Yong W, Zhao Y, Jiang X, Li P. Sodium butyrate alleviates pre-eclampsia in pregnant rats by improving the gut microbiota and short-chain fatty acid metabolites production. J Appl Microbiol. 2022;132(2):1370-1383. doi:10.1111/jam.15279
5. Li J, Wang L, Chen H, et al. The diagnostic potential of gut microbiota-derived short-chain fatty acids in preeclampsia. Front Pediatr. 2022;10:878924. doi:10.3389/fped.2022.878924