Impaired intestinal farnesoid X receptor signaling in cystic fibrosis mice

Abstract 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 (FGF19). 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 (ASBT) 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 Fgf15 (murine FGF19 ortholog) expression was strongly reduced in CF mice, compared to controls. Luminal BA levels and localization of ASBT was not affected, and BAs induced Fgf15 up to normal levels in CF ileum, ex vivo, and CF organoids. CF mice displayed a dysbiosis, which was associated with a marked upregulation of genes involved in host-microbe interactions, including those involved in mucin glycosylation, anti-microbial 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 (LPS) and pro-inflammatory 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.