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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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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 CD; Sadiq, Fouzia; Nikolova, Vanya; Mitchell, Alice; Dixon, Peter H.; Santa-Pinter, Natalie; Wahlström, Annika; Abu-Hayyeh, Shadi; Walters, Julian; Marschall, Hanns-Ulrich; Holmes, Elaine; Marchesi, Julian R.; Williamson, Catherine.

In: Hepatology, Vol. 70, No. 1, 01.07.2019, p. 276-293.

Research output: Contribution to journalArticle

Harvard

Ovadia, C, Perdones-Montero, A, Spagou, K, Smith, A, Sarafian, MH, Gomez Romero, M, Bellafante, E, Clarke, LCD, Sadiq, F, Nikolova, V, Mitchell, A, Dixon, PH, Santa-Pinter, N, Wahlström, A, Abu-Hayyeh, S, Walters, J, Marschall, H-U, Holmes, E, Marchesi, JR & Williamson, C 2019, 'Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis', Hepatology, vol. 70, no. 1, pp. 276-293. https://doi.org/10.1002/hep.30661

APA

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

Vancouver

Ovadia C, Perdones-Montero A, Spagou K, Smith A, Sarafian MH, Gomez Romero M et al. Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis. Hepatology. 2019 Jul 1;70(1):276-293. https://doi.org/10.1002/hep.30661

Author

Ovadia, Caroline ; Perdones-Montero, Alvaro ; Spagou, Konstantina ; Smith, Ann ; Sarafian, Magali H. ; Gomez Romero, Maria ; Bellafante, Elena ; Clarke, Louise CD ; Sadiq, Fouzia ; Nikolova, Vanya ; Mitchell, Alice ; Dixon, Peter H. ; Santa-Pinter, Natalie ; Wahlström, Annika ; Abu-Hayyeh, Shadi ; Walters, Julian ; Marschall, Hanns-Ulrich ; Holmes, Elaine ; Marchesi, Julian R. ; Williamson, Catherine. / Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis. In: Hepatology. 2019 ; Vol. 70, No. 1. pp. 276-293.

Bibtex Download

@article{25e0f22a88344e58aac74a9f975bc14b,
title = "Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis",
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 UPLC-MS 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 cholic acid 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 due to elevated bile salt hydrolase-producing Bacteroidetes. Cholic acid 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. This article is protected by copyright. All rights reserved.",
author = "Caroline Ovadia and Alvaro Perdones-Montero and Konstantina Spagou and Ann Smith and Sarafian, {Magali H.} and {Gomez Romero}, Maria and Elena Bellafante and Clarke, {Louise CD} and Fouzia Sadiq and Vanya Nikolova and Alice Mitchell and Dixon, {Peter H.} and Natalie Santa-Pinter and Annika Wahlstr{\"o}m and Shadi Abu-Hayyeh and Julian Walters and Hanns-Ulrich Marschall and Elaine Holmes and Marchesi, {Julian R.} and Catherine Williamson",
year = "2019",
month = "7",
day = "1",
doi = "10.1002/hep.30661",
language = "English",
volume = "70",
pages = "276--293",
journal = "Hepatology",
issn = "0270-9139",
number = "1",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis

AU - Ovadia, Caroline

AU - Perdones-Montero, Alvaro

AU - Spagou, Konstantina

AU - Smith, Ann

AU - Sarafian, Magali H.

AU - Gomez Romero, Maria

AU - Bellafante, Elena

AU - Clarke, Louise CD

AU - Sadiq, Fouzia

AU - Nikolova, Vanya

AU - Mitchell, Alice

AU - Dixon, Peter H.

AU - Santa-Pinter, Natalie

AU - Wahlström, Annika

AU - Abu-Hayyeh, Shadi

AU - Walters, Julian

AU - Marschall, Hanns-Ulrich

AU - Holmes, Elaine

AU - Marchesi, Julian R.

AU - Williamson, Catherine

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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 UPLC-MS 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 cholic acid 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 due to elevated bile salt hydrolase-producing Bacteroidetes. Cholic acid 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. This article is protected by copyright. All rights reserved.

AB - 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 UPLC-MS 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 cholic acid 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 due to elevated bile salt hydrolase-producing Bacteroidetes. Cholic acid 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. This article is protected by copyright. All rights reserved.

UR - http://www.scopus.com/inward/record.url?scp=85066117205&partnerID=8YFLogxK

U2 - 10.1002/hep.30661

DO - 10.1002/hep.30661

M3 - Article

VL - 70

SP - 276

EP - 293

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 1

ER -

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