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  • Remarkably the original manuscript from describing the prese


    Remarkably, the original manuscript from 1996, describing the presence of focal biliary cirrhosis in a small percentage of G551D mice, reports that these mice were first generated in a pathogen-free facility and followed by a move to a normal facility, where they were fed a different diet [21]. Two decades later, our knowledge in the microbiota field would certainly confirm that these mice were exposed to microbiota changes further suggesting the involvement of a liver-gut axis. CF mice are also being used as an important source for cell isolation. Our group has used both null and F508del mice for the isolation of primary cultures of cholangiocytes [[38], [39], [40]]. In vitro data using isolated cholangiocytes show that loss of CFTR at the membrane causes important structural and innate immune changes that predispose the biliary Trizma maleate to overreact when exposed to gut-derived endotoxin. These results are a confirmation of the liver phenotype previously described in CF mice treated with DSS. In fact, cholangiocytes isolated from CFTR-KO mice have increased NF-kB activation and secrete more pro-inflammatory cytokines compared to normal ones that would create a local inflammatory milieu [38]. Interestingly, our molecular data show that CFTR is part of a complex at the membrane, with proteins that are important to maintain an endotoxin tolerance against gut-derived endotoxins. In CF cholangiocytes, this mechanism of tolerance is altered and when the cells get in contact with bacterial derived components they over-react [40]. These observations impose that CFLD might be the result of a double component that involves the biliary cell in the liver and the microbiota in the gut and explain how a second “hit” in addition to the genetic mutation is necessary to develop the liver disease. New studies in the mouse model are needed to address the potential causative role of the microbiota in the liver disease.
    Large animal models The use of mouse models in the last decade or so has undoubtedly contributed to the understanding of many aspects of CF pathology and has clarified that dysfunctions of different organs might be somehow linked. However, the fact that several important biologic divergences exist between mice and humans, together with a lack of spontaneous manifestation of the CF disease in the mouse, has prompted researchers to search for larger and more representative mammal models such as the pig and the ferret [41]. Both these models are more representative of the CF manifestations seen in patients but still present some challenges [11]. Pigs have several analogies with humans in terms of life span, anatomy, physiology, size and genetics. The first CFTR null piglets were born about ten years ago at the University of Iowa [42]. They presented a very severe intestinal phenotype at birth characterized by meconium ileus similar to what is observed in about 15% of CF patients. However, in the piglets the defect is even more severe with a penetrance of 100%, and they require almost immediate surgical procedure to alleviate the intestinal obstructions and increase their survival. The same group also generated the pig model carrying the most common ΔF508 CFTR mutation [43]. Similar to the null allele, these piglets also suffered from meconium ileus, which suggested that the residual activity of CFTR protein that escape the ER and reach the membrane is not sufficient to prevent the intestinal phenotype. Besides the disadvantage of the intestinal complication, as predicted, both pig models spontaneously develop lung disease and present significant alterations of the pancreas and liver similar to human patients [[42], [43], [44], [45]]. The histological evaluation of the liver shows the presence of chronic cellular inflammation at the level of the portal space with a focal distribution in both null and ΔF508 mutated piglets [[42], [43], [44], [45]]. More interesting is the finding that a few months after birth there is a progression of the liver phenotype with the appearance of bridging fibrotic areas and steatosis, very consistent with what is seen in patients. Also similar to CF patients, the CF piglets present a micro gallbladder filled with a dense mix of mucus and bile [[42], [43], [44], [45], [46]].