Gut Microbiota Dysbiosis in Preeclampsia Patients in 2nd and 3rd Trimesters

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Gut Microbiota Dysbiosis in Preeclampsia Patients in the Second and Third Trimesters

Introduction

Preeclampsia (PE) is a pregnancy-specific multisystem disorder characterized by hypertension and proteinuria or other systemic complications after 20 weeks of gestation. Affecting 3%–8% of pregnancies globally, it remains a leading cause of maternal and perinatal morbidity and mortality. Despite extensive research, the precise etiology of PE remains unclear, though endothelial dysfunction, abnormal placentation, oxidative stress, and systemic inflammation are implicated. Recent studies suggest that gut microbiota dysbiosis—a disruption in the composition and function of intestinal microbial communities—may contribute to metabolic and inflammatory pathways linked to PE. The gut microbiota plays critical roles in host metabolism, immune regulation, and nutrient absorption, and its imbalance has been associated with conditions like obesity, hypertension, and diabetes. This study investigates longitudinal changes in gut microbiota composition during the second (T2) and third trimesters (T3) in PE patients compared to healthy controls, aiming to identify microbial biomarkers and elucidate potential mechanisms linking gut dysbiosis to PE pathogenesis.

Methods

Study Design and Participants

A nested case-control study was conducted at Nanjing Maternity and Child Health Care Hospital, involving 25 PE patients and 25 matched healthy controls. Participants were enrolled during the first trimester (T1: 6–8 weeks’ gestation), with fecal samples collected at T2 (20–24 weeks) and T3 (32–34 weeks). PE diagnosis followed American College of Obstetricians and Gynecologists criteria, requiring sustained hypertension (≥140/90 mmHg) and proteinuria (≥300 mg/24 hours) or end-organ dysfunction. Exclusion criteria included pre-existing chronic conditions, multiple pregnancies, and recent antibiotic or immunosuppressant use.

Sample Collection and Microbiota Analysis

Fecal samples were stored at -80°C after collection. DNA was extracted using the CTAB/SDS method, and the V4 region of the 16S rRNA gene was amplified using primers 515F/806R. Sequencing was performed on an Ion S5™ XL platform. After quality filtering and chimera removal, operational taxonomic units (OTUs) were clustered at 97% similarity using Uparse. Taxonomic annotation utilized the Silva Database.

Statistical Analysis

Alpha diversity (Shannon and Simpson indices) and beta diversity (weighted UniFrac distances) were calculated using QIIME. Differences in microbial composition were assessed via Wilcoxon rank-sum tests, Student’s t-tests, and ANOSIM. Linear discriminant analysis (LDA) effect size (LEfSe) identified taxa differentially abundant between groups (log LDA score >4.0).

Results

Participant Characteristics

No significant differences in age, BMI, or gestational age were observed between PE patients and controls at T2 or T3. In the PE group, 10 T3 samples were unavailable due to logistical constraints, but their baseline characteristics did not differ from the remaining 15 PE cases.

Gut Microbiota Composition

At the phylum level, Firmicutes dominated in all groups (control T2: 75.57%; PE T3: 60.62%), followed by Bacteroidetes, Actinobacteria, Proteobacteria, and Tenericutes. Fusobacteria and Verrucomicrobia constituted <1% of the microbiota. At the family level, Lachnospiraceae, Bacteroidaceae, and Ruminococcaceae were predominant.

Longitudinal Changes in Gut Microbiota

Controls (T2 vs. T3):

  • Proteobacteria decreased significantly (median T2: 2.25% [1.24%–3.30%] vs. T3: 0.64% [0.20%–1.20%]; Z = -3.880, P <0.05).
  • Tenericutes declined (median T2: 0.12% [0.03%–3.10%] vs. T3: 0.03% [0.02%–0.17%]; Z = -2.369, P <0.05).
  • Enterobacteriaceae (family within Proteobacteria) decreased markedly (median T2: 0.95% [0.25%–1.64%] vs. T3: 0.01% [0.004%–0.023%]; Z = -5.685, P <0.05).

PE Group (T2 vs. T3):

  • Bacteroidetes increased significantly (median T2: 18.16% [12.99%–30.46%] vs. T3: 31.09% [19.89%–46.06%]; Z = -2.417, P <0.05).
  • No significant changes occurred in other major phyla or families.

Differences Between PE and Controls

T2:
No significant differences in alpha diversity (Shannon/Simpson indices) or microbial composition at phylum/family levels.

T3:

  • Phylum Level:
    • Firmicutes abundance was lower in PE (60.62% ±15.17% vs. 75.57% ±11.53%; t = -3.405, P <0.05).
    • Bacteroidetes (31.09% [19.89%–46.06%] vs. 18.24% [12.90%–32.04%]; Z = -2.537, P <0.05) and Proteobacteria (1.52% [1.05%–2.61%] vs. 0.64% [0.20%–1.20%]; Z = -3.310, P <0.05) were elevated in PE.
  • Family Level:
    • Enterobacteriaceae was significantly enriched in PE (0.75% [0.20%–1.00%] vs. 0.01% [0.004%–0.023%]; Z = -4.152, P <0.05).

Beta Diversity and Taxonomic Biomarkers

PCoA based on weighted UniFrac distances revealed distinct clustering between PE and controls in T3 (P =0.016) but not T2 (P =0.040). LEfSe identified Bacteroidetes, Bacteroidia, and Bacteroidales as enriched in PE, while Firmicutes, Clostridia, Clostridiales, and Lachnospiraceae were depleted (log LDA >4.0).

Discussion

Gut Microbiota Dynamics in Pregnancy

This study highlights longitudinal shifts in gut microbiota during normal pregnancy, notably the decline of Proteobacteria and Tenericutes from T2 to T3. These phyla are associated with inflammatory responses and metabolic disturbances, suggesting a possible adaptation to mitigate systemic inflammation as pregnancy progresses. In contrast, PE patients exhibited a divergent trajectory, with Bacteroidetes increasing significantly by T3, coinciding with disease onset.

Dysbiosis and PE Pathogenesis

The T3-specific dysbiosis in PE—characterized by reduced Firmicutes and elevated Bacteroidetes/Proteobacteria—aligns with findings in metabolic and inflammatory disorders. Bacteroidetes, a major source of lipopolysaccharides (LPS), may drive systemic inflammation via Toll-like receptor 4 (TLR4) activation, contributing to endothelial dysfunction and hypertension. Conversely, Firmicutes depletion could reduce anti-inflammatory short-chain fatty acids (SCFAs), impairing blood pressure regulation. The enrichment of Enterobacteriaceae in PE further supports a pro-inflammatory milieu, as this family includes pathogens like Escherichia coli that exacerbate endotoxemia.

Methodological Considerations

While alpha diversity did not differ between groups, beta diversity analysis confirmed compositional shifts in PE. The absence of T2 differences suggests dysbiosis emerges closer to clinical PE manifestation, underscoring the importance of longitudinal sampling. However, limitations include a small sample size, lack of dietary data, and mechanistic insights, which future studies should address using metabolomics and animal models.

Conclusion

This study identifies significant gut microbiota dysbiosis in PE patients during T3, marked by Bacteroidetes and Proteobacteria expansion and Firmicutes depletion. These changes correlate with inflammatory pathways implicated in PE pathogenesis. Restoring microbial balance through dietary or probiotic interventions may offer novel preventive strategies, warranting further investigation.

doi.org/10.1097/CM9.0000000000000734

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