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Review

Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications

ORCID Icon, , , ORCID Icon &
Pages 641-656 | Received 09 Apr 2018, Accepted 24 May 2018, Published online: 06 Jun 2018

References

  • Quigley EM. Leaky gut - concept or clinical entity? Curr Opin Gastroenterol. 2016;32(2):74–79.
  • Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep. 2010;12(5):319–330.
  • Andrianifahanana M, Moniaux N, Batra SK. Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta. 2006;1765(2):189–222.
  • Johansson ME, Phillipson M, Petersson J, et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A. 2008;105(39):15064–15069.
  • Xie YR, Liu SL, Liu X, et al. Intestinal microbiota and innate immunity-related gene alteration in cirrhotic rats with liver transplantation. Transplant Proc. 2011;43(10):3973–3979.
  • Grewal RKMA. Ethanol induced changes in glycosylation of mucins in rat intestine. Ann Gastroenterol. 2009;22(3):178–183.
  • Hartmann P, Chen P, Wang HJ, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology. 2013;58(1):108–119.
  • Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14(3):141–153.
  • Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799–809.
  • Schneeberger EE, Lynch RD. The tight junction: a multifunctional complex. Am J Physiol Cell Physiol. 2004;286(6):C1213–C1228.
  • Du Plessis J, Vanheel H, Janssen CE, et al. Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function. J Hepatol. 2013;58(6):1125–1132.
  • Assimakopoulos SF, Tsamandas AC, Tsiaoussis GI, et al. Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability. Eur J Clin Invest. 2012;42(4):439–446.
  • Fouts DE, Torralba M, Nelson KE, et al. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J Hepatol. 2012;56(6):1283–1292.
  • Pijls KE, Jonkers DM, Elamin EE, et al. Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature. Liver Int. 2013;33(10):1457–1469.
  • Karthikeyan A, Mohan P, Chinnakali P, et al. Elevated systemic zonula occludens 1 is positively correlated with inflammation in cirrhosis. Clin Chim Acta. 2018;480:193–198.
  • Raparelli V, Basili S, Carnevale R, et al. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology. 2017;65(2):571–581.
  • Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in non-alcoholic fatty liver disease. Hepatology. 2018 Apr 17.
  • Ram AK, Pottakat B, Vairappan B. Increased systemic zonula occludens 1 associated with inflammation and independent biomarker in patients with hepatocellular carcinoma. BMC Cancer. 2018;18(1):572.
  • Ye D, Guo S, Al-Sadi R, et al. MicroRNA regulation of intestinal epithelial tight junction permeability. Gastroenterology. 2011;141(4):1323–1333.
  • Munoz L, Albillos A, Nieto M, et al. Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis. Hepatology. 2005;42(2):411–419.
  • Genesca J, Marti R, Rojo F, et al. Increased tumour necrosis factor alpha production in mesenteric lymph nodes of cirrhotic patients with ascites. Gut. 2003;52(7):1054–1059.
  • Du Plessis J, van der Merwe SW. Reply to: “Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: the pivotal role of enterocyte tight junctions and future perspectives”. J Hepatol. 2013;59(5):1146–1147.
  • Such J, Guardiola JV, De Juan J, et al. Ultrastructural characteristics of distal duodenum mucosa in patients with cirrhosis. Eur J Gastroenterol Hepatol. 2002;14(4):371–376.
  • Wen JB, Zhu FQ, Chen WG, et al. Oxymatrine improves intestinal epithelial barrier function involving NF-kappaB-mediated signaling pathway in CCl4-induced cirrhotic rats. PLoS One. 2014;9(8):e106082.
  • Ramachandran A, Prabhu R, Thomas S, et al. Intestinal mucosal alterations in experimental cirrhosis in the rat: role of oxygen free radicals. Hepatology. 2002;35(3):622–629.
  • Chiva M, Guarner C, Peralta C, et al. Intestinal mucosal oxidative damage and bacterial translocation in cirrhotic rats. Eur J Gastroenterol Hepatol. 2003;15(2):145–150.
  • Marnett LJ. Oxy radicals, lipid peroxidation and DNA damage. Toxicology. 2002;181-182:219–222.
  • Corradi F, Brusasco C, Fernandez J, et al. Effects of pentoxifylline on intestinal bacterial overgrowth, bacterial translocation and spontaneous bacterial peritonitis in cirrhotic rats with ascites. Dig Liver Dis. 2012;44(3):239–244.
  • Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science. 2015;350(6262):830–834.
  • Bellot P, Frances R, Such J. Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int. 2013;33(1):31–39.
  • Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9(5):313–323.
  • Hase K, Kawano K, Nochi T, et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2009;462(7270):226–230.
  • Rescigno M, Urbano M, Valzasina B, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol. 2001;2(4):361–367.
  • Knoop KA, Newberry RD. Isolated lymphoid follicles are dynamic reservoirs for the induction of intestinal IgA. Front Immunol. 2012;3:84.
  • Vaishnava S, Behrendt CL, Ismail AS, et al. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A. 2008;105(52):20858–20863.
  • Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1(2):113–118.
  • Ogle CK, Noel JG, Guo X, et al. The ability of endotoxin-stimulated enterocytes to produce bactericidal factors. Crit Care Med. 2002;30(2):428–434.
  • Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol. 2013;14(10):996–1006.
  • Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147-163.
  • Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol. 2014;61(6):1385–1396.
  • Ponziani FR, Gerardi V, Gasbarrini A. Diagnosis and treatment of small intestinal bacterial overgrowth. Expert Rev Gastroenterol Hepatol. 2016;10(2):215–227.
  • Theocharidou E, Dhar A, Patch D. Gastrointestinal Motility Disorders and Their Clinical Implications in Cirrhosis. Gastroenterol Res Pract. 2017;2017:8270310.
  • Maheshwari A, Thuluvath PJ. Autonomic neuropathy may be associated with delayed orocaecal transit time in patients with cirrhosis. Auton Neurosci. 2005;118(1–2):135–139.
  • Hendrickse MT, Thuluvath PJ, Triger DR. Natural history of autonomic neuropathy in chronic liver disease. Lancet. 1992;339(8807):1462–1464.
  • Giannelli V, Di Gregorio V, Iebba V, et al. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795–16810.
  • Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137–174.
  • Ding JW, Andersson R, Soltesz V, et al. The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur Surg Res. 1993;25(1):11–19.
  • Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006;103(10):3920–3925.
  • Lorenzo-Zuniga V, Bartoli R, Planas R, et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology. 2003;37(3):551–557.
  • Bertok L. Bile acids in physico-chemical host defence. Pathophysiology. 2004;11(3):139–145.
  • Ridlon JM, Alves JM, Hylemon PB, et al. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes. 2013;4(5):382–387.
  • Kakiyama G, Pandak WM, Gillevet PM, et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol. 2013;58(5):949–955.
  • Worlicek M, Knebel K, Linde HJ, et al. Splanchnic sympathectomy prevents translocation and spreading of E coli but not S aureus in liver cirrhosis. Gut. 2010;59(8):1127–1134.
  • Keita AV, Soderholm JD. The intestinal barrier and its regulation by neuroimmune factors. Neurogastroenterol Motil. 2010;22(7):718–733.
  • Hodin CM, Lenaerts K, Grootjans J, et al. Starvation compromises Paneth cells. Am J Pathol. 2011;179(6):2885–2893.
  • Nazli A, Yang PC, Jury J, et al. Epithelia under metabolic stress perceive commensal bacteria as a threat. Am J Pathol. 2004;164(3):947–957.
  • Casafont F, Sanchez E, Martin L, et al. Influence of malnutrition on the prevalence of bacterial translocation and spontaneous bacterial peritonitis in experimental cirrhosis in rats. Hepatology. 1997;25(6):1334–1337.
  • Norman K, Pirlich M, Schulzke JD, et al. Increased intestinal permeability in malnourished patients with liver cirrhosis. Eur J Clin Nutr. 2012;66(10):1116–1119.
  • Sheflin AM, Melby CL, Carbonero F, et al. Linking dietary patterns with gut microbial composition and function. Gut Microbes. 2017;8:113-129.
  • Sharon G, Sampson TR, Geschwind DH, et al. The central nervous system and the gut microbiome. Cell. 2016;167(4):915–932.
  • Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22(10):1079–1089.
  • Kamada N, Chen GY, Inohara N, et al. Control of pathogens and pathobionts by the gut microbiota. Nat Immunol. 2013;14(7):685–690.
  • Caricilli AM, Castoldi A, Camara NO. Intestinal barrier: A gentlemen’s agreement between microbiota and immunity. World J Gastrointest Pathophysiol. 2014;5(1):18–32.
  • Stappenbeck TS, Hooper LV, Gordon JI. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc Natl Acad Sci U S A. 2002;99(24):15451–15455.
  • Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.
  • Faith JJ, Guruge JL, Charbonneau M, et al. The long-term stability of the human gut microbiota. Science. 2013;341(6141):1237439.
  • Ponziani FR, Gerardi V, Pecere S, et al. Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications. World J Gastroenterol. 2015;21(43):12322–12333.
  • Lu H, Wu Z, Xu W, et al. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb Ecol. 2011;61(3):693–703.
  • Wei X, Yan X, Zou D, et al. Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterol. 2013;13:175.
  • Chen Y, Yang F, Lu H, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011;54(2):562–572.
  • Tuomisto S, Pessi T, Collin P, et al. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics. BMC Gastroenterol. 2014;14:40.
  • Zhang Z, Zhai H, Geng J, et al. Large-scale survey of gut microbiota associated with MHE Via 16S rRNA-based pyrosequencing. Am J Gastroenterol. 2013;108(10):1601–1611.
  • Bajaj JS, Betrapally NS, Hylemon PB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. 2015;62(4):1260–1271.
  • Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513(7516):59–64.
  • Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60(5):940–947.
  • Bauer TM, Steinbruckner B, Brinkmann FE, et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol. 2001;96(10):2962–2967.
  • Bauer TM, Schwacha H, Steinbruckner B, et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol. 2002;97(9):2364–2370.
  • Casafont Morencos F, De Las Heras Castano G, Martin RL, et al. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig Dis Sci. 1996;41(3):552–556.
  • Chang CS, Chen GH, Lien HC, et al. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology. 1998;28(5):1187–1190.
  • Yang CY, Chang CS, Chen GH. Small-intestinal bacterial overgrowth in patients with liver cirrhosis, diagnosed with glucose H2 or CH4 breath tests. Scand J Gastroenterol. 1998;33(8):867–871.
  • Chang CS, Yang SS, Kao CH, et al. Small intestinal bacterial overgrowth versus antimicrobial capacity in patients with spontaneous bacterial peritonitis. Scand J Gastroenterol. 2001;36(1):92–96.
  • Pande C, Kumar A, Sarin SK. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment Pharmacol Ther. 2009;29(12):1273–1281.
  • Jun DW, Kim KT, Lee OY, et al. Association between small intestinal bacterial overgrowth and peripheral bacterial DNA in cirrhotic patients. Dig Dis Sci. 2010;55(5):1465–1471.
  • Chesta J, Defilippi C, Defilippi C. Abnormalities in proximal small bowel motility in patients with cirrhosis. Hepatology. 1993;17(5):828–832.
  • Thalheimer U, De Iorio F, Capra F, et al. Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study. Eur J Gastroenterol Hepatol. 2010;22(10):1228–1234.
  • Sanchez E, Casafont F, Guerra A, et al. Role of intestinal bacterial overgrowth and intestinal motility in bacterial translocation in experimental cirrhosis. Rev Esp Enferm Dig. 2005;97(11):805–814.
  • Perez-Paramo M, Munoz J, Albillos A, et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology. 2000;31(1):43–48.
  • Guarner C, Runyon BA, Young S, et al. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol. 1997;26(6):1372–1378.
  • Steffen EK, Berg RD. Relationship between cecal population levels of indigenous bacteria and translocation to the mesenteric lymph nodes. Infect Immun. 1983;39(3):1252–1259.
  • Lichtman SN, Sartor RB, Keku J, et al. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth. Gastroenterology. 1990;98(2):414–423.
  • Stewart JJ, Battarbee HD, Farrar GE, et al. Intestinal myoelectrical activity and transit time in chronic portal hypertension. Am J Physiol. 1992;263(4 Pt 1):G474–G479.
  • Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. 2014;60(1):197–209.
  • Berg RD. Bacterial translocation from the gastrointestinal tract. J Med. 1992;23(3–4):217–244.
  • Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology. 2005;41(3):422–433.
  • Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–680.
  • Hapfelmeier S, Lawson MA, Slack E, et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science. 2010;328(5986):1705–1709.
  • Gautreaux MD, Deitch EA, Berg RD. T lymphocytes in host defense against bacterial translocation from the gastrointestinal tract. Infect Immun. 1994;62(7):2874–2884.
  • Lin RS, Lee FY, Lee SD, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol. 1995;22(2):165–172.
  • Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology. 2010;52(6):2044–2052.
  • Cirera I, Bauer TM, Navasa M, et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001;34(1):32–37.
  • Garcia-Tsao G, Lee FY, Barden GE, et al. Bacterial translocation to mesenteric lymph nodes is increased in cirrhotic rats with ascites. Gastroenterology. 1995;108(6):1835–1841.
  • Munoz L, Jose Borrero M, Ubeda M, et al. Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis. Hepatology. 2012;56(5):1861–1869.
  • Ubeda M, Munoz L, Borrero MJ, et al. Critical role of the liver in the induction of systemic inflammation in rats with preascitic cirrhosis. Hepatology. 2010;52(6):2086–2095.
  • Teltschik Z, Wiest R, Beisner J, et al. Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense. Hepatology. 2012;55(4):1154–1163.
  • Yan AW, Fouts DE, Brandl J, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology. 2011;53(1):96–105.
  • Vreugdenhil AC, Snoek AM, van ‘t Veer C, et al. LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction. J Clin Invest. 2001;107(2):225–234.
  • Vreugdenhil AC, Rousseau CH, Hartung T, et al. Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J Immunol. 2003;170(3):1399–1405.
  • Berbee JF, Havekes LM, Rensen PC. Apolipoproteins modulate the inflammatory response to lipopolysaccharide. J Endotoxin Res. 2005;11(2):97–103.
  • Roth RI, Levin FC, Levin J. Distribution of bacterial endotoxin in human and rabbit blood and effects of stroma-free hemoglobin. Infect Immun. 1993;61(8):3209–3215.
  • Fukui H, Tsujita S, Matsumoto M, et al. Endotoxin inactivating action of plasma in patients with liver cirrhosis. Liver. 1995;15(2):104–109.
  • Schafer C, Parlesak A, Schutt C, et al. Concentrations of lipopolysaccharide-binding protein, bactericidal/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease. Alcohol Alcohol. 2002;37(1):81–86.
  • Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol. 2012;590(3):447–458.
  • Ladman AJ, Padykula HA, Strauss EW. A morphological study of fat transport in the normal human jejunum. Am J Anat. 1963;112(389–419).
  • Frey EA, Miller DS, Jahr TG, et al. Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med. 1992;176(6):1665–1671.
  • Pugin J, Schurer-Maly CC, Leturcq D, et al. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A. 1993;90(7):2744–2748.
  • Schumann RR, Kirschning CJ, Unbehaun A, et al. The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins. Mol Cell Biol. 1996;16(7):3490–3503.
  • Landmann R, Knopf HP, Link S, et al. Human monocyte CD14 is upregulated by lipopolysaccharide. Infect Immun. 1996;64(5):1762–1769.
  • Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 2009;21(4):317–337.
  • Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–745.
  • Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139(1):323–334 e327.
  • Hackstein CP, Assmus LM, Welz M, et al. Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut. 2017;66(3):507–518.
  • Frances R, Gonzalez-Navajas JM, Zapater P, et al. Translocation of bacterial DNA from Gram-positive microorganisms is associated with a species-specific inflammatory response in serum and ascitic fluid of patients with cirrhosis. Clin Exp Immunol. 2007;150(2):230–237.
  • Pinero P, Juanola O, Caparros E, et al. Toll-like receptor polymorphisms compromise the inflammatory response against bacterial antigen translocation in cirrhosis. Sci Rep. 2017;7:46425.
  • Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–265.
  • Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–837.
  • Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology. 1992;103(1):264–274.
  • Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–1172.
  • Taylor CT, Dzus AL, Colgan SP. Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. Gastroenterology. 1998;114(4):657–668.
  • Frances R, Chiva M, Sanchez E, et al. Bacterial translocation is downregulated by anti-TNF-alpha monoclonal antibody administration in rats with cirrhosis and ascites. J Hepatol. 2007;46(5):797–803.
  • Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem. 2011;286(36):31263–31271.
  • Wiest R, Groszmann RJ. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Semin Liver Dis. 1999;19(4):411–426.
  • Tepperman BL, Brown JF, Whittle BJ. Nitric oxide synthase induction and intestinal epithelial cell viability in rats. Am J Physiol. 1993;265(2 Pt 1):G214–G218.
  • McAvoy NC, Semple S, Richards JM, et al. Differential visceral blood flow in the hyperdynamic circulation of patients with liver cirrhosis. Aliment Pharmacol Ther. 2016;43(9):947–954.
  • Brinch K, Moller S, Bendtsen F, et al. Plasma volume expansion by albumin in cirrhosis. Relation to blood volume distribution, arterial compliance and severity of disease. J Hepatol. 2003;39(1):24–31.
  • Frances R, Munoz C, Zapater P, et al. Bacterial DNA activates cell mediated immune response and nitric oxide overproduction in peritoneal macrophages from patients with cirrhosis and ascites. Gut. 2004;53(6):860–864.
  • Guarner C, Soriano G, Tomas A, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology. 1993;18(5):1139–1143.
  • Albillos A, De La Hera A, Gonzalez M, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology. 2003;37(1):208–217.
  • Steib CJ, Hartmann AC, V Hesler C, et al. Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis. Lab Invest. 2010;90(7):1024–1032.
  • Zhu Q, Zou L, Jagavelu K, et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol. 2012;56(4):893–899.
  • Bhimani EK, Serracino-Inglott F, Sarela AI, et al. Hepatic and mesenteric nitric oxide synthase expression in a rat model of CCl(4)-induced cirrhosis. J Surg Res. 2003;113(1):172–178.
  • Mishima S, Xu D, Lu Q, et al. Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth. Arch Surg. 1997;132(11):1190–1195.
  • Forsythe RM, Xu DZ, Lu Q, et al. Lipopolysaccharide-induced enterocyte-derived nitric oxide induces intestinal monolayer permeability in an autocrine fashion. Shock. 2002;17(3):180–184.
  • Lopez-Talavera JC, Merrill WW, Groszmann RJ. Tumor necrosis factor alpha: a major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats. Gastroenterology. 1995;108(3):761–767.
  • Lopez-Talavera JC, Cadelina G, Olchowski J, et al. Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats. Hepatology. 1996;23(6):1616–1621.
  • Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, et al. Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;9:CD002907.
  • Kim BI, Kim HJ, Park JH, et al. Increased intestinal permeability as a predictor of bacterial infections in patients with decompensated liver cirrhosis and hemorrhage. J Gastroenterol Hepatol. 2011;26(3):550–557.
  • Guarner C, Runyon BA, Heck M, et al. Effect of long-term trimethoprim-sulfamethoxazole prophylaxis on ascites formation, bacterial translocation, spontaneous bacterial peritonitis, and survival in cirrhotic rats. Dig Dis Sci. 1999;44(10):1957–1962.
  • Rasaratnam B, Kaye D, Jennings G, et al. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Ann Intern Med. 2003;139(3):186–193.
  • Vlachogiannakos J, Saveriadis AS, Viazis N, et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther. 2009;29(9):992–999.
  • Vlachogiannakos J, Viazis N, Vasianopoulou P, et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol. 2013;28(3):450–455.
  • Gomez-Hurtado I, Santacruz A, Peiro G, et al. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoS One. 2011;6(7):e23037.
  • Rogers GB, van der Gast CJ, Bruce KD, et al. Ascitic microbiota composition is correlated with clinical severity in cirrhosis with portal hypertension. PLoS One. 2013;8(9):e74884.
  • Hanouneh MA, Hanouneh IA, Hashash JG, et al. The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis in patients with liver cirrhosis. J Clin Gastroenterol. 2012;46(8):709–715.
  • Soriano G, Guarner C, Tomas A, et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology. 1992;103(4):1267–1272.
  • Gines P, Rimola A, Planas R, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology. 1990;12(4 Pt 1):716–724.
  • Parekh PJ, Balart LA. Ammonia and its role in the pathogenesis of hepatic encephalopathy. Clin Liver Dis. 2015;19(3):529–537.
  • Shawcross DL, Wright G, Olde Damink SW, et al. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007;22(1):125–138.
  • Montano-Loza AJ, Meza-Junco J, Prado CM, et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2012;10(2):166–173, 173 e161.
  • Olde Damink SW, Jalan R, Dejong CH. Interorgan ammonia trafficking in liver disease. Metab Brain Dis. 2009;24(1):169–181.
  • Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302(1):G168–G175.
  • Biesmans S, Meert TF, Bouwknecht JA, et al. Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators Inflamm. 2013;(2013:271359.
  • Murta V, Farias MI, Pitossi FJ, et al. Chronic systemic IL-1beta exacerbates central neuroinflammation independently of the blood-brain barrier integrity. J Neuroimmunol. 2015;278:30–43.
  • Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011;54(4):640–649.
  • Kang DJ, Betrapally NS, Ghosh SA, et al. Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice. Hepatology. 2016;64(4):1232–1248.
  • Jayakumar AR, Rama Rao KV, Norenberg MD. Neuroinflammation in hepatic encephalopathy: mechanistic aspects. J Clin Exp Hepatol. 2015;5(Suppl 1):S21–28.
  • Montoliu C, Piedrafita B, Serra MA, et al. IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy. J Clin Gastroenterol. 2009;43(3):272–279.
  • Luo M, Li L, Yang EN, et al. Correlation between interleukin-6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis. Clin Res Hepatol Gastroenterol. 2013;37(4):384–390.
  • Jain L, Sharma BC, Sharma P, et al. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012;44(12):1027–1031.
  • Goral V, Atayan Y, Kaplan A. The relation between pathogenesis of liver cirrhosis, hepatic encephalopathy and serum cytokine levels: what is the role of tumor necrosis factor alpha? Hepatogastroenterology. 2011;58(107–108):943–948.
  • Wright G, Davies NA, Shawcross DL, et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology. 2007;45(6):1517–1526.
  • Sanderson DJ, Good MA, Seeburg PH, et al. The role of the GluR-A (GluR1) AMPA receptor subunit in learning and memory. Prog Brain Res. 2008;169:159–178.
  • Wiltgen BJ, Royle GA, Gray EE, et al. A role for calcium-permeable AMPA receptors in synaptic plasticity and learning. PLoS One. 2010;5:9.
  • Lai AY, Swayze RD, El-Husseini A, et al. Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J Neuroimmunol. 2006;175(1–2):97–106.
  • Ogoshi F, Yin HZ, Kuppumbatti Y, et al. Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp Neurol. 2005;193(2):384–393.
  • Dadsetan S, Balzano T, Forteza J, et al. Reducing peripheral inflammation with infliximab reduces neuroinflammation and improves cognition in rats with hepatic encephalopathy. Front Mol Neurosci. 2016;9:106.
  • Cheng X, Shen Y, Targeting LR. TNF: a therapeutic strategy for Alzheimer’s disease. Drug Discov Today. 2014;19(11):1822–1827.
  • Cagnin A, Taylor-Robinson SD, Forton DM, et al. In vivo imaging of cerebral “peripheral benzodiazepine binding sites” in patients with hepatic encephalopathy. Gut. 2006;55(4):547–553.
  • Felipo V, Urios A, Montesinos E, et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis. 2012;27(1):51–58.
  • Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40(2):247–254.
  • Rodrigo R, Cauli O, Gomez-Pinedo U, et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology. 2010;139(2):675–684.
  • Butterworth RF. Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited. Metab Brain Dis. 2016;31(6):1211–1215.
  • Moratalla A, Ampuero J, Bellot P, et al. Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy. Liver Int. 2017;37(2):212–223.
  • O’Hair DP, Adams MB, Tunberg TC, et al. Relationships among endotoxemia, arterial pressure, and renal function in dogs. Circ Shock. 1989;27(3):199–210.
  • Huang LT, Hung JF, Chen CC, et al. Endotoxemia exacerbates kidney injury and increases asymmetric dimethylarginine in young bile duct-ligated rats. Shock. 2012;37(4):441–448.
  • Uchihara M, Izumi N, Sato C, et al. Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis. Hepatology. 1992;16(1):95–99.
  • Shah N, Dhar D. El Zahraa Mohammed F et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. J Hepatol. 2012;56(5):1047–1053.
  • Garcia-Martinez R, Noiret L, Sen S, et al. Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury. Liver Int. 2015;35(2):335–343.
  • Tarao K, Moroi T, Hirabayashi Y, et al. Effect of paromomycin sulfate on endotoxemia in patients with cirrhosis. J Clin Gastroenterol. 1982;4(3):263–267.
  • Kalambokis GN, Mouzaki A, Rodi M, et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin Gastroenterol Hepatol. 2012;10(7):815–818.
  • Ponziani FR, Zocco MA, Senzolo M, et al. Portal vein thrombosis and liver transplantation: implications for waiting list period, surgical approach, early and late follow-up. Transplant Rev (Orlando). 2014;28(2):92–101.
  • Ponziani FR, Zocco MA, Garcovich M, et al. What we should know about portal vein thrombosis in cirrhotic patients: a changing perspective. World J Gastroenterol. 2012;18(36):5014–5020.
  • Ponziani FR, Zocco MA, Tortora A, et al. Is there a role for anticoagulants in portal vein thrombosis management in cirrhotic patients? Expert Opin Pharmacother. 2010;11(9):1479–1487.
  • Zocco MA, Di Stasio E, De Cristofaro R, et al. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol. 2009;51(4):682–689.
  • Amitrano L, Guardascione MA, Brancaccio V, et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol. 2004;40(5):736–741.
  • Amitrano L, Brancaccio V, Guardascione MA, et al. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology. 2000;31(2):345–348.
  • Lancellotti S, Basso M, Veca V, et al. Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: a pilot study. Intern Emerg Med. 2016;11(7):959–967.
  • Violi F, Ferro D, Basili S, et al. Ongoing prothrombotic state in the portal circulation of cirrhotic patients. Thromb Haemost. 1997;77(1):44–47.
  • Wosiewicz P, Zorniak M, Hartleb M, et al. Portal vein thrombosis in cirrhosis is not associated with intestinal barrier disruption or increased platelet aggregability. Clin Res Hepatol Gastroenterol. 2016;40(6):722–729.
  • Sun Z, Wang X, Andersson R. Role of intestinal permeability in monitoring mucosal barrier function. History, methodology, and significance of pathophysiology. Dig Surg. 1998;15(5):386–397.
  • Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006;55(10):1512–1520.
  • Menzies V. Absorption of intact oligosaccharide in health and disease. Biochem Soc Trans. 1974;2(5):1042–1047.
  • van Wijck K, Verlinden TJ, van Eijk HM, et al. Novel multi-sugar assay for site-specific gastrointestinal permeability analysis: a randomized controlled crossover trial. Clin Nutr. 2013;32(2):245–251.
  • Cariello R, Federico A, Sapone A, et al. Intestinal permeability in patients with chronic liver diseases: its relationship with the aetiology and the entity of liver damage. Dig Liver Dis. 2010;42(3):200–204.
  • Vogt A, Reuken PA, Stengel S, et al. Dual-sugar tests of small intestinal permeability are poor predictors of bacterial infections and mortality in cirrhosis: A prospective study. World J Gastroenterol. 2016;22(11):3275–3284.
  • Sutherland LR, Verhoef M, Wallace JL, et al. A simple, non-invasive marker of gastric damage: sucrose permeability. Lancet. 1994;343(8904):998–1000.
  • Meddings JB, Gibbons I. Discrimination of site-specific alterations in gastrointestinal permeability in the rat. Gastroenterology. 1998;114(1):83–92.
  • Bjarnason I, Peters TJ, Veall N. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test. Lancet. 1983;1(8320):323–325.
  • Bjarnason I, Williams P, So A, et al. Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet. 1984;2(8413):1171–1174.
  • Rossi M, Sganga G, Mazzone M, et al. Cardiopulmonary bypass in man: role of the intestine in a self-limiting inflammatory response with demonstrable bacterial translocation. Ann Thorac Surg. 2004;77(2):612–618.
  • Ma TY, Hollander D, Krugliak P, et al. PEG 400, a hydrophilic molecular probe for measuring intestinal permeability. Gastroenterology. 1990;98(1):39–46.
  • Hollander D, Koyama S, Dadufalza V, et al. Polyethylene glycol 900 permeability of rat intestinal and colonic segments in vivo and brush border membrane vesicles in vitro. J Lab Clin Med. 1989;113(4):505–515.
  • Falth-Magnusson K, Jansson G, Stenhammar L, et al. Intestinal permeability assessed with different-sized polyethylene glycols in children undergoing small-intestinal biopsy for suspected celiac disease. Scand J Gastroenterol. 1989;24(1):40–46.
  • Maxton DG, Bjarnason I, Reynolds AP, et al. Lactulose, 51Cr-labelled ethylenediaminetetra-acetate, L-rhamnose and polyethyleneglycol 400 [corrected] as probe markers for assessment in vivo of human intestinal permeability. Clin Sci (Lond). 1986;71(1):71–80.
  • Pascual S, Such J, Esteban A, et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology. 2003;50(53):1482–1486.
  • Xu WH, Wu XJ, Li JS. Influence of portal pressure change on intestinal permeability in patients with portal hypertension. Hepatobiliary Pancreat Dis Int. 2002;1(4):510–514.
  • Dastych M, Dastych M Jr., Novotna H, et al. Lactulose/mannitol test and specificity, sensitivity, and area under curve of intestinal permeability parameters in patients with liver cirrhosis and Crohn’s disease. Dig Dis Sci. 2008;53(10):2789–2792.
  • Liboredo JC, Vilela EG, Ferrari Mde L, et al. Nutrition status and intestinal permeability in patients eligible for liver transplantation. JPEN J Parenter Enteral Nutr. 2015;39(2):163–170.
  • Campillo B, Pernet P, Bories PN, et al. Intestinal permeability in liver cirrhosis: relationship with severe septic complications. Eur J Gastroenterol Hepatol. 1999;11(7):755–759.
  • Zuckerman MJ, Menzies IS, Ho H, et al. Assessment of intestinal permeability and absorption in cirrhotic patients with ascites using combined sugar probes. Dig Dis Sci. 2004;49(4):621–626.
  • Fujii T, Seki T, Maruoka M, et al. Lactulose-L-rhamnose intestinal permeability test in patients with liver cirrhosis. Hepatol Res. 2001;19(2):158–169.
  • Reiberger T, Ferlitsch A, Payer BA, et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol. 2013;58(5):911–921.
  • Lee S, Son SC, Han MJ, et al. Increased intestinal macromolecular permeability and urine nitrite excretion associated with liver cirrhosis with ascites. World J Gastroenterol. 2008;14(24):3884–3890.
  • Parlesak A, Schafer C, Schutz T, et al. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol. 2000;32(5):742–747.
  • Pijls KE, Koek GH, Elamin EE, et al. Large intestine permeability is increased in patients with compensated liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2014;306(2):G147–G153.
  • Scarpellini E, Valenza V, Gabrielli M, et al. Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed? Am J Gastroenterol. 2010;105(2):323–327.
  • Huglo D, De Botton S, Canva-Delcambre V, et al. Simultaneous determination of pulmonary and intestinal permeability in patients with alcoholic liver cirrhosis. Eur J Nucl Med. 2001;28(10):1505–1511.
  • Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877–1887.
  • Giorgio V, Miele L, Principessa L, et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis. 2014;46(6):556–560.
  • Di Leo V, Venturi C, Baragiotta A, et al. Gastroduodenal and intestinal permeability in primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2003;15(9):967–973.
  • Travis S, Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci (Lond). 1992;82(5):471–488.
  • Rao AS, Camilleri M, Eckert DJ, et al. Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls. Am J Physiol Gastrointest Liver Physiol. 2011;301(5):G919–G928.
  • Fukui H. Gut-liver axis in liver cirrhosis: how to manage leaky gut and endotoxemia. World J Hepatol. 2015;7(3):425–442.
  • Stadlbauer V, Davies NA, Wright G, et al. Endotoxin measures in patients’ sample: how valid are the results? J Hepatol. 2007;47(5):726–727;author reply 727–723.
  • Prytz H, Holst-Christensen J, Korner B, et al. Portal venous and systemic endotoxaemia in patients without liver disease and systemic endotoxaemia in patients with cirrhosis. Scand J Gastroenterol. 1976;11(8):857–863.
  • Tachiyama G, Sakon M, Kambayashi J, et al. Endogenous endotoxemia in patients with liver cirrhosis–a quantitative analysis of endotoxin in portal and peripheral blood. Jpn J Surg. 1988;18(4):403–408.
  • Bigatello LM, Broitman SA, Fattori L, et al. Endotoxemia, encephalopathy, and mortality in cirrhotic patients. Am J Gastroenterol. 1987;82(1):11–15.
  • Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol. 1987;4(1):8–14.
  • Fukui H, Brauner B, Bode JC, et al. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J Hepatol. 1991;12(2):162–169.
  • Tarao K, So K, Moroi T, et al. Detection of endotoxin in plasma and ascitic fluid of patients with cirrhosis: its clinical significance. Gastroenterology. 1977;73(3):539–542.
  • Hanck C, Rossol S, Bocker U, et al. Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis. Alcohol Alcohol. 1998;33(6):606–608.
  • Clemente C, Bosch J, Rodes J, et al. Functional renal failure and haemorrhagic gastritis associated with endotoxaemia in cirrhosis. Gut. 1977;18(7):556–560.
  • Chan CC, Hwang SJ, Lee FY, et al. Prognostic value of plasma endotoxin levels in patients with cirrhosis. Scand J Gastroenterol. 1997;32(9):942–946.
  • Kaser A, Ludwiczek O, Waldenberger P, et al. Endotoxin and its binding proteins in chronic liver disease: the effect of transjugular intrahepatic portosystemic shunting. Liver. 2002;22(5):380–387.
  • Guerra-Ruiz A, Casafont F, Cobo M, et al. Increased bactericidal/permeability increasing protein in patients with cirrhosis. Liver Int. 2010;30(1):94–101.
  • Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology. 2011;141(4):1220–1230, 1230 e1221-e1223.
  • Albillos A, de-la-Hera A, Alvarez-Mon M. Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet. 2004;363(9421):1608–1610.
  • Agiasotelli D, Alexopoulou A, Vasilieva L, et al. High serum lipopolysaccharide binding protein is associated with increased mortality in patients with decompensated cirrhosis. Liver Int. 2016;37:576-582.
  • Myc A, Buck J, Gonin J, et al. The level of lipopolysaccharide-binding protein is significantly increased in plasma in patients with the systemic inflammatory response syndrome. Clin Diagn Lab Immunol. 1997;4(2):113–116.
  • Balagopal A, Philp FH, Astemborski J, et al. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology. 2008;135(1):226–233.
  • French AL, Evans CT, Agniel DM, et al. Microbial translocation and liver disease progression in women coinfected with HIV and hepatitis C virus. J Infect Dis. 2013;208(4):679–689.
  • Ogawa Y, Imajo K, Yoneda M, et al. Soluble CD14 levels reflect liver inflammation in patients with nonalcoholic steatohepatitis. PLoS One. 2013;8(6):e65211.
  • Guarner C, Gonzalez-Navajas JM, Sanchez E, et al. The detection of bacterial DNA in blood of rats with CCl4-induced cirrhosis with ascites represents episodes of bacterial translocation. Hepatology. 2006;44(3):633–639.
  • Such J, Frances R, Munoz C, et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology. 2002;36(1):135–141.
  • Frances R, Zapater P, Gonzalez-Navajas JM, et al. Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology. 2008;47(3):978–985.
  • Mostafa MS, El-Seidi EA, Kassem AM, et al. Detection of ascitic fluid infections in patients with liver cirrhosis and ascites. Arab J Gastroenterol. 2011;12(1):20–24.
  • Frances R, Benlloch S, Zapater P, et al. A sequential study of serum bacterial DNA in patients with advanced cirrhosis and ascites. Hepatology. 2004;39(2):484–491.
  • El-Naggar MM. Khalil el SA, El-Daker MA, Salama MF. Bacterial DNA and its consequences in patients with cirrhosis and culture-negative, non-neutrocytic ascites. J Med Microbiol. 2008;57(Pt 12):1533–1538.
  • Zapater P, Frances R, Gonzalez-Navajas JM, et al. Serum and ascitic fluid bacterial DNA: a new independent prognostic factor in noninfected patients with cirrhosis. Hepatology. 2008;48(6):1924–1931.
  • Fagan KJ, Rogers GB, Melino M, et al. Ascites bacterial burden and immune cell profile are associated with poor clinical outcomes in the absence of overt infection. PLoS One. 2015;10(3):e0120642.
  • Rincon D, Vaquero J, Hernando A, et al. Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites. Liver Int. 2014;34(10):1504–1512.
  • Mortensen C, Jensen JS, Hobolth L, et al. Association of markers of bacterial translocation with immune activation in decompensated cirrhosis. Eur J Gastroenterol Hepatol. 2014;26(12):1360–1366.
  • Mortensen C, Karlsen S, Gronbaek H, et al. No difference in portal and hepatic venous bacterial DNA in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt insertion. Liver Int. 2013;33(9):1309–1315.
  • Appenrodt B, Lehmann LE, Thyssen L, et al. Is detection of bacterial DNA in ascitic fluid of clinical relevance? Eur J Gastroenterol Hepatol. 2010;22(12):1487–1494.
  • Johne B, Fagerhol MK, Lyberg T, et al. Functional and clinical aspects of the myelomonocyte protein calprotectin. Mol Pathol. 1997;50(3):113–123.
  • Burri E, Beglinger C, Von Felten S, et al. Fecal calprotectin and the clinical activity index are both useful to monitor medical treatment in patients with ulcerative colitis. Dig Dis Sci. 2015;60(2):485–491.
  • Gundling F, Schmidtler F, Hapfelmeier A, et al. Fecal calprotectin is a useful screening parameter for hepatic encephalopathy and spontaneous bacterial peritonitis in cirrhosis. Liver Int. 2011;31(9):1406–1415.
  • Lutz P, Pfarr K, Nischalke HD, et al. The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites. Clin Chem Lab Med. 2015;53(12):2031–2039.
  • Homann C, Garred P, Graudal N, et al. Plasma calprotectin: a new prognostic marker of survival in alcohol-induced cirrhosis. Hepatology. 1995;21(4):979–985.
  • Bota DP, van Nuffelen M, Zakariah AN, et al. Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med. 2005;146(6):347–351.
  • Connert S, Stremmel W, Elsing C. Procalcitonin is a valid marker of infection in decompensated cirrhosis. Z Gastroenterol. 2003;41(2):165–170.
  • Cai ZH, Fan CL, Zheng JF, et al. Measurement of serum procalcitonin levels for the early diagnosis of spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis. BMC Infect Dis. 2015;15:55.
  • Marciano S, Haddad L, Martinez AP, et al. Ultra-sensitive procalcitonin may help rule out bacterial infections in patients with cirrhosis. Ann Hepatol. 2014;13(5):541–547.
  • Lesinska M, Hartleb M, Gutkowski K, et al. Procalcitonin and macrophage inflammatory protein-1 beta (MIP-1beta) in serum and peritoneal fluid of patients with decompensated cirrhosis and spontaneous bacterial peritonitis. Adv Med Sci. 2014;59(1):52–56.
  • Cekin Y, Cekin AH, Duman A, et al. The role of serum procalcitonin levels in predicting ascitic fluid infection in hospitalized cirrhotic and non-cirrhotic patients. Int J Med Sci. 2013;10(10):1367–1374.
  • Su DH, Zhuo C, Liao K, et al. Value of serum procalcitonin levels in predicting spontaneous bacterial peritonitis. Hepatogastroenterology. 2013;60(124):641–646.
  • Li CH, Yang RB, Pang JH, et al. Procalcitonin as a biomarker for bacterial infections in patients with liver cirrhosis in the emergency department. Acad Emerg Med. 2011;18(2):121–126.
  • Spahr L, Morard I, Hadengue A, et al. Procalcitonin is not an accurate marker of spontaneous bacterial peritonitis in patients with cirrhosis. Hepatogastroenterology. 2001;48(38):502–505.
  • Viallon A, Zeni F, Pouzet V, et al. Serum and ascitic procalcitonin levels in cirrhotic patients with spontaneous bacterial peritonitis: diagnostic value and relationship to pro-inflammatory cytokines. Intensive Care Med. 2000;26(8):1082–1088.
  • Attar BM, Moore CM, George M, et al. Procalcitonin, and cytokines document a dynamic inflammatory state in non-infected cirrhotic patients with ascites. World J Gastroenterol. 2014;20(9):2374–2382.
  • Cervoni JP, Thevenot T, Weil D, et al. C-reactive protein predicts short-term mortality in patients with cirrhosis. J Hepatol. 2012;56(6):1299–1304.
  • Di Martino V, Coutris C, Cervoni JP, et al. Prognostic value of C-reactive protein levels in patients with cirrhosis. Liver Transpl. 2015;21(6):753–760.
  • Cervoni JP, Amoros A, Banares R, et al. Prognostic value of C-reactive protein in cirrhosis: external validation from the CANONIC cohort. Eur J Gastroenterol Hepatol. 2016;28(9):1028–1034.
  • Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426–1437, 1437 e1421-e1429.
  • Papp M, Sipeki N, Vitalis Z, et al. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol. 2013;59(3):457–466.
  • Ruiz-Alcaraz AJ, Martinez-Esparza M, Cano R, et al. Peritoneal macrophage priming in cirrhosis is related to ERK phosphorylation and IL-6 secretion. Eur J Clin Invest. 2011;41(1):8–15.
  • Kronenberger B, Rudloff I, Bachmann M, et al. Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study. BMC Med. 2012;10:102.
  • Berry PA, Antoniades CG, Carey I, et al. Severity of the compensatory anti-inflammatory response determined by monocyte HLA-DR expression may assist outcome prediction in cirrhosis. Intensive Care Med. 2011;37(3):453–460.
  • Ge PS, Runyon BA. Treatment of patients with cirrhosis. N Engl J Med. 2016;375(8):767–777.

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