Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?
Open Access
- 21 July 2017
- Vol. 66 (11), 1873-1877
- https://doi.org/10.1136/gutjnl-2017-314249
Abstract
In primary sclerosing cholangitis (PSC), annular fibrosis around intrahepatic and extrahepatic bile ducts leads to progressive liver disease for which there is no effective therapy except liver transplantation.1 The concentric accumulation of connective tissue around bile ducts suggests that the cholangiocyte plays an integral role in PSC pathogenesis. However, what initiates changes in cholangiocyte phenotype and how cholangiocytes interact with cells in the peribiliary extracellular matrix like immune cells and stromal components is largely unknown. Over the last 10 years, genome-wide association studies in PSC have revealed >20 risk genes.2–5 A significant observation that can be derived from these data, which also applies to other non-Mendelian phenotypes, is that the predominant risk contribution is likely to come from one or more environmental sources, rather than the genetic aberrations. Indeed, in PSC, we estimate that <10% of the overall liability is accounted for by the genetic findings; with extrapolations into hypothetical, larger study populations, it is unlikely to exceed 30%–40%.6 7 Research dissecting the remaining environmental contribution to PSC and other complex diseases is methodologically challenging. The exposures of an organism throughout life as a whole have recently been referred to as the exposome8 and include a myriad of components of both the external (eg, xenobiotics) and internal (eg, gut microbes) milieu. There is a long tradition and effective means for detecting infectious exposures in medicine. Robert Koch in the late 19th century proposed criteria to identify a disease as infectious.9 These included (i) the organism is regularly associated with the disease, (ii) the organism can be isolated from the diseased host and grown in culture and (iii) the disease can be reproduced when the organism is introduced into a healthy susceptible host. With the development of nucleic acid sequence-based identification of microbes, as well as the …Keywords
This publication has 46 references indexed in Scilit:
- Bayesian inference analyses of the polygenic architecture of rheumatoid arthritisNature Genetics, 2012
- TLR4 Promotes Cryptosporidium parvum Clearance in a Mouse Model of Biliary CryptosporidiosisJournal of Parasitology, 2011
- Cholangiocyte N-Ras Protein Mediates Lipopolysaccharide-induced Interleukin 6 Secretion and ProliferationOnline Journal of Public Health Informatics, 2011
- The cell biology of cryptosporidium infectionMicrobes and Infection, 2011
- MicroRNA regulation of innate immune responses in epithelial cellsCellular & Molecular Immunology, 2011
- Genes and Environment: How Will Our Concepts on the Pathophysiology of IBD Develop in the Future?Digestive Diseases, 2010
- NFκB p50-CCAAT/Enhancer-binding Protein β (C/EBPβ)-mediated Transcriptional Repression of MicroRNA let-7i following Microbial InfectionOnline Journal of Public Health Informatics, 2010
- The immunobiology of cholangiocytesImmunology & Cell Biology, 2008
- A Cellular Micro-RNA, let-7i, Regulates Toll-like Receptor 4 Expression and Contributes to Cholangiocyte Immune Responses against Cryptosporidium parvum InfectionOnline Journal of Public Health Informatics, 2007
- An obesity-associated gut microbiome with increased capacity for energy harvestNature, 2006