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  • Review Article
  • Published:

Epidemiology and risk factors for IBD

Key Points

  • Crohn's disease and ulcerative colitis are complex immunologically mediated diseases that arise due to a dysregulated immune response to commensal flora in a genetically susceptible host

  • The incidence of IBD has traditionally been highest in North America and Western Europe with many cohorts suggesting a substantial secular increase over the second half of the twentieth century

  • However, incidence of IBD is increasing in emerging populations such as Asia, suggesting that changing environmental factors play an important part

  • Smoking and appendectomy were initially described to increase the risk of Crohn's disease and confer protection from ulcerative colitis; however, this relationship seems more complex and could be mediated by genetics

  • Diet, lifestyle and behaviour, as well as perturbations of the gut microbiota through use of antibiotics, might also have important roles in disease pathogenesis

  • Modification of IBD risk factors offer avenues of intervention for disease prevention and improvement of natural history

Abstract

IBD, comprising Crohn's disease and ulcerative colitis, is a chronic immunologically mediated disease at the intersection of complex interactions between genetics, environment and gut microbiota. Established high-prevalence populations of IBD in North America and Europe experienced the steepest increase in incidence towards the second half of the twentieth century. Furthermore, populations previously considered 'low risk' (such as in Japan and India) are witnessing an increase in incidence. Potentially relevant environmental influences span the spectrum of life from mode of childbirth and early-life exposures (including breastfeeding and antibiotic exposure in infancy) to exposures later on in adulthood (including smoking, major life stressors, diet and lifestyle). Data support an association between smoking and Crohn's disease whereas smoking cessation, but not current smoking, is associated with an increased risk of ulcerative colitis. Dietary fibre (particularly fruits and vegetables), saturated fats, depression and impaired sleep, and low vitamin D levels have all been associated with incident IBD. Interventional studies assessing the effects of modifying these risk factors on natural history and patient outcomes are an important unmet need. In this Review, the changing epidemiology of IBD, mechanisms behind various environmental associations and interventional studies to modify risk factors and disease course are discussed.

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Figure 1: The interaction between genetics, immunology, environment and microbiome.
Figure 2: Global map of IBD in established and emerging populations.

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References

  1. Cosnes, J. et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140, 1785–1794 (2011).

    PubMed  Google Scholar 

  2. Loftus, E. V. Jr Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004).

    PubMed  Google Scholar 

  3. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066–2078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54.e42 (2012).

    PubMed  Google Scholar 

  5. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    CAS  PubMed  Google Scholar 

  6. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    CAS  PubMed  Google Scholar 

  7. Jostins, L. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Loftus, E. V. Jr. et al. Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gut 46, 336–343 (2000).

    PubMed  PubMed Central  Google Scholar 

  9. Loftus, E. V. Jr. et al. Crohn's disease in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gastroenterology 114, 1161–1168 (1998).

    PubMed  Google Scholar 

  10. Loftus, C. G. et al. Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940–2000. Inflamm. Bowel Dis. 13, 254–261 (2007).

    PubMed  Google Scholar 

  11. Nerich, V. et al. Geographical variations of inflammatory bowel disease in France: a study based on national health insurance data. Inflamm. Bowel Dis. 12, 218–226 (2006).

    PubMed  Google Scholar 

  12. Khalili, H. et al. Geographical variation and incidence of inflammatory bowel disease among US women. Gut 61, 1686–1692 (2012).

    PubMed  PubMed Central  Google Scholar 

  13. Gearry, R. B. et al. High incidence of Crohn's disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm. Bowel Dis. 12, 936–943 (2006).

    PubMed  Google Scholar 

  14. Bernstein, C. N. et al. Assessing inflammatory bowel disease-associated antibodies in Caucasian and First Nations cohorts. Can. J. Gastroenterol. 25, 269–273 (2011).

    PubMed  PubMed Central  Google Scholar 

  15. Odes, H. S. et al. Inflammatory bowel disease in the Bedouin Arabs of southern Israel: rarity of diagnosis and clinical features. Gut 32, 1024–1026 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bernstein, C. N. et al. A population-based case control study of potential risk factors for IBD. Am. J. Gastroenterol. 101, 993–1002 (2006).

    PubMed  Google Scholar 

  17. Mahid, S. S. et al. Inflammatory bowel disease and African Americans: a systematic review. Inflamm. Bowel Dis. 14, 960–967 (2008).

    PubMed  Google Scholar 

  18. Reddy, S. I. & Burakoff, R. Inflammatory bowel disease in African Americans. Inflamm. Bowel Dis. 9, 380–385 (2003).

    PubMed  Google Scholar 

  19. Thia, K. T. et al. An update on the epidemiology of inflammatory bowel disease in Asia. Am. J. Gastroenterol. 103, 3167–3182 (2008).

    PubMed  Google Scholar 

  20. Ng, S. C. et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia–Pacific Crohn's and colitis epidemiology study. Gastroenterology 145, 158–165.e2 (2013).

    PubMed  Google Scholar 

  21. Archampong, T. N. & Nkrumah, K. N. Inflammatory bowel disease in Accra: what new trends. West Afr. J. Med. 32, 40–44 (2013).

    CAS  PubMed  Google Scholar 

  22. Ukwenya, A. Y. et al. Inflammatory bowel disease in Nigerians: still a rare diagnosis? Ann. Afr. Med. 10, 175–179 (2011).

    CAS  PubMed  Google Scholar 

  23. Al-Mofarreh, M. A. & Al-Mofleh, I. A. Emerging inflammatory bowel disease in Saudi outpatients: a report of 693 cases. Saudi J. Gastroenterol. 19, 16–22 (2013).

    PubMed  PubMed Central  Google Scholar 

  24. Sood, A. & Midha, V. Epidemiology of inflammatory bowel disease in Asia. Indian J. Gastroenterol. 26, 285–289 (2007).

    PubMed  Google Scholar 

  25. Probert, C. S. et al. Epidemiological study of ulcerative proctocolitis in Indian migrants and the indigenous population of Leicestershire. Gut 33, 687–693 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Probert, C. S. et al. Prevalence and family risk of ulcerative colitis and Crohn's disease: an epidemiological study among Europeans and south Asians in Leicestershire. Gut 34, 1547–1551 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, X. et al. Risk of inflammatory bowel disease in first- and second-generation immigrants in Sweden: a nationwide follow-up study. Inflamm. Bowel Dis. 17, 1784–1791 (2011).

    PubMed  Google Scholar 

  28. Pinsk, V. et al. Inflammatory bowel disease in the South Asian pediatric population of British Columbia. Am. J. Gastroenterol. 102, 1077–1083 (2007).

    PubMed  Google Scholar 

  29. Benchimol, E. I. et al. O-004 Inflammatory Bowel Disease in Immigrants to Canada and their Children: a Population-Based Cohort Study. Inflamm. Bowel Dis. 20 (Suppl. 1) S3–S4 (2014).

    Google Scholar 

  30. Damas, O. M. et al. Phenotypic manifestations of inflammatory bowel disease differ between Hispanics and non-Hispanic whites: results of a large cohort study. Am. J. Gastroenterol. 108, 231–239 (2013).

    PubMed  Google Scholar 

  31. Halme, L. et al. Family and twin studies in inflammatory bowel disease. World J. Gastroenterol. 12, 3668–3672 (2006).

    PubMed  PubMed Central  Google Scholar 

  32. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu, J. Z. & Anderson, C. A. Genetic studies of Crohn's disease: past, present and future. Best Pract. Res. Clin. Gastroenterol. 28, 373–386 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. Orholm, M. et al. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand. J. Gastroenterol. 35, 1075–1081 (2000).

    CAS  PubMed  Google Scholar 

  35. Russell, R. K. & Satsangi, J. IBD: a family affair. Best Pract. Res. Clin. Gastroenterol. 18, 525–539 (2004).

    CAS  PubMed  Google Scholar 

  36. Thompson, N. P. et al. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 312, 95–96 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tysk, C. et al. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29, 990–996 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang, H. et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 34, 517–524 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Halfvarson, J. et al. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology 124, 1767–1773 (2003).

    PubMed  Google Scholar 

  40. Hugot, J. P. et al. Mapping a susceptibility locus for Crohn's disease on chromosome 16. Nature 29, 821–823 (1996).

    Google Scholar 

  41. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. VanDussen, K. L. et al. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease. Gastroenterology 146, 200–209 (2014).

    CAS  PubMed  Google Scholar 

  43. Van Limbergen, J., Radford-Smith, G. & Satsangi, J. Advances in IBD genetics. Nat. Rev. Gastroenterol. Hepatol. 11, 372–385 (2014).

    CAS  PubMed  Google Scholar 

  44. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15, 382–392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kostic, A. D., Xavier, R. J. & Gevers, D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146, 1489–1499 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Morgan, X. C. et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Nagalingam, N. A. & Lynch, S. V. Role of the microbiota in inflammatory bowel diseases. Inflamm. Bowel Dis. 18, 968–984 (2012).

    PubMed  Google Scholar 

  49. Manichanh, C. et al. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599–608 (2012).

    CAS  PubMed  Google Scholar 

  50. Castiglione, F. et al. Risk factors for inflammatory bowel diseases according to the “hygiene hypothesis”: a case-control, multi-centre, prospective study in Southern Italy. J. Crohns Colitis 6, 324–329 (2012).

    PubMed  Google Scholar 

  51. Ng, S. C. et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia–Pacific. Gut http://dx.doi.org/10.1136/gutjnl-2014-307410.

  52. Timm, S. et al. Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe. Eur. J. Epidemiol. 29, 429–437 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. Willing, B. P. et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139, 1844–1854.e1 (2010).

    PubMed  Google Scholar 

  54. Lepage, P. et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141, 227–236 (2011).

    PubMed  Google Scholar 

  55. Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 127, 412–421 (2004).

    PubMed  Google Scholar 

  56. Martin, R. et al. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm. Bowel Dis. 20, 417–430 (2014).

    PubMed  Google Scholar 

  57. Sokol, H. et al. 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 (2008).

    CAS  PubMed  Google Scholar 

  58. Sokol, H. et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183–1189 (2009).

    CAS  PubMed  Google Scholar 

  59. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    CAS  PubMed  Google Scholar 

  61. Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Iliev, I. D. et al. Interaction between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 8, 1314–1347 (2012).

    Google Scholar 

  63. Harries, A. D., Baird, A. & Rhodes, J. Non-smoking: a feature of ulcerative colitis. Br. Med. J. (Clin. Res. Ed.) 284, 706 (1982).

    CAS  Google Scholar 

  64. Mahid, S. S. et al. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin. Proc. 81, 1462–1471 (2006).

    PubMed  Google Scholar 

  65. Higuchi, L. M. et al. A prospective study of cigarette smoking and the risk of inflammatory bowel disease in women. Am. J. Gastroenterol. 107, 1399–1406 (2012).

    PubMed  PubMed Central  Google Scholar 

  66. Mahid, S. S. et al. Active and passive smoking in childhood is related to the development of inflammatory bowel disease. Inflamm. Bowel Dis. 13, 431–438 (2007).

    PubMed  Google Scholar 

  67. Odes, H. S. et al. Effects of current cigarette smoking on clinical course of Crohn's disease and ulcerative colitis. Dig. Dis. Sci. 46, 1717–1721 (2001).

    CAS  PubMed  Google Scholar 

  68. Cosnes, J. et al. Gender differences in the response of colitis to smoking. Clin. Gastroenterol. Hepatol. 2, 41–48 (2004).

    PubMed  Google Scholar 

  69. Cosnes, J. What is the link between the use of tobacco and IBD? Inflamm. Bowel Dis. 14 (Suppl. 2) S14–S15 (2008).

    PubMed  Google Scholar 

  70. Cosnes, J. et al. Effects of cigarette smoking on the long-term course of Crohn's disease. Gastroenterology 110, 424–431 (1996).

    CAS  PubMed  Google Scholar 

  71. Cosnes, J. et al. Effects of current and former cigarette smoking on the clinical course of Crohn's disease. Aliment. Pharmacol. Ther. 13, 1403–1411 (1999).

    CAS  PubMed  Google Scholar 

  72. Lakatos, P. L., Szamosi, T. & Lakatos, L. Smoking in inflammatory bowel diseases: good, bad or ugly? World J. Gastroenterol. 13, 6134–6139 (2007).

    PubMed  PubMed Central  Google Scholar 

  73. Cosnes, J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract. Res. Clin. Gastroenterol. 18, 481–496 (2004).

    CAS  PubMed  Google Scholar 

  74. Birrenbach, T. & Bocker, U. Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications. Inflamm. Bowel Dis. 10, 848–859 (2004).

    PubMed  Google Scholar 

  75. Persson, P. G., Hellers, G. & Ahlbom, A. Use of oral moist snuff and inflammatory bowel disease. Int. J. Epidemiol. 22, 1101–1103 (1993).

    CAS  PubMed  Google Scholar 

  76. Hatoum, O. A., Heidemann, J. & Binion, D. G. The intestinal microvasculature as a therapeutic target in inflammatory bowel disease. Ann. NY Acad. Sci. 1072, 78–97 (2006).

    CAS  PubMed  Google Scholar 

  77. McGilligan, V. E. et al. Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis. Inflamm. Bowel Dis. 13, 108–115 (2007).

    PubMed  Google Scholar 

  78. Bergeron, V. et al. Current smoking differentially affects blood mononuclear cells from patients with Crohn's disease and ulcerative colitis: relevance to its adverse role in the disease. Inflamm. Bowel Dis. 18, 1101–1111 (2012).

    PubMed  Google Scholar 

  79. Ananthakrishnan, A. N. et al. Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases. Inflamm. Bowel Dis. 20, 783–789 (2014).

    PubMed  PubMed Central  Google Scholar 

  80. Biedermann, L. et al. Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH. Inflamm. Bowel Dis. 20, 1496–1501 (2014).

    PubMed  Google Scholar 

  81. Munyaka, P. M., Khafipour, E. & Ghia, J. E. External influence of early childhood establishment of gut microbiota and subsequent health implications. Front. Pediatr. 2, 109 (2014).

    PubMed  PubMed Central  Google Scholar 

  82. Parkes, G. C., Whelan, K. & Lindsay, J. O. Smoking in inflammatory bowel disease: impact on disease course and insights into the aetiology of its effect. J. Crohns Colitis 8, 717–725 (2014).

    PubMed  Google Scholar 

  83. Andersson, R. E. et al. Appendectomy and protection against ulcerative colitis. N. Engl. J. Med. 344, 808–814 (2001).

    CAS  PubMed  Google Scholar 

  84. Andersson, R. E. et al. Appendectomy is followed by increased risk of Crohn's disease. Gastroenterology 124, 40–46 (2003).

    PubMed  Google Scholar 

  85. Kaplan, G. G. et al. The risk of developing Crohn's disease after an appendectomy: a meta-analysis. Am. J. Gastroenterol. 103, 2925–2931 (2008).

    PubMed  Google Scholar 

  86. Cosnes, J. et al. Prior appendectomy and the phenotype and course of Crohn's disease. World J. Gastroenterol. 12, 1235–1242 (2006).

    PubMed  PubMed Central  Google Scholar 

  87. Gardenbroek, T. J. et al. The effect of appendectomy on the course of ulcerative colitis: a systematic review. Colorectal Dis. 14, 545–553 (2012).

    CAS  PubMed  Google Scholar 

  88. Radford-Smith, G. L. What is the importance of appendectomy in the natural history of IBD? Inflamm. Bowel Dis. 14 (Suppl. 2), S72–S74 (2008).

    PubMed  Google Scholar 

  89. Radford-Smith, G. L. et al. Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn's disease. Gut 51, 808–813 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Radon, K. et al. Contact with farm animals in early life and juvenile inflammatory bowel disease: a case–control study. Pediatrics 120, 354–361 (2007).

    PubMed  Google Scholar 

  92. Van Kruiningen, H. J. et al. Environmental factors in familial Crohn's disease in Belgium. Inflamm. Bowel Dis. 11, 360–365 (2005).

    PubMed  Google Scholar 

  93. Barclay, A. R. et al. Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease. J. Pediatr. 155, 421–426 (2009).

    PubMed  Google Scholar 

  94. Bager, P. et al. Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study. Inflamm. Bowel Dis. 18, 857–862 (2012).

    PubMed  Google Scholar 

  95. Sood, A. et al. Low hygiene and exposure to infections may be associated with increased risk for ulcerative colitis in a North Indian population. Ann. Gastroenterol. 27, 219–223 (2014).

    PubMed  PubMed Central  Google Scholar 

  96. Bernstein, C. N. et al. Population-based case control study of seroprevalence of Mycobacterium paratuberculosis in patients with Crohn's disease and ulcerative colitis. J. Clin. Microbiol. 42, 1129–1135 (2004).

    PubMed  PubMed Central  Google Scholar 

  97. Chacon, O., Bermudez, L. E. & Barletta, R. G. Johne's disease, inflammatory bowel disease, and Mycobacterium paratuberculosis. Annu. Rev. Microbiol. 58, 329–363 (2004).

    CAS  PubMed  Google Scholar 

  98. Feller, M. et al. Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. Lancet Infect. Dis. 7, 607–613 (2007).

    PubMed  Google Scholar 

  99. Selby, W. et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology 132, 2313–2319 (2007).

    CAS  PubMed  Google Scholar 

  100. Gradel, K. O. et al. Increased short- and long-term risk of inflammatory bowel disease after salmonella or campylobacter gastroenteritis. Gastroenterology 137, 495–501 (2009).

    PubMed  Google Scholar 

  101. Porter, C. K. et al. Infectious gastroenteritis and risk of developing inflammatory bowel disease. Gastroenterology 135, 781–786 (2008).

    PubMed  Google Scholar 

  102. Garcia Rodriguez, L. A., Ruigomez, A. & Panes, J. Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease. Gastroenterology 130, 1588–1594 (2006).

    PubMed  Google Scholar 

  103. Jess, T. et al. Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease. Gut 60, 318–324 (2011).

    PubMed  Google Scholar 

  104. Thompson, N. P. et al. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet 345, 1071–1074 (1995).

    CAS  PubMed  Google Scholar 

  105. Bernstein, C. N., Rawsthorne, P. & Blanchard, J. F. Population-based case–control study of measles, mumps, and rubella and inflammatory bowel disease. Inflamm. Bowel Dis. 13, 759–762 (2007).

    PubMed  Google Scholar 

  106. Davis, R. L. et al. Measles-mumps-rubella and other measles-containing vaccines do not increase the risk for inflammatory bowel disease: a case–control study from the Vaccine Safety Datalink project. Arch. Pediatr. Adolesc. Med. 155, 354–359 (2001).

    CAS  PubMed  Google Scholar 

  107. Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ananthakrishnan, A. N., Issa, M. & Binion, D. G. Clostridium difficile and inflammatory bowel disease. Gastroenterol. Clin. North Am. 38, 711–728 (2009).

    PubMed  Google Scholar 

  109. Singh, S., Graff, L. A. & Bernstein, C. N. Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am. J. Gastroenterol. 104, 1298–1313 (2009).

    CAS  PubMed  Google Scholar 

  110. Penders, J. et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118, 511–521 (2006).

    PubMed  Google Scholar 

  111. Shaw, S. Y., Blanchard, J. F. & Bernstein, C. N. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am. J. Gastroenterol. 105, 2687–2692 (2010).

    PubMed  Google Scholar 

  112. Virta, L. et al. Association of repeated exposure to antibiotics with the development of pediatric Crohn's disease—a nationwide, register-based finnish case–control study. Am. J. Epidemiol. 175, 775–784 (2012).

    PubMed  Google Scholar 

  113. Shaw, S. Y., Blanchard, J. F. & Bernstein, C. N. Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis. Am. J. Gastroenterol. 106, 2133–2142 (2011).

    PubMed  Google Scholar 

  114. Kronman, M. P. et al. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130, e794–e803 (2012).

    PubMed  PubMed Central  Google Scholar 

  115. Chan, S. S. et al. Aspirin in the aetiology of Crohn's disease and ulcerative colitis: a European prospective cohort study. Aliment. Pharmacol. Ther. 34, 649–655 (2011).

    CAS  PubMed  Google Scholar 

  116. Ananthakrishnan, A. N. et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann. Intern. Med. 156, 350–359 (2012).

    PubMed  PubMed Central  Google Scholar 

  117. Cornish, J. A. et al. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am. J. Gastroenterol. 103, 2394–2400 (2008).

    PubMed  Google Scholar 

  118. Khalili, H. et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut 62, 1153–1159 (2013).

    CAS  PubMed  Google Scholar 

  119. Khalili, H. et al. Hormone therapy increases risk of ulcerative colitis but not Crohn's disease. Gastroenterology 143, 1199–1206 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Chapman-Kiddell, C. A., Davies, P. S., Gillen, L. & Radford-Smith, G. L. Role of diet in the development of inflammatory bowel disease. Inflamm. Bowel Dis. 16, 137–151 (2010).

    PubMed  Google Scholar 

  121. Hou, J. K., Abraham, B. & El-Serag, H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am. J. Gastroenterol. 106, 563–573 (2011).

    CAS  PubMed  Google Scholar 

  122. Amre, D. K. et al. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children. Am. J. Gastroenterol. 102, 2016–2025 (2007).

    CAS  PubMed  Google Scholar 

  123. Ananthakrishnan, A. N. et al. A prospective study of long-term intake of dietary fiber and risk of Crohn's disease and ulcerative colitis. Gastroenterology 145, 970–977 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Galvez, J., Rodriguez-Cabezas, M. E. & Zarzuelo, A. Effects of dietary fiber on inflammatory bowel disease. Mol. Nutr. Food Res. 49, 601–608 (2005).

    PubMed  Google Scholar 

  125. Roberts, C. L. et al. Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut 59, 1331–1339 (2010).

    PubMed  PubMed Central  Google Scholar 

  126. Ananthakrishnan, A. N. et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease. Gut 63, 776–784 (2014).

    CAS  PubMed  Google Scholar 

  127. de Silva, P. S. et al. An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis. Gastroenterology 139, 1912–1917 (2010).

    CAS  PubMed  Google Scholar 

  128. D'Souza, S. et al. Dietary patterns and risk for Crohn's disease in children. Inflamm. Bowel Dis. 14, 367–373 (2008).

    PubMed  Google Scholar 

  129. Geerling, B. J. et al. Diet as a risk factor for the development of ulcerative colitis. Am. J. Gastroenterol. 95, 1008–1013 (2000).

    CAS  PubMed  Google Scholar 

  130. Hart, A. R. et al. Diet in the aetiology of ulcerative colitis: a European prospective cohort study. Digestion 77, 57–64 (2008).

    PubMed  Google Scholar 

  131. John, S. et al. Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: a UK prospective cohort study. Eur. J. Gastroenterol. Hepatol. 22, 602–606 (2010).

    CAS  PubMed  Google Scholar 

  132. Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Cabre, E. & Domenech, E. Impact of environmental and dietary factors on the course of inflammatory bowel disease. World J. Gastroenterol. 18, 3814–3822 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Costea, I. et al. Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease. Gastroenterology 146, 929–931 (2014).

    CAS  PubMed  Google Scholar 

  135. Jantchou, P. et al. Animal protein intake and risk of inflammatory bowel disease: the E3N prospective study. Am. J. Gastroenterol. 105, 2195–201 (2010).

    CAS  PubMed  Google Scholar 

  136. Chan, S. S. et al. Carbohydrate intake in the etiology of Crohn's disease and ulcerative colitis. Inflamm. Bowel Dis. 20, 2013–2021 (2014).

    PubMed  PubMed Central  Google Scholar 

  137. Zallot, C. et al. Dietary beliefs and behavior among inflammatory bowel disease patients. Inflamm. Bowel Dis. 19, 66–72 (2013).

    PubMed  Google Scholar 

  138. Cantorna, M. T. & Mahon, B. D. D-hormone and the immune system. J. Rheumatol. Suppl. 76, 11–20 (2005).

    CAS  PubMed  Google Scholar 

  139. Cantorna, M. T. & Mahon, B. D. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp. Biol. Med. (Maywood) 229, 1136–1142 (2004).

    CAS  Google Scholar 

  140. Cantorna, M. T. et al. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 80, 1717S–1720S (2004).

    CAS  PubMed  Google Scholar 

  141. Cantorna, M. T. et al. 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J. Nutr. 130, 2648–2652 (2000).

    CAS  PubMed  Google Scholar 

  142. Froicu, M. & Cantorna, M. T. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 8, 5 (2007).

    PubMed  PubMed Central  Google Scholar 

  143. Froicu, M. et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol. Endocrinol. 17, 2386–2392 (2003).

    CAS  PubMed  Google Scholar 

  144. Froicu, M., Zhu, Y. & Cantorna, M. T. Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice. Immunology 117, 310–318 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Mouli, V. P. & Ananthakrishnan, A. N. Review article: vitamin D and inflammatory bowel diseases. Aliment. Pharmacol. Ther. 39, 125–136 (2014).

    CAS  PubMed  Google Scholar 

  146. Ananthakrishnan, A. N. et al. Higher predicted vitamin D status is associated with reduced risk of Crohn's disease. Gastroenterology 142, 482–489 (2012).

    CAS  PubMed  Google Scholar 

  147. Ananthakrishnan, A. N. et al. Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn's disease. Inflamm. Bowel Dis. 19, 1921–1927 (2013).

    PubMed  PubMed Central  Google Scholar 

  148. Cerasi, M., Ammendola S. & Battistoni, A. Competition for zinc binding in the host-pathogen interaction. Front. Cell. Infect. Microbiol. 3, 108 (2013).

    PubMed  PubMed Central  Google Scholar 

  149. Haase, H. & Rink, L. Zinc signals and immune function. Biofactors 40, 27–40 (2014).

    CAS  PubMed  Google Scholar 

  150. Lahiri, A. & Abraham, C. Activation of pattern recognition receptors up-regulates metallothioneins, thereby increasing intracellular accumulation of zinc, autophagy, and bacterial clearance by macrophages. Gastroenterology 147, 835–846 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. El-Tawil, A. M. Zinc supplementation tightens leaky gut in Crohn's disease. Inflamm. Bowel Dis. 18, E399 (2012).

    CAS  PubMed  Google Scholar 

  152. Chua, A. C. et al. Dietary iron enhances colonic inflammation and IL-6/IL-11–Stat3 signaling promoting colonic tumor development in mice. PLoS ONE 8, e78850 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Carrier, J. et al. Effect of oral iron supplementation on oxidative stress and colonic inflammation in rats with induced colitis. Aliment. Pharmacol. Ther. 15, 1989–1999 (2001).

    CAS  PubMed  Google Scholar 

  154. Aamodt, G. et al. The association between water supply and inflammatory bowel disease based on a 1990–1993 cohort study in southeastern Norway. Am. J. Epidemiol. 168, 1065–1072 (2008).

    PubMed  Google Scholar 

  155. Bernstein, C. N. et al. A prospective population-based study of triggers of symptomatic flares in IBD. Am. J. Gastroenterol. 105, 1994–2002 (2010).

    PubMed  Google Scholar 

  156. Bonaz, B. L. & Bernstein, C. N. Brain–gut interactions in inflammatory bowel disease. Gastroenterology 144, 36–49 (2013).

    PubMed  Google Scholar 

  157. Bailey, M. T. et al. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav. Immun. 25, 397–407 (2011).

    CAS  PubMed  Google Scholar 

  158. Ghia, J. E. et al. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology 136, 2280–2288.e1–e4 (2009).

    CAS  PubMed  Google Scholar 

  159. Ananthakrishnan, A. N. et al. Association between depressive symptoms and incidence of Crohn's disease and ulcerative colitis: results from the Nurses' Health Study. Clin. Gastroenterol. Hepatol. 11, 57–62 (2013).

    PubMed  Google Scholar 

  160. Bitton, A. et al. Predicting relapse in Crohn's disease: a biopsychosocial model. Gut 57, 1386–1392 (2008).

    CAS  PubMed  Google Scholar 

  161. Goodhand, J. & Rampton, D. Psychological stress and coping in IBD. Gut 57, 1345–1347 (2008).

    PubMed  Google Scholar 

  162. Goodhand, J. R. et al. Mood disorders in inflammatory bowel disease: relation to diagnosis, disease activity, perceived stress, and other factors. Inflamm. Bowel Dis. 18, 2301–2309 (2012).

    CAS  PubMed  Google Scholar 

  163. Goodhand, J. R., Wahed, M. & Rampton, D. S. Management of stress in inflammatory bowel disease: a therapeutic option? Expert Rev. Gastroenterol. Hepatol. 3, 661–679 (2009).

    PubMed  Google Scholar 

  164. Lerebours, E. et al. Stressful life events as a risk factor for inflammatory bowel disease onset: a population-based case-control study. Am. J. Gastroenterol. 102, 122–131 (2007).

    PubMed  Google Scholar 

  165. Levenstein, S. et al. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am. J. Gastroenterol. 95, 1213–1220 (2000).

    CAS  PubMed  Google Scholar 

  166. Li, J. et al. Psychological stress and inflammatory bowel disease: a follow-up study in parents who lost a child in Denmark. Am. J. Gastroenterol. 99, 1129–1133 (2004).

    PubMed  Google Scholar 

  167. Maunder, R. G. Evidence that stress contributes to inflammatory bowel disease: evaluation, synthesis, and future directions. Inflamm. Bowel Dis. 11, 600–608 (2005).

    PubMed  Google Scholar 

  168. Mawdsley, J. E. & Rampton, D. S. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut 54, 1481–1491 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Rampton, D. Does stress influence inflammatory bowel disease? The clinical data. Dig. Dis. 27 (Suppl. 1), 76–79 (2009).

    PubMed  Google Scholar 

  170. Sonnenberg, A. Occupational distribution of inflammatory bowel disease among German employees. Gut 31, 1037–1040 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Cook, M. D. et al. Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis. Brain Behav. Immun. 33, 46–56 (2013).

    PubMed  PubMed Central  Google Scholar 

  172. Khalili, H. et al. Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses' Health Study cohorts. BMJ 347, f6633 (2013).

    PubMed  PubMed Central  Google Scholar 

  173. Ananthakrishnan, A. N. et al. Sleep disturbance and risk of active disease in patients with Crohn's disease and ulcerative colitis. Clin. Gastroenterol. Hepatol. 11, 965–971 (2013).

    PubMed  PubMed Central  Google Scholar 

  174. Kinnucan, J. A., Rubin, D. T. & Ali, T. Sleep and inflammatory bowel disease: exploring the relationship between sleep disturbances and inflammation. Gastroenterol. Hepatol. (N. Y.) 9, 718–727 (2013).

    Google Scholar 

  175. Swanson, G. R., Burgess, H. J. & Keshavarzian, A. Sleep disturbances and inflammatory bowel disease: a potential trigger for disease flare? Expert Rev. Clin. Immunol. 7, 29–36 (2011).

    PubMed  PubMed Central  Google Scholar 

  176. Ananthakrishnan, A. N. et al. Sleep duration affects risk for ulcerative colitis: a prospective cohort study. Clin. Gastroenterol. Hepatol. 12, 1879–1886 (2014).

    PubMed  PubMed Central  Google Scholar 

  177. Ali, T. et al. Assessment of the relationship between quality of sleep and disease activity in inflammatory bowel disease patients. Inflamm. Bowel Dis. 19, 2440–2443 (2013).

    PubMed  Google Scholar 

  178. Cosnes, J. et al. Smoking cessation and the course of Crohn's disease: an intervention study. Gastroenterology 120, 1093–1099 (2001).

    CAS  PubMed  Google Scholar 

  179. Lunney, P. C. & Leong, R. W. Review article: Ulcerative colitis, smoking and nicotine therapy. Aliment. Pharmacol. Ther. 36, 997–1008 (2012).

    CAS  PubMed  Google Scholar 

  180. Calabrese, E. et al. Low-dose smoking resumption in ex-smokers with refractory ulcerative colitis. J. Crohns Colitis 6, 756–762 (2012).

    PubMed  Google Scholar 

  181. Noh, C. H. et al. Remission of ulcerative colitis after appendectomy: a case report [Korean]. Korean J. Gastroenterol. 56, 201–204 (2010).

    PubMed  Google Scholar 

  182. Okazaki, K. et al. A patient with improvement of ulcerative colitis after appendectomy. Gastroenterology 119, 502–506 (2000).

    CAS  PubMed  Google Scholar 

  183. Tighe, M. P., Cummings, J. R. & Afzal, N. A. Nutrition and inflammatory bowel disease: primary or adjuvant therapy. Curr. Opin. Clin. Nutr. Metab. Care 14, 491–496 (2011).

    PubMed  Google Scholar 

  184. D'Argenio, V. et al. An altered gut microbiome profile in a child affected by Crohn's disease normalized after nutritional therapy. Am. J. Gastroenterol. 108, 851–852 (2013).

    PubMed  PubMed Central  Google Scholar 

  185. Cohen, S. A. et al. Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. J. Pediatr. Gastroenterol. Nutr. 59, 516–521 (2014).

    CAS  PubMed  Google Scholar 

  186. Herfarth, H. H. et al. Prevalence of a gluten-free diet and improvement of clinical symptoms in patients with inflammatory bowel diseases. Inflamm. Bowel Dis. 20, 1194–1197 (2014).

    PubMed  PubMed Central  Google Scholar 

  187. Jorgensen, S. P. et al. Clinical trial: vitamin D3 treatment in Crohn's disease—-a randomized double-blind placebo-controlled study. Aliment. Pharmacol. Ther. 32, 377–383 (2010).

    CAS  PubMed  Google Scholar 

  188. Lev-Tzion, R. et al. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD006320 http://dx.doi.org/10.1002/14651858.CD006320.pub4.

  189. Uchiyama, K. et al. N-3 polyunsaturated fatty acid diet therapy for patients with inflammatory bowel disease. Inflamm. Bowel Dis. 16, 1696–1707 (2010).

    PubMed  Google Scholar 

  190. Wahed, M. et al. Does psychological counseling alter the natural history of inflammatory bowel disease? Inflamm. Bowel Dis. 16, 664–669 (2010).

    PubMed  Google Scholar 

  191. Timmer, A. et al. Psychological interventions for treatment of inflammatory bowel disease. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD006913 http://dx.doi.org/10.1002/14651858.CD006913.pub2.

  192. Goodhand, J. R. et al. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm. Bowel Dis. 18, 1232–1239 (2011).

    Google Scholar 

  193. Wild, C. P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev. 14, 1847–1850 (2005).

    CAS  PubMed  Google Scholar 

  194. Kanaly, R. A. et al. Development of the adductome approach to detect DNA damage in humans. Antioxid. Redox Signal. 8, 993–1001 (2006).

    CAS  PubMed  Google Scholar 

  195. Bogdanos, D. P. et al. Infectome: a platform to trace infectious triggers of autoimmunity. Autoimmun. Rev. 12, 726–740 (2013).

    CAS  PubMed  Google Scholar 

  196. Crohn's and Colitis Canada Inflammatory Bowel Disease GEM Project. The GEM project [online], (2015).

  197. Connecticut Children's Medical Center. PROTECT [online], (2015).

  198. PROKIIDS data centre. PRO-KIIDS Data Centre [online], (2015).

  199. Lomer, M. C. et al. Efficacy and tolerability of a low microparticle diet in a double blind, randomized, pilot study in Crohn's disease. Eur. J. Gastroenterol. Hepatol. 13, 101–106 (2001).

    CAS  PubMed  Google Scholar 

  200. Lomer, M. C. et al. Lack of efficacy of a reduced microparticle diet in a multi-centred trial of patients with active Crohn's disease. Eur. J. Gastroenterol. Hepatol. 17, 377–384 (2005).

    PubMed  Google Scholar 

  201. Turner, D., Steinhart, A. H. & Griffiths, A. M. Omega 3 fatty acids (fish oil) for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD006443 http://dx.doi.org/10.1002/14651858.CD006443.pub2.

  202. Wright, R. & Truelove, S. C. A controlled therapeutic trial of various diets in ulcerative colitis. Br. Med. J. 2, 138–141 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Ritchie, J. K. et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br. Med. J. (Clin. Res. Ed.) 295, 517–520 (1987).

    CAS  Google Scholar 

  204. Bartel, G. et al. Ingested matter affects intestinal lesions in Crohn's disease. Inflamm. Bowel Dis. 14, 374–382 (2008).

    PubMed  Google Scholar 

  205. Chiba, M. et al. Lifestyle-related disease in Crohn's disease: relapse prevention by a semi-vegetarian diet. World J. Gastroenterol. 16, 2484–2495 (2010).

    PubMed  PubMed Central  Google Scholar 

  206. Zachos, M., Tondeur, M. & Griffiths, A. M. Enteral nutritional therapy for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD000542 http://dx.doi.org/10.1002/14651858.CD000542.pub2.

  207. Boye, B. et al. INSPIRE study: does stress management improve the course of inflammatory bowel disease and disease-specific quality of life in distressed patients with ulcerative colitis or Crohn's disease? A randomized controlled trial. Inflamm. Bowel Dis. 17, 1863–1873 (2011).

    PubMed  Google Scholar 

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Acknowledgements

A.N.A. is supported by funding from the US National Institutes of Health (K23 DK097142).

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A.N.A. has served on the scientific advisory boards for Abbvie and Cubist pharmaceuticals.

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Ananthakrishnan, A. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 12, 205–217 (2015). https://doi.org/10.1038/nrgastro.2015.34

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