Skip to main content
SpringerLink
Log in

CARD15/NOD2 Is Not a Predisposing Factor for Necrotizing Enterocolitis

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

An Erratum to this article was published on 19 December 2008

Abstract

Multiple factors are incriminated in the etiopathogeny of necrotizing enterocolitis (NEC) in premature infants, including oral feeding, vascular abnormalities, increase in pro-inflammatory cytokines, and inappropriate response of the intestinal barrier to bacterial microflora. CARD15/NOD2 is a gene recently recognized as important in the innate response to gut flora and is involved in Crohn's disease susceptibility. We thus tested its putative role in NEC. Ten children (seven boys and three girls) suffering from NEC who were admitted to Robert Debré hospital between 1999 and 2002 were retrospectively included in the study. Genetic screening of the 11 constant exons and the exon–intron junctions of CARD15/NOD2 by direct sequencing revealed no novel mutations of that gene in NEC patients. Furthermore, the three main mutations of CARD15/NOD2 (R702W, G908R, and 1007fs) associated with susceptibility to Crohn's disease were not found in these patients. Our results suggest that CARD15/NOD2 does not play a major role in genetic susceptibility to NEC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F: Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 6:6–23, 2003

    Article  PubMed  Google Scholar 

  2. Kafetzis DA, Skevaki C, Costalos C: Neonatal necrotizing enterocolitis: an overview. Curr Opin Infect Dis 16:349–355, 2003

    PubMed  CAS  Google Scholar 

  3. Israel EJ: Neonatal necrotizing enterocolitis, a disease of the immature intestinal mucosal barrier. Acta Paediatr (Suppl) 396:27–32, 1994

    Article  CAS  Google Scholar 

  4. Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA: Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci USA 97:6043–6048, 2000

    Article  PubMed  CAS  Google Scholar 

  5. Gordon S: Pattern recognition receptors: doubling up for the innate immune response. Cell 111:927–930, 2002

    Article  PubMed  CAS  Google Scholar 

  6. Miller SI, Ernst RK, Bader MW: LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol 3:36–46, 2005

    Article  PubMed  CAS  Google Scholar 

  7. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ: Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872, 2003

    Article  PubMed  CAS  Google Scholar 

  8. Berrebi D, Maudinas R, Hugot JP, Chamaillard M, Chareyre F, De Lagausie P, Yang C, Desreumaux P, Giovannini M, Cezard JP, Zouali H, Emilie D, Peuchmaur M: CARD15 gene overexpression in mononuclear and epithelial cells of the inflamed Crohn's disease colon. Gut 52:840–846, 2003

    Article  PubMed  CAS  Google Scholar 

  9. Jobin C. Intestinal epithelial cells and innate immunity in the intestine: Is CARD15/Nod2 another player? Gastroenterology 124:1145–1149, 2003

    Google Scholar 

  10. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK: CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 124:993–1000, 2003

    Article  PubMed  CAS  Google Scholar 

  11. Rosenstiel P, Fantini M, Brautigam K, Kuhbacher T, Waetzig GH, Seegert D, Schreiber S: TNF-α and IFN-γ regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 124:1001–1009, 2003

    Article  PubMed  CAS  Google Scholar 

  12. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599–603, 2001

    Article  PubMed  CAS  Google Scholar 

  13. Li J, Moran T, Swanson E, Julian C, Harris J, Bonen DK, Hedl M, Nicolae DL, Abraham C, Cho JH: Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 13:1715–1725, 2004

    Article  PubMed  CAS  Google Scholar 

  14. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603–606, 2001

    Article  PubMed  CAS  Google Scholar 

  15. Watanabe T, Kitani A, Murray PJ, Strober W: NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5:800–808, 2004

    Article  PubMed  CAS  Google Scholar 

  16. Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, Chamaillard M, Zouali H, Thomas G, Hugot JP: CARD15 mutations in Blau syndrome. Nat Genet 29:19–20, 2001

    Article  PubMed  CAS  Google Scholar 

  17. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP; EPWG-IBD Group; EPIMAD Group; GETAID Group: CARD15/NOD2 mutational analysis and genotype–phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845–857, 2002

    Article  PubMed  CAS  Google Scholar 

  18. Coutinho HB, da Mota HC, Coutinho VB, Robalinho TI, Furtado AF, Walker E, King G, Mahida YR, Sewell HF, Wakelin D: Absence of lysozyme (muramidase) in the intestinal Paneth cells of newborn infants with necrotising enterocolitis. J Clin Pathol 51:512–514, 1998

    Article  PubMed  CAS  Google Scholar 

  19. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S: Crohn's disease and the NOD2 gene: a role for Paneth cells. Gastroenterology 125:47–57, 2003

    Article  PubMed  CAS  Google Scholar 

  20. Ogura Y, Lala S, Xin W, Smith E, Dowds TA, Chen FF, Zimmermann E, Tretiakova M, Cho JH, Hart J, Greenson JK, Keshav S, Nunez G: Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52:1591–1597, 2003

    Article  PubMed  CAS  Google Scholar 

  21. Nadler EP, Stanford A, Zhang XR, Schall LC, Alber SM, Watkins SC, Ford HR: Intestinal cytokine gene expression in infants with acute necrotizing enterocolitis: interleukin–11 mRNA expression inversely correlates with extent of disease. J Pediatr Surg 36:1122–1129, 2001

    Article  PubMed  CAS  Google Scholar 

  22. Bauer CR, Morrison JC, Poole WK, Korones SB, Boehm JJ, Rigatto H, Zachman RD: A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy. Pediatrics 73:682–688, 1984

    PubMed  CAS  Google Scholar 

  23. Ozturk H, Dokucu AI, Ogun C, Buyukbayram H: Protective effects of recombinant human interleukin-10 on intestines of hypoxia-induced necrotizing enterocolitis in immature rats. J Pediatr Surg 37:1330–1333, 2002

    Article  PubMed  Google Scholar 

  24. Chamaillard M, Philpott D, Girardin SE, Zouali H, Lesage S, Chareyre F, Bui TH, Giovannini M, Zaehringer U, Penard-Lacronique V, Sansonetti PJ, Hugot JP, Thomas G: Gene–environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci USA 100:3455–3460, 2003

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Fondation Jean Dausset-CEPH, Université, Paris 7, Paris, France

    Habib Zouali & Dominique Berrebi

  2. Service de Chirurgie Pédiatrique, Université, Paris 7, Paris, France

    Arnaud Bonnard, Pascal De Lagausie & Yves Aigrain

  3. Service de Gastroentérologie Pédiatrique, Université, Paris 7, Paris, France

    Caroline Farnoux

  4. Service d'Anatomie et Cytologie Pathologiques, Université, Paris 7, Paris, France

    Jean-Pierre Cezard

  5. INSERM U458, Hôpital Robert Debré, Université, Paris 7, Paris, France

    Michel Peuchmaur & Jean-Pierre Hugot

  6. EA3102, Université, Paris 7, Paris, France

    Pascal De Lagausie, Michel Peuchmaur & Jean-Pierre Hugot

  7. Fondation Jean Dausset-CEPH 27, Rue Juliette Dodu, 75010, Paris, France

    Habib Zouali

Authors
  1. Habib Zouali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arnaud Bonnard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pascal De Lagausie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Caroline Farnoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves Aigrain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Pierre Cezard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michel Peuchmaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Pierre Hugot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dominique Berrebi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Habib Zouali.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s10620-008-0678-z.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zouali, H., Bonnard, A., De Lagausie, P. et al. CARD15/NOD2 Is Not a Predisposing Factor for Necrotizing Enterocolitis. Dig Dis Sci 50, 1684–1687 (2005). https://doi.org/10.1007/s10620-005-2915-z

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-005-2915-z

Keywords

Search

Navigation