Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis Mice
| Autor: | Hugo R. de Jonge, Kelly F. Meijsen, Johan W. Jonker, Pauline T. Ikpa, Marcel J. C. Bijvelds, Natascha D.A. Nieuwenhuijze, Henkjan J. Verkade, Marcela Doktorova |
|---|---|
| Přispěvatelé: | Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Gastroenterology & Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cystic Fibrosis Gut flora Fibroblast growth factor ACTIVATION Mice 0302 clinical medicine GROWTH-FACTOR 15 Fut2 fuc α1-2 fucosyltransferase β-MCA β-muricholic acid Gut Microbiota CFTR Original Research CA cholic acid biology Chemistry Microbiota Gastroenterology MOUSE MODEL Intestines B4galt1 β-1 4-galactosyltransferase I FXR LPS lipopolysaccharide 030211 gastroenterology & hepatology TLR Toll-like receptor Signal Transduction EXPRESSION medicine.medical_specialty BA bile acid BILE-ACID HOMEOSTASIS Cholesterol 7 alpha-hydroxylase CFLD cystic fibrosis–related liver disease Proinflammatory cytokine Bile Acids and Salts 03 medical and health sciences FXR farnesoid X receptor LIVER-DISEASE Internal medicine medicine Animals Cytoplasmic and Nuclear Receptors CFTR cystic fibrosis transmembrane conductance regulator lcsh:RC799-869 CF cystic fibrosis FAT-ABSORPTION Hepatology FGF15 medicine.disease biology.organism_classification FGF fibroblast growth factor Fibroblast Growth Factors 030104 developmental biology Endocrinology Hepatic stellate cell RISK-FACTORS Farnesoid X receptor lcsh:Diseases of the digestive system. Gastroenterology ASBT apical sodium-dependent bile acid transporter Dysbiosis |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 9, Iss 1, Pp 47-60 (2020) Cellular and molecular gastroenterology and hepatology, 9(1), 47-60. HANLEY & BELFUS-ELSEVIER INC Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, 9(1), 47-60. Elsevier Inc. |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|