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

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. NEW & NOTEWORTHY We used a swine model to demonstrate the potentially impaired transplacental bile acid (BA) export, immaturity of fetal hepatic excretory function, and elevated BA synthesis in the developing fetus. Under these conditions, we have further identified that BA sulfation plays a pivotal role in regulation of fetal BA homeostasis, which appears to depend on the balance of BA synthesis and sulfation capacity. These novel findings have uncovered a previously unknown mechanism of BA homeostasis regulation in the developing fetus.

Transcriptome Profiling of Placenta through Pregnancy Reveals Dysregulation of Bile Acids Transport and Detoxification Function

“…Consistent with results in pregnant women [15], maternal BA metabolism in pregnant swine was dysregulated with the advance of pregnancy [8]. In addition, our recent study also indicated the impairment of placental BA transport function as pregnancy advanced, which further affected the BA homeostasis of fetuses [8]. However, the genetic and molecular basis for placenta to perform preprogrammed function, particularly BA metabolism, is largely undetermined as pregnancy advances.…”

“…Studies in ICP patients and maternal cholestasis model during pregnancy have shown the impaired placental function, including the reduced fetal BA transport from fetuses to mother [18] and placental oxidative stress and apoptosis (19) [19]. Consistent with results in pregnant women [15], maternal BA metabolism in pregnant swine was dysregulated with the advance of pregnancy [8]. In addition, our recent study also indicated the impairment of placental BA transport function as pregnancy advanced, which further affected the BA homeostasis of fetuses [8].…”

“…Raised maternal serum BA is one of the most common phenomena among humans, rodents, and pigs during pregnancy [8,50,51,52]. High levels of maternal serum BA have been implicated in high levels of fetal BA through impairing transplacental export of BA from fetal into maternal system, especially when the fetal liver was able to synthesis BA, but not able to eliminate it, thus resulting in high risk of fetal death [10,53,54].…”

“…However, the situation is different for the fetus during pregnancy. Owing to its immaturity, fetal liver can produce BA, but is not able to eliminate them into bile [5,6,7,8,9]. Placenta is the major organ responsible for fetal BA and biliary pigments transport.…”

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…It was found that sulfation played a pivotal role in maintaining BA homeostasis in the fetus. Furthermore, fetal mortality showed an exponential increase in relation to the total BA increase from week 60 to week 90 [109]. A controversial condition related to ICP that is asymptomatic and difficult to distinguish from ICP is asymptomatic hypercholanemia of pregnancy (AHP).…”