Cystic Fibrosis-Related Liver Disease (CFLD)
The cartoon describes how, in our working model, the loss of CFTR impacts intracellular pathways that normally control biliary epithelial innate immunity and, in association with changes in the gut microbiota, lead to the progression of cystic fibrosis-related liver disease. For more details see Fabris et al, Nature Rev Gastroenterol Hepatol, 2019 and selected publications.
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.
Selected publications:
- Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.Fabris L, Fiorotto R, Spirli C, Cadamuro M, Mariotti V, Perugorria MJ, Banales JM, Strazzabosco M. Nat Rev Gastroenterol Hepatol. 2019 Aug. PMID: 31165788.
- Animal models for cystic fibrosis liver disease (CFLD).Fiorotto R, Amenduni M, Mariotti V, Cadamuro M, Fabris L, Spirli C, Strazzabosco M. Biochim Biophys Acta Mol Basis Dis. 2019 May 1; 2018 Jul 30. PMID: 30071276.
- Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota.Fiorotto R, Strazzabosco M. Cell Mol Gastroenterol Hepatol. 2019; 2019 May 7. PMID: 31075352.
- Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy.Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Hepatology. 2018 Mar; 2018 Jan 26. PMID: 28836688.
- The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity.Fiorotto R, Villani A, Kourtidis A, Scirpo R, Amenduni M, Geibel PJ, Cadamuro M, Spirli C, Anastasiadis PZ, Strazzabosco M. Hepatology. 2016 Dec; 2016 Oct 27. PMID: 27629435.
- Cystic Fibrosis-Related Liver Diseases: New Paradigm for Treatment Based on Pathophysiology.Fiorotto R, Strazzabosco M. Clin Liver Dis (Hoboken). 2016 Nov; 2016 Nov 30. PMID: 31041076.
- Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium.Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirli C, Strazzabosco M. Hepatology. 2015 Nov; 2015 Aug 28. PMID: 26199136.
- Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice.Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Gastroenterology. 2011 Oct; 2011 Jun 26. PMID: 21712022.
- Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion.Fiorotto R, Spirlì C, Fabris L, Cadamuro M, Okolicsanyi L, Strazzabosco M. Gastroenterology. 2007 Nov; 2007 Sep 2. PMID: 17983806.
- Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a cystic fibrosis transmembrane conductance regulator-independent mechanism.Spirlì C, Fiorotto R, Song L, Santos-Sacchi J, Okolicsanyi L, Masier S, Rocchi L, Vairetti MP, De Bernard M, Melero S, Pozzan T, Strazzabosco M. Gastroenterology. 2005 Jul. PMID: 16012949.
- Correction of CFTR malfunction and stimulation of Ca-activated Cl channels restore HCO3- secretion in cystic fibrosis bile ductular cells.Zsembery A, Jessner W, Sitter G, Spirlí C, Strazzabosco M, Graf J. Hepatology. 2002 Jan. PMID: 11786964.