Targeted metabolomics analysis of maternal-placental-fetal metabolism in pregnant swine reveals links in fetal bile acid homeostasis and sulfation capacity

Authors: WANG, PENG - Sichuan University; ZHONG, HEJU - Sichuan University; SONG, YUMO - Sichuan University; YUAN, PEIQIANG - Sichuan University; LI, YUNXIA - Sichuan University; LIN, SEN - Sichuan University; ZHANG, XIAOLING - Sichuan University; LI, JIAN - Sichuan University; CHE, LIANQIANG - Sichuan University; FENG, BIN - Sichuan University; LIN, YAN - Sichuan University; XU, SHENGYU - Sichuan University; ZHUO, YONG - Sichuan University; TIAN, GANG - Sichuan University; CHEN, DAIWEN - Sichuan University; WE, DE - Sichuan University; Burrin, Douglas - Doug; FANG, ZHENGFENG - Sichuan University

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/15/2019
Publication Date: 4/15/2019
Publication URL: https://handle.nal.usda.gov/10113/6487971
Citation: Wang, P., Zhong, H., Song, Y., Yuan, P., Li, Y., Lin, S., Zhang, X., Li, J., Che, L., Feng, B., Lin, Y., Xu, S., Zhuo, Y., Tian, G., Chen, D., We, D., Burrin, D.G., Fang, Z. 2019. Targeted metabolomics analysis of maternal-placental-fetal metabolism in pregnant swine reveals links in fetal bile acid homeostasis and sulfation capacity. American Journal of Physiology - Gastrointestinal and Liver Physiology. 317:G8-G16. https://doi.org/10.1152/ajpgi.00056.2019.
DOI: https://doi.org/10.1152/ajpgi.00056.2019

Interpretive Summary: A clinically important problem in pregnant women is intrahepatic cholestasis (ICP), a jaundice condition, resulting from accumulation of bile acids in the blood. The condition of ICP increases the risk of fetal distress and fetal mortality. The precise cause of ICP is poorly understood and it is difficulty to perform research studies on pregnant women. Thus, in this study, we used pregnant pigs and studied the relationship between accumulation of bile acids and other metabolites in the blood, placenta, and fetus and outcomes of fetal death. We found that bile acid accumulation in the mother's blood and placenta was due to poor transporter function. We also found that the reason for bile acid accumulation in the fetus was mainly associated with the process of sulfation rather than glucuronidation; both processes function to clear bile acids from the fetal circulation. This study provides new information about bile acid metabolism in the pregnant mother and developing fetus that may help treat or prevent ICP.

Technical Abstract: Cholestasis of pregnancy endangers fetal and neonatal survival, yet systematic knowledge of the cause and effect of disrupted bile acid (BA) homeostasis in pregnancy is limited. Here we show that gestation stage associated BA dysregulation in swine correlated with fetal death resulting from compromised capacity for BA secretion and increased alternative systemic efflux. The balance of BA input and output in the developing uterus suggested little uptake and metabolism of maternal BA by the placenta fetus unit, implying a protection role of placenta in preventing maternal BA transported into the fetus. We showed that the maternal origin of BA accounted for the increase in placental total BA, leading to dysregulated expression of genes involved in BA transport and potentially impaired transplacental export of fetus-derived BA. Correspondingly, the secondary BA, mainly derived from the mother, gradually decreased in the fetus. Finally, we identified that sulfation rather than glucuronidation played pivotal roles in maintaining BA homeostasis of the developing fetus. These novel and systemic findings contribute to a whole picture of BA metabolism in pregnancy and provide new insights into mechanisms responsible for maternal and fetal BA homeostasis.