Dysregulation of bile acids increases the risk for preterm birth in pregnant women

Preterm birth (PTB), defined as birth before 37 weeks of gestation, is a significant global health concern, leading to high rates of infant mortality and long-term health complications for survivors. Despite extensive research, the underlying mechanisms of PTB remain incompletely understood, hindering the development of effective preventive interventions. Current interventions show inconsistent benefits. Bile acids, synthesized in the liver and regulated through enterohepatic circulation, are signaling molecules with diverse cellular and metabolic roles. While elevated bile acids have been associated with increased PTB risk in pregnant women with intrahepatic cholestasis of pregnancy (ICP), a direct causal link has not been established. This study aimed to determine if elevated bile acids, independent of liver injury, are a direct cause of PTB.

Previous research has highlighted the complex and multifactorial nature of PTB. While several risk factors have been identified, our understanding of the underlying mechanisms remains limited. Studies on pregnant women with ICP have shown a correlation between elevated bile acid levels and increased PTB risk, but a direct causal link remained unclear. The role of bile acids as signaling molecules in various cellular and metabolic processes is increasingly recognized. However, the specific mechanism by which dysregulated bile acids might lead to PTB needed further investigation. This study aimed to bridge this gap by using a large cohort study and animal models to investigate the direct causal relationship between bile acid dysregulation and PTB.

This study employed a hospital-based prospective cohort study of 36,755 pregnant women, primarily ethnic Chinese, to investigate the association between serum total bile acid (sTBA) levels and PTB rates. Data on maternal characteristics (age, BMI, parity, history of PTB or stillbirth), liver function tests (AST, ALT, GGT, total bilirubin), and sTBA levels were collected. PTB was categorized as spontaneous (sPTB) or iatrogenic (iPTB). Mouse models were used to investigate the causal link between bile acid dysregulation and PTB. Pregnant mice were treated with 17α-ethinyl estradiol (EE2) to induce liver injury and bile acid dysregulation, and with carbon tetrachloride (CCl4) and cholic acid (CA) to induce liver injury and elevated bile acids, respectively. The effects of these treatments on PTB, gestation length, live birth rates, sTBA levels, and AST levels were assessed. The effect of FXR activation on PTB was also studied using a synthetic FXR agonist (GW4064). Statistical analysis included Pearson correlation, Student's t-test, ANOVA, Chi-squared test, and Poisson regression.

The study found a significant positive correlation between sTBA levels and PTB rates in the cohort of pregnant women (r = 0.988; p = 0.12). This correlation held true even after adjusting for confounding factors like maternal age and BMI. Elevated sTBA levels were observed in both sPTB and iPTB cases compared to full-term births. In mouse models, both EE2 and CCl4 induced liver injury and PTB, with increased sTBA levels. Importantly, CA treatment dose-dependently induced PTB in pregnant mice, even with minimal liver injury, indicating that elevated bile acids themselves are a cause of PTB. Restoring bile acid homeostasis through FXR activation with GW4064 significantly reduced CCl4-induced PTB and improved newborn survival rates. The expression levels of bile salt export pump (Bsep) and cholesterol 7α-hydroxylase (Cyp7a1) were significantly altered by GW4064, indicating its effect on bile acid homeostasis.

This study provides strong evidence establishing a causal link between bile acid dysregulation and PTB. The findings from both human and mouse studies consistently demonstrate that elevated sTBA levels are associated with increased PTB risk. The mouse models, particularly the CA model, clearly show that elevated bile acids, independently of significant liver injury, can directly induce PTB. This suggests that targeting bile acid homeostasis could be a novel therapeutic strategy to prevent or delay PTB. The success of FXR activation in reducing PTB and improving newborn survival further supports this approach. Advanced maternal age and obesity, previously linked to increased PTB risk, may also be related to elevated bile acid levels. The study also highlights the importance of considering sTBA levels as a potential predictor of PTB, potentially superior to traditional liver function tests.

This research demonstrates a causal relationship between elevated bile acids and preterm birth. The findings highlight the potential of targeting bile acid homeostasis, specifically through FXR activation, as a novel therapeutic strategy to prevent or delay preterm birth. Further research is needed to fully elucidate the mechanisms underlying bile acid-induced PTB and to optimize therapeutic interventions targeting this pathway.

The study population was primarily composed of ethnic Chinese women, which might limit the generalizability of the findings to other populations. The mouse models, while useful for establishing causality, may not fully capture the complexity of human pregnancy. Further research is necessary to validate these findings in diverse populations and to explore potential interactions between bile acids and other risk factors for PTB.