Maternal and Fetal Bile Acid Homeostasis Regulated by Sulfated Progesterone Metabolites through FXR Signaling Pathway in a Pregnant Sow Model

Abstract

Abnormally elevated circulating bile acids (BA) during pregnancy endanger fetal survival and offspring health; however, the pathology and underlying mechanisms are poorly understood. A total of nineteen pregnant sows were randomly assigned to day 60 of gestation, day 90 of gestation (G60, G90), and the farrowing day (L0), to investigate the intercorrelation of reproductive hormone, including estradiol, progesterone and sulfated progesterone metabolites (PMSs), and BA in the peripheral blood of mother and fetuses during pregnancy. All data were analyzed by Student’s t-test or one-way ANOVA of GraphPad Prism and further compared by using the Student–Newman–Keuls test. Correlation analysis was also carried out using the CORR procedure of SAS to study the relationship between PMSs and BA levels in both maternal and fetal serum at G60, G90, and L0. Allopregnanolone sulphate (PM4S) and epiallopregnanolone sulphate (PM5S) were firstly identified in the maternal and fetal peripheral blood of pregnant sows by using newly developed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Correlation analysis showed that pregnancy-associated maternal BA homeostasis was correlated with maternal serum PM4S levels, whereas fetal BA homeostasis was correlated with fetal serum PM5S levels. The antagonist activity role of PM5S on farnesoid X receptor (FXR)-mediated BA homeostasis and fibroblast growth factor 19 (FGF19) were confirmed in the PM5S and FXR activator co-treated pig primary hepatocytes model, and the antagonist role of PM4S on FXR-mediated BA homeostasis and FGF19 were also identified in the PM4S-treated pig primary hepatocytes model. Together with the high relative expression of FGF19 in pig hepatocytes, the pregnant sow is a promising animal model to investigate the pathogenesis of cholestasis during pregnancy.

Gut microbiota involved in desulfation of sulfated progesterone metabolites: A potential regulation pathway of maternal bile acid homeostasis during pregnancy

“…In support of this, our studies also demonstrated the promoting role of PM5S on BA pool. Moreover, our previous studies have shown that both PM4S and PM5S promoted BA synthesis in pig primary hepatocytes through inhibiting farnesoid X receptor ( Wang et al, 2022 ). Consequently, the decrease of secondary BA after VAN treatment may be the carry-over effect of primary BA.…”

“…Serum estradiol was measured by estradiol radioimmunoassay kits (Iodine[125I] Estradiol radioimmunoassay Kit, Beijing North institute of Biotechnology, Beijing, China) according to the manufacturer’s specifications. Progesterone, PM4S, and PM5S were measured by the ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system (ACQUITY UPLC-Xevo TQ-S, Waters Corp, MA, United States) according to previous literature ( Wang et al, 2022 ). Briefly, the Multiple Reaction Monitoring (MRM) transitions of the progesterone (315.2/97.0), PM4-S (397.1/97.2), and PM5-S (397.1/97.2) were monitored.…”

“…It has long been recognized that antibiotic treatment can induce profound changes in BA metabolism ( Canzi et al, 1985 ; Zhang et al, 2014 ) through microbiota mediation of BA deconjugation ( Begley et al, 2006 ), oxidation and 7α-dehydroxylation ( Ridlon et al, 2006 ; Lefebvre et al, 2009 ). Recently, our study in pregnant sows have identified a role for PMSs in dysregulation of maternal BA metabolism during pregnancy ( Wang et al, 2022 ). UDCA administration, as a useful treatment for cholestasis, failed to reduce the production or enhance the elimination of PM4S and PM5S ( Estiu et al, 2015 ).…”

“…Consistent with results in pregnant women and mice ( Pascual et al, 2002 ; Milona et al, 2010 ), our previous study revealed the hypercholanemia in pregnant sows ( Wang et al, 2019b ). Moreover, PM5S does exist in pregnant sows and mice, and its regulation role on BA metabolism have been demonstrated in non-pregnant mice and pregnant sows ( Abu-Hayyeh et al, 2013 ; Wang et al, 2022 ).Therefore, the aim of the current study was to test whether oral vancomycin, which is nonabsorbable from the intestine and shown to impact intestinal BA metabolism ( Vrieze et al, 2014 ), could be used to modify the gut-liver metabolism of BA and progesterone and thereby prevent hypercholanemia in pregnant sows.…”

Zearalenone Decreases Food Intake by Disrupting the Gut–Liver–Hypothalamus Axis Signaling via Bile Acids

“…Porcine primary hepatocytes were collected following a method described in another study with slight modifications. 16 The pig liver lobes were perfused in two steps. First, a buffer was infused through a vessel of an appropriate size for 10 min.…”