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Cholangiocytes and the Environment in Primary Sclerosing Cholangitis

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Cholangiocytes and the Environment in Primary Sclerosing Cholangitis Gut Online First, published on July 21, 2017 as 10.1136/gutjnl-2017-314249 Leading article microbial infection (eg, Cryptosporidium Cholangiocytes and the environment in parvum)16 and PSC; (iii) accumulating evidence supporting a critical role for the Gut: first published as 10.1136/gutjnl-2017-314249 on 21 July 2017. Downloaded from primary sclerosing cholangitis: where is intestinal microbiome in the pathogenesis of PSC17; (iv) a similar genetic architecture the link? in PSC as in a prototypical exposure-driven autoimmune disease, coeliac disease18; and 1 2,3 1 (v) a similar genetic architecture in PSC as Steven P O’Hara, Tom H Karlsen, Nicholas F LaRusso 19 20 in cholestatic drug-induced injury. We began studying the cholangiopathy In primary sclerosing cholangitis (PSC), in medicine. Robert Koch in the late 19th in HIV-infected patients (a form of SSC annular fibrosis around intrahepatic and century proposed criteria to identify a due to biliary tract infection by opportu- extrahepatic bile ducts leads to progres- disease as infectious.9 These included nistic pathogens, including C parvum)21 sive liver disease for which there is no (i) the organism is regularly associated both because it was a significant clinical effective therapy except liver transplanta- with the disease, (ii) the organism can problem and as a result of our own clinical tion.1 The concentric accumulation of be isolated from the diseased host and experience with C parvum-induced SSC.22 connective tissue around bile ducts grown in culture and (iii) the disease To summarise key points from multiple suggests that the cholangiocyte plays an can be reproduced when the organism in vitro and in vivo studies,16 23 we found integral role in PSC pathogenesis. is introduced into a healthy susceptible that C parvum, presumably via retrograde However, what initiates changes in chol- host. With the development of nucleic invasion of the biliary tree from the small angiocyte phenotype and how acid sequence-based identification of intestine, resulted in a pro-inflammatory, cholangiocytes interact with cells in the microbes, as well as the recognition that activated cholangiocyte phenotype and peribiliary extracellular matrix like the behaviour of a particular microbe can that the process involved a number of key immune cells and stromal components is be influenced by the community in which molecules (eg, toll-like receptors, nuclear largely unknown. Over the last 10 years, it resides, Koch’s original postulates have factor KB, C/EBP Beta and NRAS).24 25 genome-wide association studies in PSC evolved.10 11 More specifically, the concept Moreover, the infection was associated have revealed >20 risk genes.2–5 A signifi- has developed to incorporate culture-in- with altered cholangiocyte cytokine and cant observation that can be derived from dependent techniques that can identify miRNA expression26 27 as well as inflam- these data, which also applies to other putative pathogen nucleic acid sequences mation and fibrosis.16 More recently, and non-Mendelian phenotypes, is that the or even microbe-derived products (eg, relevant to this commentary, we noted predominant risk contribution is likely to short-chain fatty acids) in association that virtually all of the changes described come from one or more environmental with a diseased tissue that decrease with as a result of cholangiocyte invasion by C sources, rather than the genetic aberra- resolution of disease and increase with parvum also occurred when microbial-de- 11 tions. Indeed, in PSC, we estimate that clinical relapse. These ideas suggest rived products (eg, lipopolysaccharide, http://gut.bmj.com/ <10% of the overall liability is accounted that ‘the scientific community should flagellin) were used as an alternative for by the genetic findings; with extrapo- consider infectious disease causation in to the microbe itself.25 28 Additionally, lations into hypothetical, larger a broader systems biology context …’ cholangiocytes in vitro develop a senes- study populations, it is unlikely to exceed and ‘… as technology advances and new cent phenotype (ie, proliferative arrest), 30%–40%.6 7 Research dissecting the scientific discoveries are made, there likely involving these same pathways and remaining environmental contribution to must be dynamic adaptation of Koch’s processes, when chronically exposed to 29 PSC and other complex diseases is meth- postulates …’.10 Recent examples of an microbial-derived- products (figure 1). on September 26, 2021 by guest. Protected copyright. odologically challenging. The exposures expanded paradigm thus incorporate the Importantly, we discovered that these of an organism throughout life as a whole transfer of body weight-associated, IgA-as- pathways and processes are likely opera- have recently been referred to as the expo- sociated or liver injury-associated gut tive in human PSC. some8 and include a myriad of components microbiota in causation of obesity, IBD or A series of divergent published and of both the external (eg, xenobiotics) and alcoholic hepatitis, respectively.12–14 unpublished data are evolving that inde- internal (eg, gut microbes) milieu. There is less of a tradition and only pendently suggest, from a different There is a long tradition and effective preliminary tools to detect non-infectious perspective, microbial contributions means for detecting infectious exposures environmental exposures in medicine. In to PSC. These data in patients with light of the strong environmental compo- PSC include (i) expression of microbial 30 1Division of Gastroenterology and Hepatology nent in PSC liability determined by the receptors on cholangiocytes, and the 31 32 and the Mayo Clinic Center for Cell Signaling in genetic studies, a reconsideration as to occurrence of bacterobilia, (iii) bacte- Gastroenterology, Mayo Clinic, Rochester, Minnesota, how PSC may fulfil the revised Koch’s raemia of the portal venous system,33 USA 2 criteria is however timely. A rationale for (iv) promising results of antibiotics in Division of Surgery, Inflammatory Diseases and uncontrolled studies34–37 and (v) genomic Transplantation, Department of Transplantation this proposition can be made on several Medicine, Norwegian PSC Research Center, Oslo sets of considerations, each of which associations with loci implicated in host/ University Hospital Rikshospitalet, Oslo, Norway will be addressed in this commentary. microbiome interactions.38 The clinical 3 Institute of Clinical Medicine, University of Oslo, Oslo, These include (i) the evolution of Koch’s relationship between the gut (including Norway postulates to account for complex expo- potentially those microbes that reside Correspondence to Dr. Tom H Karlsen, sure-driven disease,10 11for example, therein) and the liver in PSC was estab- Department of Transplantation Medicine, Division of obesity and IBD12 15; (ii) similarities in lished 50 years ago with the observation Surgery,Inflammatory Medicine and Transplantation, cholangiocyte phenotype and downstream that PSC frequently occurred in the setting Oslo University Hospital Rikshospitalet, Postboks4950 39 40 Nydalen, N-0424 Oslo, Norway; t. h. karlsen@ medisin. signalling pathways between secondary of IBD. A series of studies recently uio. no sclerosing cholangitis (SSC) due to a direct published in Gut have demonstrated that O’Hara SP, et al. Gut Month 2017 Vol 0 No 0 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Leading article Gut: first published as 10.1136/gutjnl-2017-314249 on 21 July 2017. Downloaded from http://gut.bmj.com/ Figure 1 Model of cholangiocyte activation. (A) Bile ducts are lined by cholangiocytes, specialised epithelia that under normal physiological conditions modify bile through the transport of water, ions and solutes. Portal myofibroblasts are adjacent to bile duct epithelia within the portal tract and are distinct from hepatic stellate cells which line the hepatic sinusoids; both can differentiate to matrix depositing myofibroblasts under injurious conditions. (B) Cholangiocytes exist in a harsh environment and are exposed to a variety of insults such as microbes, pathogen-associated molecular patterns, danger-associated molecular patterns, xenobiotics and bile acid-induced damage during cholestasis (from a variety of potential mechanisms, eg, oxidative stress). Recognition of these insults, for example, via pathogen recognition receptors or damage-associated molecular pattern receptors, on September 26, 2021 by guest. Protected copyright. promotes an activated cholangiocyte phenotype characterised by increased proliferation and secretion of profibrotic (eg, connective tissue growth factor) and proinflammatory (eg, interleukin 6 and 8) mediators. In this model, the activated cholangiocyte promotes hepatobiliary repair processes and recruits a variety of innate (eg, macrophages) and professional (eg, T cell) immune cells. On persistent insult, some injured cholangiocytes enter the cellular state of senescence, characterised by withdrawal from the cell cycle, and transition to a hypersecretory proinflammatory state, that is, senescence-associated secretory phenotype. On persistence, such an inflammatory/fibrotic environment will lead to sclerosing cholangitis. Reproduced with permission of Kari C. Toverud. the gut microbiome in PSC is distinct from model (Abcb4-/-), an aggravation of bile immunological consequences for hepato- those microbial communities observed in duct disease was observed in the germ-free
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