Caroline Ovadia
Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis
Ovadia, Caroline; Perdones‐Montero, Alvaro; Spagou, Konstantina; Smith, Ann; Sarafian, Magali H.; Gomez‐Romero, Maria; Bellafante, Elena; Clarke, Louise C.D.; Sadiq, Fouzia; Nikolova, Vanya; Mitchell, Alice; Dixon, Peter H.; Santa‐Pinter, Natalie; Wahlström, Annika; Abu‐Hayyeh, Shadi; Walters, Julian R.F.; Marschall, Hanns‐Ulrich; Holmes, Elaine; Marchesi, Julian R.; Williamson, Catherine
Authors
Alvaro Perdones‐Montero
Konstantina Spagou
Ann Smith
Magali H. Sarafian
Maria Gomez‐Romero
Elena Bellafante
Louise C.D. Clarke
Fouzia Sadiq
Vanya Nikolova
Alice Mitchell
Peter H. Dixon
Natalie Santa‐Pinter
Annika Wahlström
Shadi Abu‐Hayyeh
Julian R.F. Walters
Hanns‐Ulrich Marschall
Elaine Holmes
Julian R. Marchesi
Catherine Williamson
Abstract
Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia.
Citation
Ovadia, C., Perdones‐Montero, A., Spagou, K., Smith, A., Sarafian, M. H., Gomez‐Romero, M., …Williamson, C. (2019). Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis. Hepatology, 70(1), 276-293. https://doi.org/10.1002/hep.30661
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 28, 2019 |
Online Publication Date | Apr 15, 2019 |
Publication Date | Jul 1, 2019 |
Deposit Date | Oct 2, 2019 |
Publicly Available Date | Mar 29, 2024 |
Journal | Hepatology |
Print ISSN | 0270-9139 |
Electronic ISSN | 1527-3350 |
Publisher | Wiley |
Peer Reviewed | Peer Reviewed |
Volume | 70 |
Issue | 1 |
Pages | 276-293 |
DOI | https://doi.org/10.1002/hep.30661 |
Keywords | Hepatology |
Public URL | https://uwe-repository.worktribe.com/output/3429311 |
Publisher URL | https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.30661 |
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Enhanced Microbial Bile Acid Deconjugation and Impaired Ileal Uptake in Pregnancy Repress Intestinal Regulation of Bile Acid Synthesis
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Copyright Statement
© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution License, which permits use and distribution in any medium, provided the original work is properly cited
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