Bacterial translocation in liver cirrhosis: Site and role in fibrogenesis
Authors: Claude Matuchansky
Journal: Journal of Hepatology (2014)

Pathological bacterial translocation in liver cirrhosisJournal of HepatologyVol. 60Issue 1PreviewHumans harbor nearly 100 trillion intestinal bacteria, which in terms of numbers, represents around ten times more microbial cells than eukaryotic cells. The gastrointestinal (GI) tract, the largest surface area of the body with an epithelial surface of approximately 400 m2, is in constant exposure to these live microorganisms. Their peaceful coexistence demonstrated by the lack of pro-inflammatory responses against commensal bacteria implicates the presence of clearly defined lines of communication. Full-Text PDF Open AccessReply to: "Bacterial translocation in liver cirrhosis: Site and role in fibrogenesis"Journal of HepatologyVol. 61Issue 3PreviewWe greatly appreciate the comments raised by Dr Matuchansky regarding our recent review on pathological bacterial translocation (BT) in liver cirrhosis [1]. As for the site of BT in cirrhosis we acknowledge the investigation in compensated cirrhotic patients utilizing a multisugar test [2]. The study described by Dr Matuchansky reports in cirrhotic individuals an increased sucralose/erythritol ratio in 5–24 h urine (supposed to indicate colonic permeability) whereas the lactulose/rhamnose ratio in 0–5 h urine (supposed to represent small intestinal permeability) was not altered. Full-Text PDF Open Access I read with great interest the comprehensive review by Wiest and colleagues [[1]Wiest R. Lawson M. Geuking M. Pathological bacterial translocation in liver cirrhosis.J Hepatol. 2014; 60: 197-209Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar] on pathological bacterial translocation in liver cirrhosis. They remarkably analyzed the compartments involved and their influencing factors. My concern regards the possible site(s) of bacterial translocation (BT), and the role of BT in the progress of both precirrhotic chronic liver damage, particularly fibrosis, and installed liver cirrhotic lesions themselves. Regarding the site of bacterial translocation in cirrhosis, the authors rightly outline that, whereas small intestinal bacterial overgrowth has the greatest potential for promoting BT and bacteria causing spontaneous infections are most frequently exactly those overgrowing in the small intestine [2Benten D. Wiest R. Gut microbiome and intestinal barrier failure – The ''Achilles heel" in hepatology?.J Hepatol. 2012; 56: 1221-1223Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 3Wiest R. Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis.Hepatology. 2005; 41: 422-433Crossref PubMed Scopus (564) Google Scholar], studies of experimental liver injury in mice revealed that the cecum and the colon might be the sites with largest rate of BT and increase in intestinal permeability [[1]Wiest R. Lawson M. Geuking M. Pathological bacterial translocation in liver cirrhosis.J Hepatol. 2014; 60: 197-209Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar]. Data in humans were lacking. A recent in vivo human study, not referenced in the Wiest's review [[1]Wiest R. Lawson M. Geuking M. Pathological bacterial translocation in liver cirrhosis.J Hepatol. 2014; 60: 197-209Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar], has reported that colonic permeability was increased in patients with compensated liver cirrhosis, as compared to matched controls using a multisugar test, whereas gastroduodenal and small intestine permeability were not altered [[4]Pijls K.E. Koek G.H. Elamin E.E. de Vries H. Masclee A.A. et al.Large intestine permeability is increased in patients with compensated liver cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G147-G153Crossref PubMed Scopus (34) Google Scholar]. Whether or not these changes preceded alterations of the gut microbiome is not known. A second point of increasing importance, not discussed in the review [[1]Wiest R. Lawson M. Geuking M. Pathological bacterial translocation in liver cirrhosis.J Hepatol. 2014; 60: 197-209Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar], regards the experimental role of inflammasomes at the colonic level in both local microbiota taxonomy and potential translocation associated with chronic precirrhotic liver disease, namely non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). There is suggestive evidence that a deficiency in components of two inflammasomes (NLRP6 and NLRP3) – which are large multiprotein complexes that sense intracellular danger signals via NOD-like receptors (NLRs), the sensor, NLR, forming a complex with the effector molecule, pro-caspase-1, with or without the contribution of an adapter molecule, such as the apoptosis-associated speck like CARD-domain containing protein (ASC) – normally acting as sensors of endogenous or exogenous pathogen-associated molecular patterns (PAMPs) and regulators of the colonic microbiota, leads to dysbiosis associated with aggravation of NAFLD and progression to NASH [[5]Henao-Mejia J. Elinav E. Jin C. Hao L. Mehal W.Z. Strowig T. et al.Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature. 2012; 482: 179-186Crossref PubMed Scopus (1746) Google Scholar]. Thus, members of the altered colonic microbiota in inflammasome-deficient mice may promote a signalling cascade in the liver upon translocation, resulting in progression to NASH in susceptible animals. Toll-like receptors (TLRs) have a major role in NAFLD pathophysiology due to the liver's exposure to relatively large amounts of PAMPs derived from the intestine and delivered via the portal circulation. Intact bacteria or bacterial products derived from the intestine trigger TLR4 and TLR9 activation, which results in an increased rate of chronic liver disease progression in mice that house a colitogenic gut microbiota associated with inflammasome deficiency [[5]Henao-Mejia J. Elinav E. Jin C. Hao L. Mehal W.Z. Strowig T. et al.Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature. 2012; 482: 179-186Crossref PubMed Scopus (1746) Google Scholar]. Indeed bacterial overgrowth, including in colon [[7]Bajaj J.S. Hylemon P.B. Ridlon J.M. Heuman D.M. Daita K. White M.B. et al.Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G675-G685Crossref PubMed Scopus (401) Google Scholar], is particularly important in patients with a leaky gut because it increases the luminal amount of PAMPs. It is noteworthy that mice deficient in sensing PAMPs or downstream signaling are resistant to NASH [[6]Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar]. Finally, the consequences of intestinal dysbiosis or bacterial overgrowth associated with gut leakage may not be limited to infectious complications, as spontaneous bacterial peritonitis, due to translocation. Animal studies have clearly pointed that intestinal microbiota may contribute to progression of chronic liver damage, especially liver fibrogenesis [[8]De Minicis S. Rychlicki C. Agostinelli L. Saccomanno S. Candelaresi C. Trozzi L. et al.Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice.Hepatology. 2014; 59: 1738-1749Crossref PubMed Scopus (205) Google Scholar], which in turn may aggravate not only installed cirrhotic lesions through increased inflammation and fibrosis, but also accelerate or provoke progression of NASH and alcoholic steatohepatitis to cirrhosis. Thus, the role, in humans, of BT in the progression of chronic hepatic damage, both in installed cirrhosis and precirrhotic lesions, may appear of paramount importance, in conjunction with persistent alcohol consumption in cases of alcoholic chronic liver disease and cirrhosis. There is increasing suggestive evidence that bacterial translocation and intestinal flora dysfunction are associated with the development of liver fibrosis [[9]Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (319) Google Scholar], and that bacteria and microbial products, including endotoxins – like lipopolysaccharides (LPS) macromolecules, the major molecular component of the outer membrane of Gram-negative bacteria –, bacterial DNA or microbial metabolites – like ethanol produced by the intestinal microbiome or choline – may contribute to the pathogenesis of NAFLD and NASH, and presumably to progression to overt cirrhosis due to increased fibrogenesis [[6]Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar]. Finally, this clearly suggests the possible associated role of chronic, repetitive BT, not only in mesenteric lymph nodes but also in portal blood and the liver itself [[10]Tuomisto S. Pessi T. Collin P. Vuento R. Aittoniemi A. Karhunen P.J. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics.BMC Gastroenterol. 2014; 14: 40Crossref PubMed Scopus (98) Google Scholar], as elicited by a chronically leaky intestine (which may precede and/or be the consequence of cirrhosis and be aggravated – in alcohol-induced chronic liver disease – by persistent chronic alcohol consumption), in cirrhosis pathogenesis itself. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.