Acta Med. 2014, 57: 89-96

https://doi.org/10.14712/18059694.2014.46

Crohn’s Disease: a Role of Gut Microbiota and Nod2 Gene Polymorphisms in Disease Pathogenesis

Lucia Hrnčířováa,b, Jan Krejseka, Igor Šplíchalb, Tomáš Hrnčířb

aDepartment of Clinical Immunology and Allergology, Charles University in Prague, Faculty of Medicine and University Hospital in Hradec Králové, Czech Republic
bDepartment of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Doly 183, 549 22 Nový Hrádek, Czech Republic

Received April 30, 2014
Accepted September 8, 2014

References

1. Sartor RB. Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. Gastroenterology 2010; 139(6): 1816–9. <https://doi.org/10.1053/j.gastro.2010.10.036>
2. Colombel JF, et al. Epidemiology and risk factors of inflammatory bowel diseases. Bulletin de l’Academie nationale de medecine 2007; 191(6): 1105–18; discussion 1118–23. <https://doi.org/10.1016/S0001-4079(19)32982-6>
3. Cosnes J, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011; 140(6): 1785–94. <https://doi.org/10.1053/j.gastro.2011.01.055>
4. Hiatt RA, Kaufman L. Epidemiology of inflammatory bowel disease in a defined northern California population. West J Med 1988; 149(5): 541–6.
5. Moum B, et al. Incidence of Crohn’s disease in four counties in southeastern Norway, 1990–93. A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists. Scand J Gastroenterol 1996; 31(4): 355–61. <https://doi.org/10.3109/00365529609006410>
6. Baumgart DC, et al. IBD Around the world: comparing the epidemiology, diagnosis, and treatment: proceedings of the World Digestive Health Day 2010 – Inflammatory Bowel Disease Task Force meeting. Inflammatory bowel diseases 2011; 17(2): 639–44. <https://doi.org/10.1002/ibd.21409>
7. Molodecky NA, Kaplan GG. Environmental risk factors for inflammatory bowel disease. Gastroenterol Hepatol (NY) 2010; 6(5): 339–46.
8. Tlaskalova-Hogenova H, et al. Interaction of mucosal microbiota with the innate immune system. Scand J Immunol 2005; 62(Suppl 1): 106–13. <https://doi.org/10.1111/j.1365-3083.2005.01618.x>
9. Weiner HL, et al. Oral tolerance. Immunol Rev 2011; 241(1): 241–59. <https://doi.org/10.1111/j.1600-065X.2011.01017.x> <PubMed>
10. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011; 474(7351): 307–17. <https://doi.org/10.1038/nature10209> <PubMed>
11. Tlaskalova-Hogenova H, et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cellular & molecular immunology 2011; 8(2): 110–20. <https://doi.org/10.1038/cmi.2010.67> <PubMed>
12. Hrncir T, et al. Gut microbiota and lipopolysaccharide content of the diet influence development of regulatory T cells: studies in germ-free mice. BMC Immunol 2008; 9: 65. <https://doi.org/10.1186/1471-2172-9-65> <PubMed>
13. Stepankova R, et al. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflammatory bowel diseases 2007; 13(10): 1202–11. <https://doi.org/10.1002/ibd.20221>
14. Singh B, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001; 182: 190–200. <https://doi.org/10.1034/j.1600-065X.2001.1820115.x>
15. Klimesova K, et al. Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflammatory bowel diseases 2013; 19(6): 1266–77. <https://doi.org/10.1097/MIB.0b013e318281330a> <PubMed>
16. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmunity reviews 2004; 3(5): 394–400. <https://doi.org/10.1016/j.autrev.2004.03.002>
17. Cadwell K, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 2010; 141(7): 1135–45. <https://doi.org/10.1016/j.cell.2010.05.009> <PubMed>
18. Shanahan F, Bernstein CN. The evolving epidemiology of inflammatory bowel disease. Curr Opin Gastroenterol 2009; 25(4): 301–5. <https://doi.org/10.1097/MOG.0b013e32832b12ef>
19. Gent AE, et al. Inflammatory bowel disease and domestic hygiene in infancy. Lancet 1994; 343(8900): 766–7. <https://doi.org/10.1016/S0140-6736(94)91841-4>
20. Halme L, et al. Family and twin studies in inflammatory bowel disease. World journal of gastroenterology 2006; 12(23): 3668–72. <https://doi.org/10.3748/wjg.v12.i23.3668> <PubMed>
21. Franke A, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 2010; 42(12): 1118–25. <https://doi.org/10.1038/ng.717> <PubMed>
22. Saleh M, Elson CO. Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity 2011; 34(3): 293–302. <https://doi.org/10.1016/j.immuni.2011.03.008> <PubMed>
23. Hugot JP, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001; 411(6837): 599–603. <https://doi.org/10.1038/35079107>
24. Ogura Y, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001; 411(6837): 603–6. <https://doi.org/10.1038/35079114>
25. Inohara N, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. The Journal of biological chemistry 2003; 278(8): 5509–12. <https://doi.org/10.1074/jbc.C200673200>
26. Seiderer J, et al. Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn’s disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis. Scand J Gastroenterol 2006; 41(12): 1421–32. <https://doi.org/10.1080/00365520600703900>
27. Seiderer J, et al. Predictive value of the CARD15 variant 1007fs for the diagnosis of intestinal stenoses and the need for surgery in Crohn’s disease in clinical practice: results of a prospective study. Inflammatory bowel diseases 2006; 12(12): 1114–21. <https://doi.org/10.1097/01.mib.0000235836.32176.5e>
28. Mardini HE, et al. Gastroduodenal Crohn’s disease is associated with NOD2/CARD15 gene polymorphisms, particularly L1007P homozygosity. Dig Dis Sci 2005; 50(12): 2316–22. <https://doi.org/10.1007/s10620-005-3054-2>
29. Miceli-Richard C, et al. CARD15 mutations in Blau syndrome. Nature genetics 2001; 29(1): 19–20. <https://doi.org/10.1038/ng720>
30. Kanazawa N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood 2005; 105(3): 1195–7. <https://doi.org/10.1182/blood-2004-07-2972>
31. Lesage S, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. American journal of human genetics 2002; 70(4): 845–57. <https://doi.org/10.1086/339432> <PubMed>
32. Linde K, et al. Card15 and Crohn’s disease: healthy homozygous carriers of the 3020insC frameshift mutation. The American journal of gastroenterology 2003; 98(3): 613–7. <https://doi.org/10.1111/j.1572-0241.2003.07287.x>
33. Kobayashi KS, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005; 307(5710): 731–4. <https://doi.org/10.1126/science.1104911>
34. Esters N, et al. Transmission of CARD15 (NOD2) variants within families of patients with inflammatory bowel disease. The American journal of gastroenterology 2004; 99(2): 299–305. <https://doi.org/10.1111/j.1572-0241.2004.04040.x>
35. Yamazaki K, et al. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. Journal of human genetics 2002; 47(9): 469–72. <https://doi.org/10.1007/s100380200067>
36. Guo QS, et al. NOD2 3020insC frameshift mutation is not associated with inflammatory bowel disease in Chinese patients of Han nationality. World journal of gastroenterology : WJG 2004; 10(7): 1069–71. <https://doi.org/10.3748/wjg.v10.i7.1069> <PubMed>
37. Jang JY, et al. Lack of common NOD2 mutations in Korean pediatric patients with inflammatory bowel disease. Pediatrics international: official journal of the Japan Pediatric Society 2010; 52(6): 888–9. <https://doi.org/10.1111/j.1442-200X.2010.03269.x>
38. Holler E, et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 2004; 104(3): 889–94. <https://doi.org/10.1182/blood-2003-10-3543>
39. Barnich N, et al. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition. J Cell Biol 2005; 170(1): 21–6. <https://doi.org/10.1083/jcb.200502153> <PubMed>
40. Sabbah A, et al. Activation of innate immune antiviral responses by Nod2. Nature immunology 2009; 10(10): 1073–80. <https://doi.org/10.1038/ni.1782> <PubMed>
41. Ogura Y, et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. The Journal of biological chemistry 2001; 276(7): 4812–8. <https://doi.org/10.1074/jbc.M008072200>
42. Hisamatsu T, et al. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 2003; 124(4): 993–1000. <https://doi.org/10.1053/gast.2003.50153>
43. Xavier RJ and Podolsky DK, Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448(7152): 427–34. <https://doi.org/10.1038/nature06005>
44. Barrett JC, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nature genetics 2008; 40(8): 955–62. <https://doi.org/10.1038/ng.175>
45. Coombes JL, Powrie F. Dendritic cells in intestinal immune regulation. Nature reviews. Immunology 2008; 8(6): 435–46. <https://doi.org/10.1038/nri2335> <PubMed>
46. Shaw MH, et al. T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat Immunol 2009; 10(12): 1267–74. <https://doi.org/10.1038/ni.1816> <PubMed>
47. Fritz JH, et al. Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity. Immunity 2007; 26(4): 445–59. <https://doi.org/10.1016/j.immuni.2007.03.009>
48. Magalhaes JG, et al. Nod2-dependent Th2 polarization of antigen-specific immunity. Journal of immunology 2008; 181(11): 7925–35. <https://doi.org/10.4049/jimmunol.181.11.7925>
49. van Beelen AJ, et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 2007; 27(4): 660–9. <https://doi.org/10.1016/j.immuni.2007.08.013>
50. Hasegawa M, et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J 2008; 27(2): 373–83. <https://doi.org/10.1038/sj.emboj.7601962> <PubMed>
51. Abbott DW, et al. The Crohn’s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 2004; 14(24): 2217–27. <https://doi.org/10.1016/j.cub.2004.12.032>
52. Tao M, et al. ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol 2009; 19(15): 1255–63. <https://doi.org/10.1016/j.cub.2009.06.038> <PubMed>
53. Yeretssian G, et al. Non-apoptotic role of BID in inflammation and innate immunity. Nature 2011; 474(7349): 96–9. <https://doi.org/10.1038/nature09982>
54. Strober W, Watanabe T. NOD2, an intracellular innate immune sensor involved in host defense and Crohn’s disease. Mucosal immunology 2011.
55. Mizushima N, et al. Autophagy fights disease through cellular self-digestion. Nature 2008; 451(7182): 1069–75. <https://doi.org/10.1038/nature06639> <PubMed>
56. Travassos LH, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nature immunology 2010; 11(1): 55–62. <https://doi.org/10.1038/ni.1823>
57. Cooney R, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010; 16(1): 90–7. <https://doi.org/10.1038/nm.2069>
58. Zhou R, et al. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011; 469(7329): 221–5. <https://doi.org/10.1038/nature09663>
59. Maloy KJ and Powrie F, Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 2011; 474(7351): 298–306. <https://doi.org/10.1038/nature10208>
60. Biswas A, et al. Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proceedings of the National Academy of Sciences of the United States of America 2010; 107(33): 14739–44. <https://doi.org/10.1073/pnas.1003363107> <PubMed>
61. Petnicki-Ocwieja T, et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A 2009; 106(37): 15813–8. <https://doi.org/10.1073/pnas.0907722106> <PubMed>
62. Watanabe T, et al. Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 2006; 25(3): 473–85. <https://doi.org/10.1016/j.immuni.2006.06.018>
63. Frutuoso MS, et al. The pattern recognition receptors Nod1 and Nod2 account for neutrophil recruitment to the lungs of mice infected with Legionella pneumophila. Microbes Infect 2010; 12(11): 819–27. <https://doi.org/10.1016/j.micinf.2010.05.006>
64. Geddes K, et al. Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model. Infection and immunity 2010; 78(12): 5107–15. <https://doi.org/10.1128/IAI.00759-10> <PubMed>
65. Petnicki-Ocwieja T, et al. Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance. PLoS One 2011; 6(2): e17414. <https://doi.org/10.1371/journal.pone.0017414> <PubMed>
66. Hedl M, et al. Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci U S A 2007; 104(49): 19440–5. <https://doi.org/10.1073/pnas.0706097104> <PubMed>
67. Kullberg BJ, et al. Crohn’s disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli. Immunology 2008; 123(4): 600–5. <https://doi.org/10.1111/j.1365-2567.2007.02735.x> <PubMed>
68. Watanabe T, et al. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nature immunology 2004; 5(8): 800–8. <https://doi.org/10.1038/ni1092>
69. Shaw MH, et al. The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation. Trends in immunology 2011; 32(2): 73–9. <https://doi.org/10.1016/j.it.2010.12.007> <PubMed>
70. Seder RA, et al. CD28-mediated costimulation of interleukin 2 (IL-2) production plays a critical role in T cell priming for IL-4 and interferon gamma production. J Exp Med 1994; 179(1): 299–304. <https://doi.org/10.1084/jem.179.1.299> <PubMed>
71. Barreau F, et al. Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer’s patches. Gut 2010; 59(2): 207–17. <https://doi.org/10.1136/gut.2008.171546>
72. Sartor RB. Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation. Mucosal immunology 2011; 4(2): 127–32. <https://doi.org/10.1038/mi.2010.87>
73. Chassaing B, Darfeuille-Michaud A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011; 140(6): 1720–28. <https://doi.org/10.1053/j.gastro.2011.01.054>
74. Willing BP, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 2010; 139(6): 1844–1854 e1. <https://doi.org/10.1053/j.gastro.2010.08.049>
75. Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol 2011; 12(1): 5–9. <https://doi.org/10.1038/ni0111-5>
76. Atarashi K, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331(6015): 337–41. <https://doi.org/10.1126/science.1198469> <PubMed>
77. Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proceedings of the National Academy of Sciences of the United States of America 2008; 105(43): 16731–6. <https://doi.org/10.1073/pnas.0804812105> <PubMed>
78. Darfeuille-Michaud A, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 2004; 127(2): 412–21. <https://doi.org/10.1053/j.gastro.2004.04.061>
79. Kotlowski R, et al. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut 2007; 56(5): 669–75. <https://doi.org/10.1136/gut.2006.099796> <PubMed>
80. Barnich N, et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. The Journal of clinical investigation 2007; 117(6): 1566–74. <https://doi.org/10.1172/JCI30504> <PubMed>
81. Rolhion N, et al. Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion. Gut 2010; 59(10): 1355–62. <https://doi.org/10.1136/gut.2010.207456> <PubMed>
82. Eaves-Pyles T, et al. Escherichia coli isolated from a Crohn’s disease patient adheres, invades, and induces inflammatory responses in polarized intestinal epithelial cells. Int J Med Microbiol 2008; 298(5–6): 397–409. <https://doi.org/10.1016/j.ijmm.2007.05.011>
83. Chassaing B, et al. Crohn disease – associated adherent-invasive E. coli bacteria target mouse and human Peyer’s patches via long polar fimbriae. The Journal of clinical investigation 2011; 121(3): 966–75. <https://doi.org/10.1172/JCI44632> <PubMed>
84. Glasser AL, et al. Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death. Infection and immunity 2001; 69(9): 5529–37. <https://doi.org/10.1128/IAI.69.9.5529-5537.2001> <PubMed>
85. Meconi S, et al. Adherent-invasive Escherichia coli isolated from Crohn’s disease patients induce granulomas in vitro. Cellular microbiology 2007; 9(5): 1252–61. <https://doi.org/10.1111/j.1462-5822.2006.00868.x>
86. Glimcher LH. Trawling for treasure: tales of T-bet. Nature immunology 2007; 8(5): 448–50. <https://doi.org/10.1038/ni0507-448>
87. Stucchi A, et al. A new transcription factor that regulates TNF-alpha gene expression, LITAF, is increased in intestinal tissues from patients with CD and UC. Inflammatory bowel diseases 2006; 12(7): 581–7. <https://doi.org/10.1097/01.MIB.0000225338.14356.d5>
88. Baker PI, Love DR, Ferguson LR. Role of gut microbiota in Crohn’s disease. Expert Rev Gastroenterol Hepatol 2009; 3(5): 535–46. <https://doi.org/10.1586/egh.09.47>
89. Neurath MF Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 2011; 22(2): 83–9. <https://doi.org/10.1016/j.cytogfr.2011.02.003>
90. Lee YK, et al. Developmental plasticity of Th17 and Treg cells. Current opinion in immunology 2009; 21(3): 274–80. <https://doi.org/10.1016/j.coi.2009.05.021>
91. Kamada N, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. The Journal of clinical investigation 2008; 118(6): 2269–80.
92. Ahern PP, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 2010; 33(2): 279–88. <https://doi.org/10.1016/j.immuni.2010.08.010> <PubMed>
93. Maloy KJ, Kullberg MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal immunology 2008; 1(5): 339–49. <https://doi.org/10.1038/mi.2008.28>
94. Leppkes M, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 2009; 136(1): 257–67. <https://doi.org/10.1053/j.gastro.2008.10.018>
95. Sonnenberg GF, et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J Exp Med 2010; 207(6): 1293–305. <https://doi.org/10.1084/jem.20092054> <PubMed>
96. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 2011; 12(5): 383–90. <https://doi.org/10.1038/ni.2025>
97. Wolk K, et al. Biology of interleukin-22. Semin Immunopathol 2010; 32(1): 17–31. <https://doi.org/10.1007/s00281-009-0188-x>
98. Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011; 140(6): 1756–67. <https://doi.org/10.1053/j.gastro.2011.02.016> <PubMed>
99. Smith PD. Principles of Mucosal Immunology, Garland Science, Taylor & Francis Groupe, LLC 2013: 529.
front cover

ISSN 1211-4286 (Print) ISSN 1805-9694 (Online)

Open access journal

Archive