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.