Digestive Diseases and Sciences

, Volume 61, Issue 6, pp 1545–1552 | Cite as

Nucleotide-Binding Oligomerization Domain-Containing Protein 2 Variants in Patients with Spontaneous Bacterial Peritonitis

  • Murat M. M. Harputluoglu
  • Ramazan Dertli
  • Baris Otlu
  • Ulvi Demirel
  • Ozkan Yener
  • Yilmaz Bilgic
  • Mehmet Ali Erdogan
  • Yahya Atayan
  • Yasir Furkan Cagin
Original Article

Abstract

Background

The occurrence of spontaneous bacterial peritonitis (SBP) is significantly increased in carriers of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants, suggesting that local immune alterations might be implicated in bacterial translocation (BT).

Aims

We aimed to assess the role of the NOD2 gene in conferring susceptibility to SBP. We also sought to determine whether levels of serum interleukin-6 (IL-6), lipopolysaccharide-binding protein, and soluble TNF-α receptor, along with the presence of bacterial DNA (bactDNA) in ascitic fluid, are appropriate markers for BT in patients with liver cirrhosis and SBP.

Methods

A cohort of 171 patients was divided into two groups: patients with SBP (n = 82) and those without SBP (n = 89). The presence of the most common NOD2 variants (p.R702W, p.G908R, and c.3020insC) was determined in these patients.

Results

We detected the p.G908R variant in four patients (4.9 %) of the SBP group. No significant difference was observed between the SBP and non-SBP groups for NOD2 risk variants. The frequency of bactDNA in ascitic fluid was higher for patients with NOD2 variants than for patients without variants (p = 0.021). Serum IL-6 levels in the SBP group were higher than those in the non-SBP group.

Conclusions

The frequent detection of bactDNA in ascites of patients with the p.G908R variant suggests there is a strong association between NOD2 risk variants and BT in SBP patients. In addition, increased serum IL-6 levels and bactDNA in ascitic fluid could be considered surrogate markers for BT in patients with cirrhosis.

Keywords

NOD2 Bacterial translocation Spontaneous bacterial peritonitis Cirrhosis 

Notes

Compliance with ethical standards

Conflict of interest

No conflict of interest.

References

  1. 1.
    Loo NM, Souza FF, Garcia-Tsao G. Non-hemorrhagic acute complications associated with cirrhosis and portal hypertension. Best Pract Res Clin Gastroenterol. 2013;27:665–678.CrossRefPubMedGoogle Scholar
  2. 2.
    Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology. 2005;41:422–433.CrossRefPubMedGoogle Scholar
  3. 3.
    Pinzone MR, Celesia BM, Di Rosa M, Cacopardo B, Nunnari G. Microbial translocation in chronic liver diseases. Int J Microbiol. 2012;2012:694629.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bellot P, Francés R, Such J. Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int. 2013;33:31–39.CrossRefPubMedGoogle Scholar
  5. 5.
    Appenrodt B, Grunhage F, Gentemann MG, Thyssen L, Sauerbruch T, Lammert F. Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology. 2010;51:1327–1333.CrossRefPubMedGoogle Scholar
  6. 6.
    Bruns T, Peter J, Reuken PA, et al. NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis. Liver Int. 2012;32:223–230.CrossRefPubMedGoogle Scholar
  7. 7.
    Trebicka J, Krag A, Gansweid S, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. Eur J Gastroenterol Hepatol. 2011;23:1218–1225.CrossRefPubMedGoogle Scholar
  8. 8.
    Tang NY, Chen WQ. Significance of lipopolysaccharide binding protein in serum and ascites of patients with hepatic cirrhosis complicated with spontaneous bacterial peritonitis. Zhonghua Gan Zang Bing Za Zhi. 2012;20:492–496.PubMedGoogle Scholar
  9. 9.
    Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000;32:142–153.CrossRefPubMedGoogle Scholar
  10. 10.
    Yao Q. Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. Semin Arthritis Rheum. 2013;43:125–130.CrossRefPubMedGoogle Scholar
  11. 11.
    Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–606.CrossRefPubMedGoogle Scholar
  12. 12.
    Hugot JP, Zaccaria I, Cavanaugh J, et al. Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol. 2007;102:1259–1267.CrossRefPubMedGoogle Scholar
  13. 13.
    Kobak S, Orman M, Berdeli A. NOD2/CARD15 mutations in Turkish patients with ankylosing spondylitis. Scand J Rheumatol. 2013;42:249–250.CrossRefPubMedGoogle Scholar
  14. 14.
    Tekin D, Dalgic N, Kayaalti Z, Soylemezoglu T, Diler B, Kutlubay BI. Importance of NOD2/CARD15 gene variants for susceptibility to and outcome of sepsis in Turkish children. Pediatr Crit Care Med. 2012;13:e73–e77.CrossRefPubMedGoogle Scholar
  15. 15.
    Ozen SC, Dagli U, Kiliç MY, et al. NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene polymorphisms in Turkish patients with inflammatory bowel disease. J Gastroenterol. 2006;41:304–310.CrossRefPubMedGoogle Scholar
  16. 16.
    Filik L. NOD2 gene variants and spontaneous bacterial peritonitis. Liver Int. 2012;32:521.PubMedGoogle Scholar
  17. 17.
    Cavanaugh J. NOD2: ethnic and geographic differences. World J Gastroenterol. 2006;12:3673–3677.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ekman A, Cardell LO. The expression and function of Nod-like receptors in neutrophils. Immunology. 2010;130:55–63.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Suliman MA, Khalil FM, Alkindi SS, Pathare AV, Almadhani AA, Soliman NA. Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis. World J Gastrointest Pathophysiol. 2012;3:92–98.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Navasa M, Follo A, Filella X, et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology. 1998;27:1227–1232.CrossRefPubMedGoogle Scholar
  21. 21.
    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;58:911–921.CrossRefPubMedGoogle Scholar
  22. 22.
    Albillos A, de la Hera A, González M, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology. 2003;37:208–217.CrossRefPubMedGoogle Scholar
  23. 23.
    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;363:1608–1610.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen YY, Lien JM, Peng YS, et al. Lipopolysaccharide binding protein in cirrhotic patients with severe sepsis. J Chin Med Assoc. 2014;77:68–74.CrossRefPubMedGoogle Scholar
  25. 25.
    Gutsmann T, Müller M, Carroll SF, MacKenzie RC, Wiese A, Seydel U. Dual role of lipopolysaccharide (LPS)-binding protein in neutralization of LPS and enhancement of LPS-induced activation of mononuclear cells. Infect Immun. 2001;69:6942–6950.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lamping N, Dettmer R, Schröder NW, et al. LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest. 1998;101:2065–2071.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Opal SM, Scannon PJ, Vincent JL, et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS binding protein in patients with severe sepsis and septic shock. J Infect Dis. 1999;180:1584–1589.CrossRefPubMedGoogle Scholar
  28. 28.
    Blairon L, Wittebole X, Laterre PF. Lipopolysaccharide binding protein serum levels in patients with severe sepsis due to gram-positive and fungal infections. J Infect Dis. 2003;187:287–291.CrossRefPubMedGoogle Scholar
  29. 29.
    Aukrust P, Liabakk NB, Müller F, Lien E, Espevik T, Frøland SS. Serum levels of tumor necrosis factor-alpha (TNF alpha) and soluble TNF receptors in human immunodeficiency virus type 1 infection—correlations to clinical, immunologic, and virologic parameters. J Infect Dis. 1994;169:420–424.CrossRefPubMedGoogle Scholar
  30. 30.
    Zangerle R, Gallati H, Sarcletti M, Wachter H, Fuchs D. Tumor necrosis factor alpha and soluble tumor necrosis factor receptors in individuals with human immunodeficiency virus infection. Immunol Lett. 1994;41:229–234.CrossRefPubMedGoogle Scholar
  31. 31.
    Montes-de-Oca M, Blanco MJ, Marquez M, Soto MJ, Fernandez-Gutiérrez C, Rodriguez-Ramos C. Haemodynamic derangement in human immunodeficiency virus-infected patients with hepatitis C virus-related cirrhosis: the role of bacterial translocation. Liver Int. 2011;31:850–858.CrossRefPubMedGoogle Scholar
  32. 32.
    Rodríguez-Ramos C, Galan F, Díaz F, Elvira J, Martín-Herrera L, Girón-González JA. Expression of proinflammatory cytokines and their inhibitors during the course of spontaneous bacterial peritonitis. Dig Dis Sci. 2001;46:1668–1676.CrossRefPubMedGoogle Scholar
  33. 33.
    Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. Hepatology. 1984;4:53–58.CrossRefPubMedGoogle Scholar
  34. 34.
    Bruns T, Sachse S, Straube E, Assefa S, Herrmann A, Hagel S. Identification of bacterial DNA in neutrocytic and non-neutrocytic cirrhotic ascites by means of a multiplex polymerase chain reaction. Liver Int. 2009;29:1206–1214.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Gastroenterology, Medical FacultyInonu UniversityMalatyaTurkey
  2. 2.Department of Internal Medicine, Medical FacultyInonu UniversityMalatyaTurkey
  3. 3.Department of Microbiology, Medical FacultyInonu UniversityMalatyaTurkey
  4. 4.Department of Gastroenterology, Medical FacultyFirat UniversityElazigTurkey

Personalised recommendations