Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary
Background & Aims: The bile acid (BA)-activated farnesoid X receptor (FXR) controls hepatic BA synthesis and cell proliferation via the intestinal hormone fibroblast growth factor 19. Because cystic fibrosis (CF) is associated with intestinal dysbiosis, anomalous BA handling, and biliary cirrhos...
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doaj-0a415309b75c4917861654a9a812df3d2020-11-24T21:55:01ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-01914760Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummaryPauline T. Ikpa0Marcela Doktorova1Kelly F. Meijsen2Natascha D.A. Nieuwenhuijze3Henkjan J. Verkade4Johan W. Jonker5Hugo R. de Jonge6Marcel J.C. Bijvelds7Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The NetherlandsSection of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The NetherlandsSection of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsSection of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Correspondence Address correspondence to: Marcel J. C. Bijvelds, PhD, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, PO Box 2040, 3000CA Rotterdam, The Netherlands. fax: (31) 10-7032793.Background & Aims: The bile acid (BA)-activated farnesoid X receptor (FXR) controls hepatic BA synthesis and cell proliferation via the intestinal hormone fibroblast growth factor 19. Because cystic fibrosis (CF) is associated with intestinal dysbiosis, anomalous BA handling, and biliary cirrhosis, we investigated FXR signaling in CF. Methods: Intestinal and hepatic expression of FXR target genes and inflammation markers was assessed in Cftr null mice and controls. Localization of the apical sodium-dependent BA transporter was assessed, and BAs in gastrointestinal tissues were analyzed. The CF microbiota was characterized and FXR signaling was investigated in intestinal tissue and organoids. Results: Ileal murine fibroblast growth factor 19 ortholog (Fgf15) expression was strongly reduced in CF mice, compared with controls. Luminal BA levels and localization of apical sodium-dependent BA transporter was not affected, and BAs induced Fgf15 up to normal levels in CF ileum, ex vivo, and CF organoids. CF mice showed a dysbiosis that was associated with a marked up-regulation of genes involved in host–microbe interactions, including those involved in mucin glycosylation, antimicrobial defense, and Toll-like receptor signaling. Antibiotic treatment reversed the up-regulation of inflammatory markers and restored intestinal FXR signaling in CF mice. Conversely, FXR-dependent gene induction in ileal tissue and organoids was repressed by bacterial lipopolysaccharide and proinflammatory cytokines, respectively. Loss of intestinal FXR activity was associated with a markedly blunted hepatic trophic response to oral BA supplementation, and with impaired repression of Cyp7a1, the gene encoding the rate-limiting enzyme in BA synthesis. Conclusions: In CF mice, the gut microbiota represses intestinal FXR activity, and, consequently, FXR-dependent hepatic cell proliferation and feedback control of BA synthesis. Keywords: Bile Acids and Salts, Gut Microbiota, Fibroblast Growth Factors, Cytoplasmic and Nuclear Receptorshttp://www.sciencedirect.com/science/article/pii/S2352345X19301122 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pauline T. Ikpa Marcela Doktorova Kelly F. Meijsen Natascha D.A. Nieuwenhuijze Henkjan J. Verkade Johan W. Jonker Hugo R. de Jonge Marcel J.C. Bijvelds |
spellingShingle |
Pauline T. Ikpa Marcela Doktorova Kelly F. Meijsen Natascha D.A. Nieuwenhuijze Henkjan J. Verkade Johan W. Jonker Hugo R. de Jonge Marcel J.C. Bijvelds Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary Cellular and Molecular Gastroenterology and Hepatology |
author_facet |
Pauline T. Ikpa Marcela Doktorova Kelly F. Meijsen Natascha D.A. Nieuwenhuijze Henkjan J. Verkade Johan W. Jonker Hugo R. de Jonge Marcel J.C. Bijvelds |
author_sort |
Pauline T. Ikpa |
title |
Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary |
title_short |
Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary |
title_full |
Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary |
title_fullStr |
Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary |
title_full_unstemmed |
Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis MiceSummary |
title_sort |
impaired intestinal farnesoid x receptor signaling in cystic fibrosis micesummary |
publisher |
Elsevier |
series |
Cellular and Molecular Gastroenterology and Hepatology |
issn |
2352-345X |
publishDate |
2020-01-01 |
description |
Background & Aims: The bile acid (BA)-activated farnesoid X receptor (FXR) controls hepatic BA synthesis and cell proliferation via the intestinal hormone fibroblast growth factor 19. Because cystic fibrosis (CF) is associated with intestinal dysbiosis, anomalous BA handling, and biliary cirrhosis, we investigated FXR signaling in CF. Methods: Intestinal and hepatic expression of FXR target genes and inflammation markers was assessed in Cftr null mice and controls. Localization of the apical sodium-dependent BA transporter was assessed, and BAs in gastrointestinal tissues were analyzed. The CF microbiota was characterized and FXR signaling was investigated in intestinal tissue and organoids. Results: Ileal murine fibroblast growth factor 19 ortholog (Fgf15) expression was strongly reduced in CF mice, compared with controls. Luminal BA levels and localization of apical sodium-dependent BA transporter was not affected, and BAs induced Fgf15 up to normal levels in CF ileum, ex vivo, and CF organoids. CF mice showed a dysbiosis that was associated with a marked up-regulation of genes involved in host–microbe interactions, including those involved in mucin glycosylation, antimicrobial defense, and Toll-like receptor signaling. Antibiotic treatment reversed the up-regulation of inflammatory markers and restored intestinal FXR signaling in CF mice. Conversely, FXR-dependent gene induction in ileal tissue and organoids was repressed by bacterial lipopolysaccharide and proinflammatory cytokines, respectively. Loss of intestinal FXR activity was associated with a markedly blunted hepatic trophic response to oral BA supplementation, and with impaired repression of Cyp7a1, the gene encoding the rate-limiting enzyme in BA synthesis. Conclusions: In CF mice, the gut microbiota represses intestinal FXR activity, and, consequently, FXR-dependent hepatic cell proliferation and feedback control of BA synthesis. Keywords: Bile Acids and Salts, Gut Microbiota, Fibroblast Growth Factors, Cytoplasmic and Nuclear Receptors |
url |
http://www.sciencedirect.com/science/article/pii/S2352345X19301122 |
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