Nod2: A key regulator linking microbiota to intestinal mucosal immunity

Journal of Molecular Medicine

Volumn 90, Issue 1, 2012, Pages 15-24

  Biswas, Amlan ^a   Petnicki Ocwieja, Tanja ^a,b   Kobayashi, Koichi S ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b TUFTS MEDICAL CENTER   (United States)

Author keywords

Commensal microflora; Crohn's disease; NLR proteins; Nod2; Paneth cells

Indexed keywords

ANTIINFECTIVE AGENT; CASPASE RECRUITMENT DOMAIN PROTEIN 15;

CROHN DISEASE; DISEASE ASSOCIATION; DISEASE PREDISPOSITION; ESCHERICHIA COLI; GENETIC ASSOCIATION; HUMAN; ILEUM; INTESTINE FLORA; MUCOSAL IMMUNITY; MUTATION; NONHUMAN; PANETH CELL; PROTEIN EXPRESSION; REVIEW;

ANIMALS; BACTERIA; CROHN DISEASE; HUMANS; IMMUNITY, MUCOSAL; INTESTINES; METAGENOME; MICE; MODELS, BIOLOGICAL; MUTATION; NOD2 SIGNALING ADAPTOR PROTEIN; SIGNAL TRANSDUCTION;

EID: 84857365925     PISSN: 09462716     EISSN: 14321440     Source Type: Journal    
DOI: 10.1007/s00109-011-0802-y     Document Type: Review

References (91)

1. Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427-434 (Pubitemid 47123518)
2. Sartor RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134:577-594 (Pubitemid 351173057)
3. Abraham C, Cho JH (2009) Inflammatory bowel disease. N Engl J Med 361:2066-2078
4. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197-216 (Pubitemid 34293424)
5. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599-603 (Pubitemid 32531408)
6. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603-606 (Pubitemid 32531409)
7. Cho JH (2008) The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev 8:458-466 (Pubitemid 351733422)
8. Abraham C, Cho JH (2006) Functional consequences of NOD2 (CARD15) mutations. Inflam Bowel Dis 12:641-650 (Pubitemid 43977746)
9. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA et al (2008) The NLR gene family: a standard nomenclature. Immunity 28:285-287 (Pubitemid 351350631)
10. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A et al (2006) Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 7:576-582 (Pubitemid 43797338)
11. Inohara N, Nunez G (2003) Cell death and immunity: NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev 3:371-382 (Pubitemid 37323197)
12. Koonin EV, Aravind L (2000) The NACHT family-a new group of predicted NTPases implicated in apoptosis and MHC transcription activation. Trends Biochem Sci 25:223-224 (Pubitemid 30236216)
13. Tschopp J, Martinon F, Burns K (2003) NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4:95-104 (Pubitemid 36172693)
14. Bertin J, DiStefano PS (2000) The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ 7:1273-1274 (Pubitemid 32042236)
15. Inohara N, Nunez G (2001) The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20:6473-6481 (Pubitemid 32977852)
16. Martinon F, Hofmann K, Tschopp J (2001) The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol 11:R118-R120 (Pubitemid 32185314)
17. FairbrotherWJ, Gordon NC, HumkeEW, O'Rourke KM, Starovasnik MA, Yin JP, Dixit VM (2001) The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci 10:1911-1918 (Pubitemid 32848788)
18. Pawlowski K, Pio F, Chu Z, Reed JC, Godzik A (2001) PAAD-a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci 26:85-87 (Pubitemid 32144740)
19. Weber CH, Vincenz C (2001) The death domain superfamily: a tale of two interfaces? Trends Biochem Sci 26:475-481 (Pubitemid 32735448)
20. Staub E, Dahl E, Rosenthal A (2001) The DAPIN family: a novel domain links apoptotic and interferon response proteins. Trends Biochem Sci 26:83-85 (Pubitemid 32144739)
21. Birnbaum MJ, Clem RJ, Miller LK (1994) An apoptosisinhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs. J Virol 68:2521-2528 (Pubitemid 24091932)
22. Franchi L, Warner N, Viani K, Nunez G (2009) Function of Nodlike receptors in microbial recognition and host defense. Immunol Rev 227:106-128
23. Bertin J, Nir WJ, Fischer CM, Tayber OV, Errada PR, Grant JR, Keilty JJ, GosselinML, Robison KE,Wong GH et al (1999) Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB. J Biol Chem 274:12955-12958
24. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, Carrio R, Merino J, Liu D, Ni J, Nunez G (1999) Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 274:14560-14567
25. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276:4812-4818
26. Tada H, Aiba S, Shibata K, Ohteki T, Takada H (2005) Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun 73:7967-7976 (Pubitemid 41740282)
27. Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J (2006) NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281:2005-2011 (Pubitemid 43845788)
28. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK (2003) CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 124:993-1000 (Pubitemid 36389802)
29. Uehara A, Fujimoto Y, Fukase K, Takada H (2007) Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol 44:3100-3111 (Pubitemid 46610510)
30. Uehara A, Sugawara Y, Kurata S, Fujimoto Y, Fukase K, Kusumoto S, Satta Y, Sasano T, Sugawara S, Takada H (2005) Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like receptors, NOD1 and NOD2 in human oral epithelial cells. Cell Microbiol 7:675-686 (Pubitemid 40585009)
31. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F, Nunez G, Fernandez-Luna JL (2002) Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factorkappa B activation. J Biol Chem 277:41701-41705 (Pubitemid 35257477)
32. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869-8872 (Pubitemid 36800360)
33. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M et al (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 278:5509-5512 (Pubitemid 36800790)
34. Hasegawa M, Yang K, Hashimoto M, Park JH, Kim YG, Fujimoto Y, Nunez G, Fukase K, Inohara N (2006) Differential release and distribution of Nod1 and Nod2 immunostimulatory molecules among bacterial species and environments. J Biol Chem 281:29054-29063 (Pubitemid 44507049)
35. Wilmanski JM, Petnicki-Ocwieja T, Kobayashi KS (2008) NLR proteins: integral members of innate immunity and mediators of inflammatory diseases. J Leukoc Biol 83:13-30
36. Tanabe T, Chamaillard M, Ogura Y, Zhu L, Qiu S, Masumoto J, Ghosh P, Moran A, Predergast MM, Tromp G et al (2004) Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J 23:1587-1597 (Pubitemid 38579519)
37. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM et al (2008) A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA 105:7803-7808 (Pubitemid 351872719)
38. Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Nunez G (2000) An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275:27823-27831
39. Abbott DW, Wilkins A, Asara JM, Cantley LC (2004) The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 14:2217-2227 (Pubitemid 40033358)
40. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, Inohara N, Nunez G (2007) RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178:2380-2386 (Pubitemid 46233437)
41. Windheim M, Lang C, Peggie M, Plater LA, Cohen P (2007) Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J 404:179-190 (Pubitemid 46849589)
42. da Silva CJ, Miranda Y, Leonard N, Hsu J, Ulevitch RJ (2007) Regulation of Nod1-mediated signaling pathways. Cell Death Differ 14:830-839 (Pubitemid 46444520)
43. Kufer TA, Kremmer E, Banks DJ, Philpott DJ (2006) Role for erbin in bacterial activation of Nod2. Infect Immun 74:3115-3124 (Pubitemid 43794500)
44. McDonald C, Chen FF,OllendorffV,OguraY,Marchetto S, Lecine P, Borg JP, Nunez G (2005) A role for Erbin in the regulation of Nod2- dependent NF-kappaB signaling. J Biol Chem 280:40301-40309 (Pubitemid 41779167)
45. Hooper LV, Macpherson AJ (2010) Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev Immunol 10:159-169
46. Macpherson AJ, Uhr T (2004) Compartmentalization of the mucosal immune responses to commensal intestinal bacteria. Ann N Y Acad Sci 1029:36-43 (Pubitemid 40298513)
47. Bauer H, Horowitz RE, Levenson SM, Popper H (1963) The response of the lymphatic tissue to the microbial flora. Studies on germfree mice. Am J Pathol 42:471-483
48. Macpherson AJ, Hunziker L, McCoy K, Lamarre A (2001) IgA responses in the intestinal mucosa against pathogenic and nonpathogenic microorganisms. Microb Infect 3:1021-1035 (Pubitemid 32913701)
49. Macpherson AJ, Martinic MM, Harris N (2002) The functions of mucosal T cells in containing the indigenous commensal flora of the intestine. Cell Mol Life Sci 59:2088-2096 (Pubitemid 36140282)
50. Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H, Kobayashi KS (2009) Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci USA 106:15813-15818
51. Ouellette AJ, Bevins CL (2001) Paneth cell defensins and innate immunity of the small bowel. Inflam Bowel Dis 7:43-50
52. Wehkamp J, Fellermann K, Herrlinger KR, Bevins CL, Stange EF (2005) Mechanisms of disease: defensins in gastrointestinal diseases. Nat Clin Pract Gastroenterol Hepatol 2:406-415 (Pubitemid 41486093)
53. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S (2003) Crohn's disease and the NOD2 gene: a role for paneth cells. Gastroenterology 125:47-57 (Pubitemid 36799106)
54. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 105:20858-20863
55. Begue B, Dumant C, Bambou JC, Beaulieu JF, Chamaillard M, Hugot JP, Goulet O, Schmitz J, Philpott DJ, Cerf-Bensussan N et al (2006) Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop. J Cell Physiol 209:241-252 (Pubitemid 44484613)
56. Ogura Y, Lala S, Xin W, Smith E, Dowds TA, Chen FF, Zimmermann E, Tretiakova M, Cho JH, Hart J et al (2003) Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52:1591-1597 (Pubitemid 37363443)
57. Rehman A, Sina C, Gavrilova O, Hasler R, Ott S, Baines JF, Schreiber S, Rosenstiel P (2011) Nod2 is essential for temporal development of intestinal microbial communities. Gut (in press)
58. Sokol H, Seksik P, Rigottier-Gois L, Lay C, Lepage P, Podglajen I, Marteau P, Dore J (2006) Specificities of the fecal microbiota in inflammatory bowel disease. Inflam Bowel Dis 12:106-111
59. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, Nalin R, Jarrin C, Chardon P, Marteau P et al (2006) Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55:205-211 (Pubitemid 43117279)
60. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G et al (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105:16731-16736
61. Umesaki Y, Setoyama H (2000) Structure of the intestinal flora responsible for development of the gut immune system in a rodent model. Microb Infect 2:1343-1351
62. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417-429 (Pubitemid 34851835)
63. Shih DQ, Targan SR, McGovern D (2008) Recent advances in IBD pathogenesis: genetics and immunobiology. Curr Gastroenterol Rep 10:568-575
64. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42:1118-1125
65. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V et al (2002) CARD15/ NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845-857 (Pubitemid 34259301)
66. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M (2005) Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science 307:734-738 (Pubitemid 40194645)
67. Netea MG, Ferwerda G, de Jong DJ, Girardin SE, Kullberg BJ, van der Meer JW (2005) NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype. Neth J Med 63:305-308 (Pubitemid 41404265)
68. Netea MG, Ferwerda G, de Jong DJ, Werts C, Boneca IG, Jehanno M, Van Der Meer JW, Mengin-Lecreulx D, Sansonetti PJ, Philpott DJ, Dharancy S, Girardin SE (2005) The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2- but also Nod1-activating peptidoglycan agonists. J Biol Chem 280:35859-35867 (Pubitemid 41633853)
69. van Heel DA, Ghosh S, Butler M, Hunt KA, Lundberg AM, Ahmad T, McGovern DP, Onnie C, Negoro K, Goldthorpe S et al (2005) Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet 365:1794-1796 (Pubitemid 40744660)
70. Kramer M, Netea MG, de Jong DJ, Kullberg BJ, Adema GJ (2006) Impaired dendritic cell function in Crohn's disease patients with NOD2 3020insC mutation. J Leukoc Biol 79:860-866 (Pubitemid 44835619)
71. Watanabe T, Kitani A, Murray PJ, Strober W (2004) NOD2 negative regulator of Toll-like receptor 2 is a-mediated T helper type 1 responses. Nat Immunol 5:800-808 (Pubitemid 39172973)
72. Watanabe T, Kitani A, Murray PJ, Wakatsuki Y, Fuss IJ, Strober W (2006) Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigenspecific colitis. Immunity 25:473-485 (Pubitemid 44355006)
73. Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev 3:521-533 (Pubitemid 37328672)
74. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731-734 (Pubitemid 40194644)
75. Rosenzweig HL, Jann MJ, Vance EE, Planck SR, Rosenbaum JT, Davey MP (2010) Nucleotide-binding oligomerization domain 2 and Toll-like receptor 2 function independently in a murine model of arthritis triggered by intraarticular peptidoglycan. Arthritis Rheum 62:1051-1059
76. Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ, Kitani A, Strober W (2008) Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Investig 118:545-559 (Pubitemid 351206545)
77. Petnicki-Ocwieja T, DeFrancesco AS, Chung E, Darcy CT, Bronson RT, Kobayashi KS, Hu LT (2011) Nod2 suppresses Borrelia burgdorferi mediated murine Lyme arthritis and carditis through the induction of tolerance. PloS one 6:e17414
78. Hedl M, Li J, Cho JH, Abraham C (2007) Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci USA 104:19440-19445
79. Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ (2000) Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 1:113-118
80. Gasche C, Grundtner P (2005) Genotypes and phenotypes in Crohn's disease: do they help in clinical management? Gut 54:162-167 (Pubitemid 40007237)
81. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P et al (2004) NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53:1658-1664 (Pubitemid 39434112)
82. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R et al (2005) Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci USA 102:18129-18134 (Pubitemid 41798513)
83. Simms LA, Doecke JD, Walsh MD, Huang N, Fowler EV, Radford-Smith GL (2008) Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease. Gut 57:903-910 (Pubitemid 351919524)
84. Perminow G, Beisner J, Koslowski M, Lyckander LG, Stange E, Vatn MH, Wehkamp J (2009) Defective Paneth cell-mediated host defense in pediatric ileal Crohn's disease. Am J Gastroenterol 105:452-459
85. Bevins CL, Stange EF, Wehkamp J (2009) Decreased Paneth cell defensin expression in ileal Crohn's disease is independent of inflammation, but linked to the NOD2 1007 fs genotype. Gut 58:882-883, discussion 883-884
86. Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL, Kobayashi KS (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci USA 107:14739-14744
87. Noguchi E, Homma Y, Kang X, Netea MG, Ma X (2009) A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol 10:471-479
88. Netea MG, Kullberg BJ, de Jong DJ, Franke B, Sprong T, Naber TH, Drenth JP, Van der Meer JW (2004) NOD2 mediates antiinflammatory signals induced by TLR2 ligands: implications for Crohn's disease. Eur J Immunol 34:2052-2059 (Pubitemid 39256086)
89. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med 16:90-97
90. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, Yuan L, Soares F, Chea E, Le Bourhis L et al (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11:55-62
91. Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C (2010) ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology 139:1630-1641, 1641 e1631-1632