Cystic Fibrosis-Related Liver Disease (CFLD)

Cystic fibrosis is a common and severe genetic disease, caused by mutations in CFTR, a membrane protein that mediates the secretion of chloride, bicarbonate and fluids in many secretory epithelia, including the epithelium of the bile ducts. Hepatic complications affect up to 30% of patients with Cystic Fibrosis and affects their survival and quality of life. In these patients, CFTR dysfunction in the biliary epithelium causes progressive chronic cholangitis that develops into biliary cirrhosis.

Therapy in CFLD has proved unsatisfactory to date, being limited to the administration of ursodeoxycholic acid or on organ transplantation in cases that progress. Novel small molecules able to improve the function of the mutated CFTR are being investigated.

Our studies uncovered an important correlation between CFTR and TLR4 signaling and demonstrated that CFTR deficiency alters the control of innate immunity in the biliary epithelium by reducing its tolerance to gut-derived endotoxins and favoring a stronger inflammatory response.

Our hypothesis is that CFLD results from a complex interplay between genetic susceptibility and environmental factors and that changes in the intestinal microbiota, a “leaky gut”, and altered innate immune responses of the biliary epithelia constitute the milieu for the development and progression of CFLD.

Current studies in the lab aim to understand the complex interplay between genetic susceptibility of the biliary epithelium and the causal role of the gut microbiota in the development and progression of CFLD.