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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

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Authors

Caroline Ovadia

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 Oct 4, 2019
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 (2.2 Mb)
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Licence
http://creativecommons.org/licenses/by/4.0/

Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

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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