Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis Mice

Aug 31, 2019Cellular and molecular gastroenterology and hepatology

Reduced Intestinal Farnesoid X Receptor Signaling in Mice with Cystic Fibrosis

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Abstract

Ileal expression of fibroblast growth factor 19 was strongly reduced in cystic fibrosis mice compared to controls.

Cystic fibrosis mice exhibited dysbiosis, which was linked to an increase in genes related to host-microbe interactions.
Bile acids could induce fibroblast growth factor 15 expression to normal levels in cystic fibrosis ileum and organoids.
Antibiotic treatment reversed the inflammation markers and restored intestinal FXR signaling in cystic fibrosis mice.
Intestinal FXR activity loss was associated with a reduced hepatic response to oral bile acid supplementation.
Bacterial lipopolysaccharide and proinflammatory cytokines suppressed FXR-dependent gene induction in intestinal tissue.

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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.

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Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis Mice

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