Cystic fibrosis defects in intestinal bile acid and guanylin signaling

Cystic fibrosis (CF) is caused by dysfunction of the Cystic fibrosis transmembrane conductance regulator (CFTR) resulting in dehydration and acidification of the luminal surface of CFTR-expressing epithelia. Combined, these factors lead to accretion of viscous mucus and inspissation of the contents of exocrine pancreatic and biliary ducts, and the gut lumen leading to maldigestion, malabsorption, bacterial overgrowth, intestinal obstruction, CF liver and lung disease. Lung disease in CF is major cause of morbidity and mortality. Also, the gastrointestinal complication of CF have become a significant cause of morbidity and distress among patients as clinical management of CF patient has improved their life expectancy leading to an increased frequent of CF gastrointestinal complications. However, there remains an unmet need for effective treatment of the pulmonary as well as the non-pulmonary (gastrointestinal) complications of CF. Presently, available treatment of CF disease either targets the end organ pathology (old strategy) or the new strategy which is the CFTR-target pharmacotherapy. This new strategy is prohibitively expensive and targets a subset of patient. Therefore a search for cost effect, mutation-agnostic therapies which rely on improving symptomatic treatment and/or on alternative strategies to correct the luminal dehydration/acidification defect, is still warranted. In this thesis, we showed that CF mice have defective intestinal bile acid and guanylin signaling which contributes to intestinal bacterial dysbiosis and inflammation in the CF intestine. We showed antibiotic administration restores the intestinal microflora and bile signaling in CF. We also suggested that manipulating the bile acid and guanylin pathway can restore luminal fluidity and bile acid metabolism in CF

Transcriptome analysis of the distal small intestine of Cftr null mice

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CFTR anion channel. Loss of CFTR function in pancreatic, biliary and intestinal epithelia, severely affects gastrointestinal function. Transcriptome analysis indicated the activation of an innate and adaptive immune response in the distal small intestine of Cftr null mice. Inflammation was associated with differential regulation of numerous genes involved in the transport and metabolism of nutrients and, particularly, lipids, that are targeted by ligand-dependent nuclear receptors and/or HNF4α. Among the most strongly down-regulated genes are the FXR targets Fgf15 and Nr0b2, the PPARα target Pdk4, and the PXR target Ces2a, whereas expression of the CF modifier gene Slc6a14 was strongly increased. Most changes in gene expression were reversed by bacterial containment. Our data suggest that the gut microbiota has a pervasive effect on gene expression in CF mice, affecting enterocyte maturation, lipid metabolism, and nutrient absorption in CF

Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis Mice

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