Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot Password? Reset your password

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login (Shibboleth)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Table of Contents
Vol. 28, No. 3, 2010
Issue release date: October 2010
Section title: Impact of New Keys in Pathophysiology on IBD Treatment
Free Access
Dig Dis 2010;28:395–405
(DOI:10.1159/000320393)

Genes and Environment: How Will Our Concepts on the Pathophysiology of IBD Develop in the Future?

Kaser A.a · Zeissig S.b · Blumberg R.S.c
aDepartment of Medicine II (Gastroenterology and Hepatology), Innsbruck Medical University, Innsbruck, Austria; bFirst Medical Department, Christina Albrechts University, Kiel, Germany; cDivision of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass., USA
email Corresponding Author

Richard S. Blumberg

Division of Gastroenterology, Brigham and Women’s Hospital

Harvard Medical School, 75 Francis Street

Boston, MA 02115 (USA)

Tel. +1 617 732 6917, Fax +1 617 264 5185, E-Mail rblumberg@partners.org


References

  1. Crohn BB, Ginzburg L, Oppenheimer GD: Regional ileitis: a pathologic and clinical entity. 1932. Mt Sinai J Med 2000;67:263–268.
  2. Greenstein RJ: Is Crohn’s disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne’s disease. Lancet Infect Dis 2003;3:507–514.
  3. Kaser A, Zeissig S, Blumberg RS: Inflammatory bowel disease. Annu Rev Immunol 2010;28:573–621.
  4. Halme L, Paavola-Sakki P, Turunen U, Lappalainen M, Farkkila M, Kontula K: Family and twin studies in inflammatory bowel disease. World J Gastroenterol 2006;12:3668–3672.
  5. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M: Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005;102:10604–10609.
  6. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20–21.
  7. Maillard MH, Cotta-de-Almeida V, Takeshima F, Nguyen DD, Michetti P, Nagler C, Bhan AK, Snapper SB: The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med 2007;204:381–391.
  8. Marangoni F, Trifari S, Scaramuzza S, Panaroni C, Martino S, Notarangelo LD, Baz Z, Metin A, Cattaneo F, Villa A, Aiuti A, Battaglia M, Roncarolo MG, Dupre L: WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J Exp Med 2007;204:369–380.
  9. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009;361:2033–2045.
  10. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W: Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993;75:263–274.
  11. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ: Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008;40:955–962.
  12. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A: IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008;118:534–544.
  13. Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, Cui Y, Yan XX, Yang HT, Yang RD, Chu TS, Zhang C, Zhang L, Han JW, Yu GQ, Quan C, Yu YX, Zhang Z, Shi BQ, Zhang LH, Cheng H, Wang CY, Lin Y, Zheng HF, Fu XA, Zuo XB, Wang Q, Long H, Sun YP, Cheng YL, Tian HQ, Zhou FS, Liu HX, Lu WS, He SM, Du WL, Shen M, Jin QY, Wang Y, Low HQ, Erwin T, Yang NH, Li JY, Zhao X, Jiao YL, Mao LG, Yin G, Jiang ZX, Wang XD, Yu JP, Hu ZH, Gong CH, Liu YQ, Liu RY, Wang DM, Wei D, Liu JX, Cao WK, Cao HZ, Li YP, Yan WG, Wei SY, Wang KJ, Hibberd ML, Yang S, Zhang XJ, Liu JJ: Genomewide association study of leprosy. N Engl J Med 2009;361:2609–2618.
  14. Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H, Kobayashi KS: Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci USA 2009;106:15813–15818.
  15. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS, Virgin HWt: A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 2008;456:259–263.
  16. Lewin K: The Paneth cell in disease. Gut 1969;10:804–811.
  17. Lakatos PL: Environmental factors affecting inflammatory bowel disease: have we made progress? Dig Dis 2009;27:215–225.
  18. Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, Finlay BB: Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2007;2:204.
  19. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–1031.
  20. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI: A core gut microbiome in obese and lean twins. Nature 2009;457:480–484.
  21. Dethlefsen L, Huse S, Sogin ML, Relman DA: The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 2008;6:e280.
  22. Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, Bushman FD, Artis D: Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol 2010;3:148–158.
  23. Beaudet AL: Epigenetics and complex human disease: is there a role in IBD? J Pediatr Gastroenterol Nutr 2008;46(suppl 1):E2.
    External Resources
  24. Sartor RB: Microbial influences in inflammatory bowel diseases. Gastroenterology 2008;134:577–594.
  25. Boirivant M, Amendola A, Butera A: Intestinal microflora and immunoregulation. Mucosal Immunol 2008;1(suppl 1):S47–S49.
    External Resources
  26. Rahimi R, Nikfar S, Rezaie A, Abdollahi M: A meta-analysis of antibiotic therapy for active ulcerative colitis. Dig Dis Sci 2007;52:2920–2925.
  27. Rahimi R, Nikfar S, Rezaie A, Abdollahi M: A meta-analysis of broad-spectrum antibiotic therapy in patients with active Crohn’s disease. Clin Ther 2006;28:1983–1988.
  28. Strober W, Fuss IJ, Blumberg RS: The immunology of mucosal models of inflammation. Annu Rev Immunol 2002;20:495–549.
  29. Garrett WS, Gordon JI, Glimcher LH: Homeostasis and inflammation in the intestine. Cell 2010;140:859–870.
  30. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Jian M, Zhou Y, Li Y, Zhang X, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Bork P, Ehrlich SD: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59–65.
  31. Ley RE, Peterson DA, Gordon JI: Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006;124:837–848.
  32. Ha EM, Lee KA, Seo YY, Kim SH, Lim JH, Oh BH, Kim J, Lee WJ: Coordination of multiple dual oxidase-regulatory pathways in responses to commensal and infectious microbes in drosophila gut. Nat Immunol 2009;10:949–957.
  33. Ha EM, Oh CT, Bae YS, Lee WJ: A direct role for dual oxidase in Drosophila gut immunity. Science 2005;310:847–850.
  34. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW, Shugart YY, Griffiths AM, Targan SR, Ippoliti AF, Bernard EJ, Mei L, Nicolae DL, Regueiro M, Schumm LP, Steinhart AH, Rotter JI, Duerr RH, Cho JH, Daly MJ, Brant SR: Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604.
  35. Macpherson AJ, Uhr T: Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662–1665.
  36. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA: Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731–734.
  37. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV: Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 2008;105:20858–20863.
  38. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL: Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 2003;422:522–526.
  39. Wehkamp J, Fellermann K, Stange EF: Human defensins in Crohn’s disease. Chem Immunol Allergy 2005;86:42–54.
  40. Vaishnava S, Behrendt CL, Hooper LV: Innate immune responses to commensal bacteria in the gut epithelium. J Pediatr Gastroenterol Nutr 2008;46(suppl 1):E10–E11.
    External Resources
  41. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS: XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743–756.
  42. Wehkamp J, Wang G, Kubler I, Nuding S, Gregorieff A, Schnabel A, Kays RJ, Fellermann K, Burk O, Schwab M, Clevers H, Bevins CL, Stange EF: The Paneth cell alpha-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. J Immunol 2007;179:3109–3118.
  43. 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 2001;411:599–603.
  44. He C, Klionsky DJ: Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67–93.
  45. Mizushima N, Levine B, Cuervo AM, Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069–1075.
  46. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Gunther S, Prescott NJ, Onnie CM, Hasler R, Sipos B, Folsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S: A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007;39:207–211.
  47. Meylan E, Tschopp J, Karin M: Intracellular pattern recognition receptors in the host response. Nature 2006;442:39–44.
  48. Abbott DW, Yang Y, Hutti JE, Madhavarapu S, Kelliher MA, Cantley LC: Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol 2007;27:6012–6025.
  49. Abbott DW, Wilkins A, Asara JM, Cantley LC: The Crohn’s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 2004;14:2217–2227.
  50. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G: Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001;276:4812–4818.
  51. 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: CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002;70:845–857.
  52. Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ, Kitani A, Strober W: Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest 2008;118:545–559.
  53. Watanabe T, Kitani A, Murray PJ, Wakatsuki Y, Fuss IJ, Strober W: Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 2006;25:473–485.
  54. 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 2004;5:800–808.
  55. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A: NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010;16:90–97.
  56. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima H Jr, Fellermann K, Ganz T, Stange EF, Bevins CL: Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA 2005;102:18129–18134.
  57. Ron D, Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519–529.
  58. Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N, Zeitlmann L, Grosse J, Ruf N, Nurnberg P, Costello CM, Onnie C, Mathew C, Platzer M, Schreiber S, Hampe J: Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun 2006;7:11–18.
  59. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R: The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet 2010;19:111–121.
  60. Zhao F, Edwards R, Dizon D, Afrasiabi K, Mastroianni JR, Geyfman M, Ouellette AJ, Andersen B, Lipkin SM: Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2–/– mice. Dev Biol 2010;338:270–279.
  61. Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D, Thornton DJ, Png CW, Crockford TL, Cornall RJ, Adams R, Kato M, Nelms KA, Hong NA, Florin TH, Goodnow CC, McGuckin MA: Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 2008;5:e54.
  62. Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, Brandewie JR, Taurog JD, Colbert RA: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 2005;175:2438–2448.
  63. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR: Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:1282–1286.
  64. Rubin DT, Hanauer SB: Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12:855–862.
  65. Kikuchi H, Itoh J, Fukuda S: Chronic nicotine stimulation modulates the immune response of mucosal T cells to Th1-dominant pattern via nAChR by upregulation of Th1-specific transcriptional factor. Neurosci Lett 2008;432:217–221.
  66. Andersson RE, Olaison G, Tysk C, Ekbom A: Appendectomy and protection against ulcerative colitis. N Engl J Med 2001;344:808–814.
  67. Bhan AK, Mizoguchi E, Smith RN, Mizoguchi A: Spontaneous chronic colitis in TCR alpha-mutant mice; an experimental model of human ulcerative colitis. Int Rev Immunol 2000;19:123–138.
  68. Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK: Role of appendix in the development of inflammatory bowel disease in TCR-alpha mutant mice. J Exp Med 1996;184:707–715.
  69. Singh S, Graff LA, Bernstein CN: Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am J Gastroenterol 2009;104:1298–1313; quiz 1314.
  70. Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN, Glimcher LH: Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 2007;131:33–45.
  71. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR: Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA 2007;104:13780–13785.
  72. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottiere HM, Dore J, Marteau P, Seksik P, Langella P: Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:16731–16736.
  73. Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY, Knight R, Ahima RS, Bushman F, Wu GD: High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009;137:1716-24e1–2.
  74. Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, Siminovitch KA: Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004;36:471–475.
  75. Foster DW: The role of the carnitine system in human metabolism. Ann NY Acad Sci 2004;1033:1–16.
  76. Shekhawat PS, Srinivas SR, Matern D, Bennett MJ, Boriack R, George V, Xu H, Prasad PD, Roon P, Ganapathy V: Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2(–/–)) mice. Mol Genet Metab 2007;92:315–324.