Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA.
Nantong Maternal and Child Health Hospital, Nantong University, Nantong, China.
Nat Commun. 2020 Apr 30;11(1):2111. doi: 10.1038/s41467-020-15923-4.
Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications. Bile acids are recognized as signaling molecules regulating a myriad of cellular and metabolic activities but have not been etiologically linked to PTB. In this study, a hospital-based cohort study with 36,755 pregnant women is conducted. We find that serum total bile acid levels directly correlate with the PTB rates regardless of the characteristics of the subjects and etiologies of liver disorders. Consistent with the findings from pregnant women, PTB is successfully reproduced in mice with liver injuries and dysregulated bile acids. More importantly, bile acids dose-dependently induce PTB with minimal hepatotoxicity. Furthermore, restoring bile acid homeostasis by farnesoid X receptor activation markedly reduces PTB and dramatically improves newborn survival rates. The findings thus establish an etiologic link between bile acids and PTB, and open an avenue for developing etiology-based therapies to prevent or delay PTB.
早产（PTB）是围产期死亡和新生儿并发症的主要原因。胆汁酸被认为是调节多种细胞和代谢活动的信号分子，但与 PTB 并无病因学联系。本研究通过对 36755 名孕妇进行基于医院的队列研究，发现血清总胆汁酸水平与 PTB 发生率直接相关，而与受试者的特征和肝脏疾病的病因无关。与孕妇的研究结果一致，通过肝损伤和胆汁酸失调的小鼠成功复制了 PTB。更重要的是，胆汁酸以最小的肝毒性剂量依赖性地诱导 PTB。此外，通过激活法尼醇 X 受体恢复胆汁酸动态平衡可显著降低 PTB 发生率，并显著提高新生儿存活率。这些发现确立了胆汁酸与 PTB 之间的病因学联系，并为开发基于病因的疗法以预防或延迟 PTB 提供了新的途径。
