Reply to: “Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: The pivotal role of enterocyte tight junctions and future perspectives”
Authors: Johannie du Plessis, Schalk W. van der Merwe
Journal: Journal of Hepatology (2013)

Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: The pivotal role of enterocyte tight junctions and future perspectivesJournal of HepatologyVol. 59Issue 5PreviewWe read with great interest the recently published research study by Dr. Du Plessis and colleagues on the role of intestinal macrophages in intestinal epithelial barrier dysfunction and hyperpermeability in patients with cirrhosis [1]. The authors demonstrated that decompensated liver cirrhosis was associated with the presence of significantly higher numbers of activated intestinal macrophages (CD33+/CD14+/Trem-1+) expressing iNOS and secreting NO and IL-6, in conjunction with increased duodenal paracellular permeability and increased expression of the tight junction (TJ) protein Claudin-2. Full-Text PDF Open AccessActivated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier functionJournal of HepatologyVol. 58Issue 6PreviewProposed model of intestinal macrophage activation in ASH/NASH cirrhosis. Following changes in bacterial flora, intestinal macrophage activation occurs. CD14+iNOS+ intestinal macrophages release NO and IL-6. In addition CCL-13, IL-8, and CCL-2/MCP-1 are produced that may attract monocytes from the circulation. Full-Text PDF We thank Assimakopoulos and colleagues for their interest in our recent article [[1]Du Plessis J. Vanheel H. Janssen C.E. Roos L. Slavik T. Stivaktas P.I. et al.Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function.J Hepatol. 2013; 58: 1125-1132Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. As suggested, important efforts are being made to understand why the intestinal barrier fails in cirrhosis and the mechanism by which viable bacteria translocate from the gastrointestinal tract. In our study, we assessed the following: Firstly, we studied the morphology and function of the intestinal barrier in decompensated and compensated ASH/NASH cirrhotic patients. We could show that the morphology of the intestinal barrier was intact at the ultrastructural level, suggesting that permeability was functionally altered and not just secondarily increased due to widened intracellular junctions induced by portal hypertension [2Seo Y.S. Shah V.H. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension.Clin Mol Hepatol. 2012; 18: 337-346Crossref PubMed Scopus (103) Google Scholar, 3Wiest R. Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis.Hepatology. 2005; 41: 422-433Crossref PubMed Scopus (564) Google Scholar]. At a functional level, we could indeed confirm that transepithelial resistance was decreased and permeability increased in patients with decompensated cirrhosis. We fully agree with the comments by Assimakopoulos et al. that emphasize the important role of TJ proteins in intestinal barrier function in cirrhosis as demonstrated in their recent study [[4]Assimakopoulos S.F. Tsamandas A.C. Tsiaoussis G.I. Karatza E. Triantos C. Vagianos C.E. et al.Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.Eur J Clin Invest. 2012; 42: 439-446Crossref PubMed Scopus (117) Google Scholar]. The difference in the implicated TJ proteins between our study [[1]Du Plessis J. Vanheel H. Janssen C.E. Roos L. Slavik T. Stivaktas P.I. et al.Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function.J Hepatol. 2013; 58: 1125-1132Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar] and that of Assimakopoulos et al. [[4]Assimakopoulos S.F. Tsamandas A.C. Tsiaoussis G.I. Karatza E. Triantos C. Vagianos C.E. et al.Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.Eur J Clin Invest. 2012; 42: 439-446Crossref PubMed Scopus (117) Google Scholar] can partly be explained by the patient populations included in each study and the TJ proteins analysed. Their study included patients with liver cirrhosis from various aetiologies, including viral infection, which were deliberately excluded from our study. It has been shown that the expression of claudin proteins changes during development, differentiation, and in disease, in response to stressors – including cytokines – in intestinal epithelial cells [5Turner J.R. Intestinal mucosal barrier function in health and disease.Nat Rev Immunol. 2009; 9: 799-809Crossref PubMed Scopus (2387) Google Scholar, 6Suzuki T. Regulation of intestinal epithelial permeability by tight junctions.Cell Mol Life Sci. 2013; 70: 631-659Crossref PubMed Scopus (809) Google Scholar]. Thus specific aetiological factors might influence TJ expression. Secondly, we assessed the role of intestinal macrophages in cirrhosis. Intestinal macrophages have been shown to be activated in Crohn’s disease [[7]Kamada N. Hisamatsu T. Okamoto S. Chinen H. Kobayashi T. Sato T. et al.Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis.J Clin Invest. 2008; 118: 2269-2280PubMed Google Scholar] and in HIV enteropathy (manuscript submitted) and have been shown to produce inflammatory cytokines. Barrier defects are caused by disruption of normal regulatory mechanisms that control gene expression, tight junction structure and cytoskeletal signalling [[8]Marchiando A.M. Graham W.V. Turner J.R. Epithelial barriers in homeostasis and disease.Annu Rev Pathol. 2010; 5: 119-144Crossref PubMed Scopus (442) Google Scholar]. We could show for the first time that intestinal macrophages are activated in decompensated cirrhosis that may influence enterocyte TJ regulation. Specifically, we could demonstrate an increase in IL-6 and NO production, which have been previously shown to influence intestinal permeability in inflammatory conditions, such as IBD and necrotizing enterocolitis [6Suzuki T. Regulation of intestinal epithelial permeability by tight junctions.Cell Mol Life Sci. 2013; 70: 631-659Crossref PubMed Scopus (809) Google Scholar, 7Kamada N. Hisamatsu T. Okamoto S. Chinen H. Kobayashi T. Sato T. et al.Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis.J Clin Invest. 2008; 118: 2269-2280PubMed Google Scholar, 8Marchiando A.M. Graham W.V. Turner J.R. Epithelial barriers in homeostasis and disease.Annu Rev Pathol. 2010; 5: 119-144Crossref PubMed Scopus (442) Google Scholar]. Although we have identified important mechanisms associated with macrophage activation in cirrhosis, it remains unclear to what extent these factors are responsible for translocation of viable bacteria. Such studies should be conducted using epithelial cultures exposed to intestinal macrophages obtained from patients with liver disease. These studies are currently ongoing in our laboratory. The data and comments presented by Assimakopoulos et al. highlight our findings that intestinal barrier TJ proteins play an important role in bacterial translocation in liver cirrhosis. Although we have identified activated intestinal macrophages as potential players in the pathogenesis of BT in cirrhosis, we have only reached the tip of the iceberg. Additional human animal and culture studies as well as more sophisticated methods of measuring BT will shed light on how the intestinal epithelial barrier, gut microbiota, and immune system interact and influence disease progression in cirrhosis. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.