Modifiable Environmental Factors in Inflammatory Bowel Disease

  • Kristin E. Burke
  • Christine Boumitri
  • Ashwin N. Ananthakrishnan
Inflammatory Bowel Disease (S Hanauer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Inflammatory Bowel Disease


Purpose of Review

Environmental factors may influence predisposition to develop inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) or alter its natural history by modification of both the host immune response and intestinal microbial composition. The purpose of this review is to translate such evidence into clinical practice by a focus on interventional studies that have modified such environmental influences to improve disease outcomes.

Recent Findings

Several environmental influences have been identified in the recent literature including tobacco use, diet, antibiotics, vitamin D deficiency, stress, appendectomy, and oral contraceptive use. Some risk factors have similar influences on both Crohn’s disease and ulcerative colitis while others are disease-specific or have divergent effects.


Emerging epidemiologic evidence has confirmed the association of many of these factors with incident disease using prospective data. In addition, laboratory data has supported their mechanistic plausibility and relevance to intestinal inflammation.


Crohn’s disease Ulcerative colitis Environment Diet Smoking 


Compliance with Ethical Standards

Conflict of Interest

Ashwin Ananthakrishnan reports serving on scientific advisory boards for Abbvie, Takeda, and Merck, outside the submitted work. Christine Boumitri and Kristin Burke declare no conflict of interest.

Grant Support

Ashwin Ananthakrishnan is supported by funding from the US National Institutes of Health (K23 DK097142) and the Crohn’s and Colitis Foundation of America.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Torres J, Mehandru S, Colombel JF, et al. Crohn’s disease. Lancet 2016.Google Scholar
  2. 2.
    Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet 2016.Google Scholar
  3. 3.
    Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–17.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54 e42. quiz e30PubMedCrossRefGoogle Scholar
  5. 5.
    Thia KT, Loftus Jr EV, Sandborn WJ, et al. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol. 2008;103:3167–82.PubMedCrossRefGoogle Scholar
  6. 6.
    Ray G. Inflammatory bowel disease in India—past, present and future. World J Gastroenterol. 2016;22:8123–36.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    •• Benchimol EI, Mack DR, Guttmann A, et al. Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study. Am J Gastroenterol. 2015;110:553–63. This study elegantly linked administrative data to immigration data demonstrating that second-generation immigrants had the same risk of developing IBD as native Caucasian Canadians.PubMedCrossRefGoogle Scholar
  8. 8.
    Carr I, Mayberry JF. The effects of migration on ulcerative colitis: a three-year prospective study among Europeans and first- and second-generation South Asians in Leicester (1991-1994). Am J Gastroenterol. 1999;94:2918–22.PubMedGoogle Scholar
  9. 9.
    Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17.PubMedCrossRefGoogle Scholar
  10. 10.
    Monick MM, Powers LS, Walters K, et al. Identification of an autophagy defect in smokers’ alveolar macrophages. J Immunol. 2010;185:5425–35.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Benjamin JL, Hedin CR, Koutsoumpas A, et al. Smokers with active Crohn’s disease have a clinically relevant dysbiosis of the gastrointestinal microbiota. Inflamm Bowel Dis. 2012;18:1092–100.PubMedCrossRefGoogle Scholar
  12. 12.
    Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105:16731–6.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Quevrain E, Maubert MA, Michon C, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut. 2016;65:415–25.PubMedCrossRefGoogle Scholar
  14. 14.
    •• Bergeron V, Grondin V, Rajca S, 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. 2012;18:1101–11. This important study demonstrated a differential effect of cigarette smoking on mononuclear cells in Crohn’s disease or ulcerative colitis, thereby providing support for the divergent effects of cigarette smoke on established disease.PubMedCrossRefGoogle Scholar
  15. 15.
    To N, Gracie DJ, Ford AC. Systematic review with meta-analysis: the adverse effects of tobacco smoking on the natural history of Crohn’s disease. Aliment Pharmacol Ther. 2016;43:549–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Nunes T, Etchevers MJ, Garcia-Sanchez V, et al. Impact of smoking cessation on the clinical course of Crohn’s disease under current therapeutic algorithms: a multicenter prospective study. Am J Gastroenterol. 2016;111:411–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology. 1996;110:424–31.PubMedCrossRefGoogle Scholar
  18. 18.
    Nunes T, Etchevers MJ, Merino O, et al. Does smoking influence Crohn’s disease in the biologic era? The TABACROHN study. Inflamm Bowel Dis. 2013;19:23–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Seksik P, Nion-Larmurier I, Sokol H, et al. Effects of light smoking consumption on the clinical course of Crohn’s disease. Inflamm Bowel Dis. 2009;15:734–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Lakatos PL, Vegh Z, Lovasz BD, et al. Is current smoking still an important environmental factor in inflammatory bowel diseases? Results from a population-based incident cohort. Inflamm Bowel Dis. 2013;19:1010–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Arnott ID, McNeill G, Satsangi J. An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn’s disease. Aliment Pharmacol Ther. 2003;17:1451–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Lindberg E, Jarnerot G, Huitfeldt B. Smoking in Crohn’s disease: effect on localisation and clinical course. Gut. 1992;33:779–82.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Picco MF, Bayless TM. Tobacco consumption and disease duration are associated with fistulizing and stricturing behaviors in the first 8 years of Crohn’s disease. Am J Gastroenterol. 2003;98:363–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Nunes T, Etchevers MJ, Domenech E, et al. Smoking does influence disease behaviour and impacts the need for therapy in Crohn’s disease in the biologic era. Aliment Pharmacol Ther. 2013;38:752–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Sutherland LR, Ramcharan S, Bryant H, et al. Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology. 1990;98:1123–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120:1093–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Nunes T, Etchevers MJ, Merino O, et al. High smoking cessation rate in Crohn’s disease patients after physician advice—the TABACROHN study. J Crohns Colitis. 2013;7:202–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Higuchi LM, Khalili H, Chan AT, et al. A prospective study of cigarette smoking and the risk of inflammatory bowel disease in women. Am J Gastroenterol. 2012;107:1399–406.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    van der Heide F, Dijkstra A, Weersma RK, et al. Effects of active and passive smoking on disease course of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2009;15:1199–207.PubMedCrossRefGoogle Scholar
  30. 30.
    Beaugerie L, Massot N, Carbonnel F, et al. Impact of cessation of smoking on the course of ulcerative colitis. Am J Gastroenterol. 2001;96:2113–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Boyko EJ, Perera DR, Koepsell TD, et al. Effects of cigarette smoking on the clinical course of ulcerative colitis. Scand J Gastroenterol. 1988;23:1147–52.PubMedCrossRefGoogle Scholar
  32. 32.
    McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2004:CD004722.Google Scholar
  33. 33.
    Calabrese E, Yanai H, Shuster D, et al. Low-dose smoking resumption in ex-smokers with refractory ulcerative colitis. J Crohns Colitis. 2012;6:756–62.PubMedCrossRefGoogle Scholar
  34. 34.
    Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity. 2014;40:833–42.PubMedCrossRefGoogle Scholar
  35. 35.
    Richards JL, Yap YA, McLeod KH, et al. Dietary metabolites and the gut microbiota: an alternative approach to control inflammatory and autoimmune diseases. Clin Transl Immunology. 2016;5:e82.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489–99.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Gevers D, Kugathasan S, Denson LA, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15:382–92. This landmark study elegantly described changes in the microbiome in newly diagnosed pediatric Crohn’s disease and alterations in functional pathways.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Navarro J, Vargas J, Cezard JP, et al. Prolonged constant rate elemental enteral nutrition in Crohn’s disease. J Pediatr Gastroenterol Nutr. 1982;1:541–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Sanderson IR, Udeen S, Davies PS, et al. Remission induced by an elemental diet in small bowel Crohn’s disease. Arch Dis Child. 1987;62:123–7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zachos M, Tondeur, M. & Griffiths, A. M.. Enteral nutritional therapy for induction of remission in Crohn’s disease.Google Scholar
  43. 43.
    Dziechciarz P, Horvath A, Shamir R, et al. Meta-analysis: enteral nutrition in active Crohn’s disease in children. Aliment Pharmacol Ther. 2007;26:795–806.PubMedCrossRefGoogle Scholar
  44. 44.
    Heuschkel RB, Menache CC, Megerian JT, et al. Enteral nutrition and corticosteroids in the treatment of acute Crohn’s disease in children. J Pediatr Gastroenterol Nutr. 2000;31:8–15.PubMedCrossRefGoogle Scholar
  45. 45.
    Grogan JL, Casson DH, Terry A, et al. Enteral feeding therapy for newly diagnosed pediatric Crohn’s disease: a double-blind randomized controlled trial with two years follow-up. Inflamm Bowel Dis. 2012;18:246–53.PubMedCrossRefGoogle Scholar
  46. 46.
    Hirai F, Ishihara H, Yada S, et al. Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn’s disease in adults. Dig Dis Sci. 2013;58:1329–34.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee D, Baldassano RN, Otley AR, et al. Comparative effectiveness of nutritional and biological therapy in North American children with active Crohn’s disease. Inflamm Bowel Dis. 2015;21:1786–93.PubMedCrossRefGoogle Scholar
  48. 48.
    Kim HJ, Kim Y, Cho JM, et al. Therapeutic efficacy of oral enteral nutrition in pediatric Crohn’s disease: a single center non-comparative retrospective study. Yonsei Med J. 57:1185–91.Google Scholar
  49. 49.
    Haas SV, Haas MP. The treatment of celiac disease with the specific carbohydrate diet; report on 191 additional cases. Am J Gastroenterol. 1955;23:344–60.PubMedGoogle Scholar
  50. 50.
    E. G. Breaking the vicious cycle: intestinal health through diet. Baltimore, Canada:: Kirkton PressGoogle Scholar
  51. 51.
    Cohen SA, Gold BD, Oliva S, et al. Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2014;59:516–21.PubMedCrossRefGoogle Scholar
  52. 52.
    Obih C, Wahbeh G, Lee D, et al. Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic IBD center. Nutrition. 2016;32:418–25.PubMedCrossRefGoogle Scholar
  53. 53.
    Sigall-Boneh R, Pfeffer-Gik T, Segal I, et al. Partial enteral nutrition with a Crohn’s disease exclusion diet is effective for induction of remission in children and young adults with Crohn’s disease. Inflamm Bowel Dis. 2014;20:1353–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Rajendran N, Kumar D. Food-specific IgG4-guided exclusion diets improve symptoms in Crohn’s disease: a pilot study. Color Dis. 2011;13:1009–13.CrossRefGoogle Scholar
  55. 55.
    Gunasekeera V, Mendall MA, Chan D, et al. Treatment of Crohn’s disease with an IgG4-guided exclusion diet: a randomized controlled trial. Dig Dis Sci. 2016;61:1148–57.PubMedCrossRefGoogle Scholar
  56. 56.
    Brown AC, Rampertab SD, Mullin GE. Existing dietary guidelines for Crohn’s disease and ulcerative colitis. Expert Rev Gastroenterol Hepatol. 2011;5:411–25.PubMedCrossRefGoogle Scholar
  57. 57.
    Pituch-Zdanowska A, Banaszkiewicz A, Albrecht P. The role of dietary fibre in inflammatory bowel disease. Prz Gastroenterol. 2015;10:135–41.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Li Y, Innocentin S, Withers DR, et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011;147:629–40.PubMedCrossRefGoogle Scholar
  59. 59.
    Parigi SM, Eldh M, Larssen P, et al. Breast milk and solid food shaping intestinal immunity. Front Immunol. 2015;6:415.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Monteleone I, MacDonald TT, Pallone F, et al. The aryl hydrocarbon receptor in inflammatory bowel disease: linking the environment to disease pathogenesis. Curr Opin Gastroenterol. 2012;28:310–3.PubMedCrossRefGoogle Scholar
  61. 61.
    Joossens M, De Preter V, Ballet V, et al. Effect of oligofructose-enriched inulin (OF-IN) on bacterial composition and disease activity of patients with Crohn’s disease: results from a double-blinded randomised controlled trial. Gut. 2012;61:958.PubMedCrossRefGoogle Scholar
  62. 62.
    Ananthakrishnan AN, Khalili H, Konijeti GG, et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology. 2013;145:970–7.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011;106:563–73.PubMedCrossRefGoogle Scholar
  64. 64.
    Brotherton CS, Martin CA, Long MD, et al. Avoidance of fiber is associated with greater risk of Crohn’s disease flare in a 6-month period. Clin Gastroenterol Hepatol. 2016;14:1130–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Faghfoori Z, Shakerhosseini R, Navai L, et al. Effects of an oral supplementation of germinated barley foodstuff on serum CRP level and clinical signs in patients with ulcerative colitis. Health Promot Perspect. 2014;4:116–21.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Wedlake L, Slack N, Andreyev HJ, et al. Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis. 2014;20:576–86.PubMedCrossRefGoogle Scholar
  67. 67.
    Denis MC, Roy D, Yeganeh PR, et al. Apple peel polyphenols: a key player in the prevention and treatment of experimental inflammatory bowel disease. Clin Sci (Lond). 2016;130:2217–37.CrossRefGoogle Scholar
  68. 68.
    John S, Luben R, Shrestha SS, et al. Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: a UK prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22:602–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease. Gut. 2014;63:776–84.PubMedCrossRefGoogle Scholar
  70. 70.
    Wall R, Ross RP, Fitzgerald GF, et al. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68:280–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Lev-Tzion R, Griffiths AM, Leder O, et al. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2014:CD006320.Google Scholar
  72. 72.
    Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials. JAMA. 2008;299:1690–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Farrukh A, Mayberry JF. Is there a role for fish oil in inflammatory bowel disease? World J Clin Cases. 2014;2:250–2.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Hawthorne AB, Daneshmend TK, Hawkey CJ, et al. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial. Gut. 1992;33:922–8.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Stenson WF, Cort D, Rodgers J, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609–14.PubMedCrossRefGoogle Scholar
  76. 76.
    Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992;87:432–7.PubMedGoogle Scholar
  77. 77.
    Dichi I, Frenhane P, Dichi JB, et al. Comparison of omega-3 fatty acids and sulfasalazine in ulcerative colitis. Nutrition. 2000;16:87–90.PubMedCrossRefGoogle Scholar
  78. 78.
    Benjamin J, Makharia G, Ahuja V, et al. Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn’s disease: a randomized controlled trial. Dig Dis Sci. 2012;57:1000–12.PubMedCrossRefGoogle Scholar
  79. 79.
    Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005;50:2191–3.PubMedCrossRefGoogle Scholar
  80. 80.
    Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis—a randomized, placebo-controlled, pilot study. J Crohns Colitis. 2014;8:208–14.PubMedCrossRefGoogle Scholar
  81. 81.
    Lang A, Salomon N, Wu JC, et al. Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial. Clin Gastroenterol Hepatol. 2015;13:1444–9. e1PubMedCrossRefGoogle Scholar
  82. 82.
    Muluye RA, Bian Y, Alemu PN. Anti-inflammatory and antimicrobial effects of heat-clearing Chinese herbs: a current review. J Tradit Complement Med. 2014;4:93–8.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Tang T, Targan SR, Li ZS, et al. Randomised clinical trial: herbal extract HMPL-004 in active ulcerative colitis—a double-blind comparison with sustained release mesalazine. Aliment Pharmacol Ther. 2011;33:194–202.PubMedCrossRefGoogle Scholar
  84. 84.
    Sandborn WJ, Targan SR, Byers VS, et al. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. Am J Gastroenterol. 2013;108:90–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Bar-Sela G, Cohen M, Ben-Arye E, et al. The medical use of wheatgrass: review of the gap between basic and clinical applications. Mini Rev Med Chem. 2015;15:1002–10.PubMedCrossRefGoogle Scholar
  86. 86.
    Weisshof R, Chermesh I. Micronutrient deficiencies in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care. 2015;18:576–81.PubMedCrossRefGoogle Scholar
  87. 87.
    Hwang C, Ross V, Mahadevan U. Micronutrient deficiencies in inflammatory bowel disease: from A to zinc. Inflamm Bowel Dis. 2012;18:1961–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Torki M, Gholamrezaei A, Mirbagher L, et al. Vitamin D deficiency associated with disease activity in patients with inflammatory bowel diseases. Dig Dis Sci. 2015;60:3085–91.PubMedCrossRefGoogle Scholar
  89. 89.
    Del Pinto R, Pietropaoli D, Chandar AK, et al. Association between inflammatory bowel disease and vitamin D deficiency: a systematic review and meta-analysis. Inflamm Bowel Dis. 2015;21:2708–17.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Frigstad SO, Hoivik M, Jahnsen J, et al. Vitamin D deficiency in inflammatory bowel disease: prevalence and predictors in a Norwegian outpatient population. Scand J Gastroenterol 2016:1–7.Google Scholar
  91. 91.
    Ananthakrishnan AN, Cagan A, Gainer VS, et al. Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn’s disease. Inflamm Bowel Dis. 2013;19:1921–7.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Ananthakrishnan AN, Cagan A, Gainer VS, et al. Higher plasma vitamin D is associated with reduced risk of Clostridium difficile infection in patients with inflammatory bowel diseases. Aliment Pharmacol Ther. 2014;39:1136–42.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Gubatan J, Mitsuhashi S, Zenlea T, et al. Low serum vitamin D during remission increases risk of clinical relapse in patients with ulcerative colitis. Clin Gastroenterol Hepatol 2016.Google Scholar
  94. 94.
    Martinesi M, Treves C, d’Albasio G, et al. Vitamin D derivatives induce apoptosis and downregulate ICAM-1 levels in peripheral blood mononuclear cells of inflammatory bowel disease patients. Inflamm Bowel Dis. 2008;14:597–604.PubMedCrossRefGoogle Scholar
  95. 95.
    Stio M, Bonanomi AG, d’Albasio G, et al. Suppressive effect of 1,25-dihydroxyvitamin D3 and its analogues EB 1089 and KH 1060 on T lymphocyte proliferation in active ulcerative colitis. Biochem Pharmacol. 2001;61:365–71.PubMedCrossRefGoogle Scholar
  96. 96.
    Cantorna MT, Mahon BD. D-hormone and the immune system. J Rheumatol Suppl. 2005;76:11–20.PubMedGoogle Scholar
  97. 97.
    Raman M, Milestone AN, Walters JR, et al. Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer. Therap Adv Gastroenterol. 2011;4:49–62.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Boonstra A, Barrat FJ, Crain C, et al. 1alpha,25-dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167:4974–80.PubMedCrossRefGoogle Scholar
  99. 99.
    Alhassan Mohammed H, Saboor-Yaraghi AA, Mirshafiey A, et al. Immunomodulatory and immunosuppressive roles of 1alpha,25(OH)2D3 in autoimmune diseases. Scand J Immunol 2016.Google Scholar
  100. 100.
    Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–3.PubMedCrossRefGoogle Scholar
  101. 101.
    Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005;19:1067–77.PubMedCrossRefGoogle Scholar
  102. 102.
    Jorgensen SP, Agnholt J, Glerup H, et al. Clinical trial: vitamin D3 treatment in Crohn’s disease—a randomized double-blind placebo-controlled study. Aliment Pharmacol Ther. 2010;32:377–83.PubMedCrossRefGoogle Scholar
  103. 103.
    Narula N, Cooray M, Anglin R, et al. Impact of high-dose vitamin D3 supplementation in patients with Crohn’s disease in remission: a pilot randomized double-blind controlled study. Dig Dis Sci 2016.Google Scholar
  104. 104.
    Sharifi A, Hosseinzadeh-Attar MJ, Vahedi H, et al. A randomized controlled trial on the effect of vitamin D3 on inflammation and cathelicidin gene expression in ulcerative colitis patients. Saudi J Gastroenterol. 2016;22:316–23.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Sunuwar L, Medini M, Cohen L, et al. The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis. Philos Trans R Soc Lond B Biol Sci 2016;371.Google Scholar
  106. 106.
    Bao B, Prasad AS, Beck FW, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. 2010;91:1634–41.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Barollo M, Medici V, D’Inca R, et al. Antioxidative potential of a combined therapy of anti TNFalpha and Zn acetate in experimental colitis. World J Gastroenterol. 2011;17:4099–103.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Ananthakrishnan AN, Khalili H, Song M, et al. Zinc intake and risk of Crohn’s disease and ulcerative colitis: a prospective cohort study. Int J Epidemiol. 2015;44:1995–2005.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Siva S, Rubin DT, Gulotta G, et al. Zinc deficiency is associated with poor clinical outcomes in patients with inflammatory bowel disease. Inflamm Bowel Dis 2016.Google Scholar
  110. 110.
    Sturniolo GC, Di Leo V, Ferronato A, et al. Zinc supplementation tightens "leaky gut" in Crohn’s disease. Inflamm Bowel Dis. 2001;7:94–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Ananthakrishnan AN, Khalili H, Pan A, et al. Association between depressive symptoms and incidence of Crohn’s disease and ulcerative colitis: results from the Nurses’ Health Study. Clin Gastroenterol Hepatol. 2013;11:57–62.PubMedCrossRefGoogle Scholar
  112. 112.
    Lerebours E, Gower-Rousseau C, Merle V, et al. Stressful life events as a risk factor for inflammatory bowel disease onset: a population-based case-control study. Am J Gastroenterol. 2007;102:122–31.PubMedCrossRefGoogle Scholar
  113. 113.
    Ghia JE, Blennerhassett P, Deng Y, et al. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology. 2009;136:2280–2288.e1-4.PubMedCrossRefGoogle Scholar
  114. 114.
    Bailey MT, Dowd SE, Galley JD, et al. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011;25:397–407.PubMedCrossRefGoogle Scholar
  115. 115.
    Watanabe Y, Arase S, Nagaoka N, et al. Chronic psychological stress disrupted the composition of the murine colonic microbiota and accelerated a murine model of inflammatory bowel disease. PLoS One. 2016;11:e0150559.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Singh S, Graff LA, Bernstein CN. Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am J Gastroenterol. 2009;104:1298–313. quiz 1314PubMedCrossRefGoogle Scholar
  117. 117.
    Gaines LS, Slaughter JC, Horst SN, et al. Association between affective-cognitive symptoms of depression and exacerbation of Crohn’s disease. Am J Gastroenterol. 2016;111:864–70.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22:101–10.PubMedCrossRefGoogle Scholar
  119. 119.
    Bernstein CN, Singh S, Graff LA, et al. A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol. 2010;105:1994–2002.PubMedCrossRefGoogle Scholar
  120. 120.
    Goodhand JR, Wahed M, Rampton DS. Management of stress in inflammatory bowel disease: a therapeutic option? Expert Rev Gastroenterol Hepatol. 2009;3:661–79.PubMedCrossRefGoogle Scholar
  121. 121.
    Timmer A, Preiss JC, Motschall E, et al. Psychological interventions for treatment of inflammatory bowel disease. Cochrane Database Syst Rev 2011:CD006913.Google Scholar
  122. 122.
    Szigethy E, Youk AO, Gonzalez-Heydrich J, et al. Effect of 2 psychotherapies on depression and disease activity in pediatric Crohn’s disease. Inflamm Bowel Dis. 2015;21:1321–8.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Szigethy E, Bujoreanu SI, Youk AO, et al. Randomized efficacy trial of two psychotherapies for depression in youth with inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry. 2014;53:726–35.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Gerbarg PL, Jacob VE, Stevens L, et al. The effect of breathing, movement, and meditation on psychological and physical symptoms and inflammatory biomarkers in inflammatory bowel disease: a randomized controlled trial. Inflamm Bowel Dis. 2015;21:2886–96.PubMedCrossRefGoogle Scholar
  125. 125.
    McCombie A, Gearry R, Andrews J, et al. Does computerized cognitive behavioral therapy help people with inflammatory bowel disease? A randomized controlled trial. Inflamm Bowel Dis. 2016;22:171–81.PubMedCrossRefGoogle Scholar
  126. 126.
    Schoultz M, Atherton I, Watson A. Mindfulness-based cognitive therapy for inflammatory bowel disease patients: findings from an exploratory pilot randomised controlled trial. Trials. 2015;16:379.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Thompson RD, Craig A, Crawford EA, et al. Longitudinal results of cognitive behavioral treatment for youths with inflammatory bowel disease and depressive symptoms. J Clin Psychol Med Settings. 2012;19:329–37.PubMedCrossRefGoogle Scholar
  128. 128.
    Bennebroek Evertsz F, Bockting CL, Stokkers PC, et al. The effectiveness of cognitive behavioral therapy on the quality of life of patients with inflammatory bowel disease: multi-center design and study protocol (KL!C- study). BMC Psychiatry. 2012;12:227.PubMedCrossRefGoogle Scholar
  129. 129.
    Vogelaar L, van’t Spijker A, Timman R, et al. Fatigue management in patients with IBD: a randomised controlled trial. Gut. 2014;63:911–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Mizrahi MC, Reicher-Atir R, Levy S, et al. Effects of guided imagery with relaxation training on anxiety and quality of life among patients with inflammatory bowel disease. Psychol Health. 2012;27:1463–79.PubMedCrossRefGoogle Scholar
  131. 131.
    Jedel S, Hoffman A, Merriman P, et al. A randomized controlled trial of mindfulness-based stress reduction to prevent flare-up in patients with inactive ulcerative colitis. Digestion. 2014;89:142–55.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Berrill JW, Sadlier M, Hood K, et al. Mindfulness-based therapy for inflammatory bowel disease patients with functional abdominal symptoms or high perceived stress levels. J Crohns Colitis. 2014;8:945–55.PubMedCrossRefGoogle Scholar
  133. 133.
    Daghaghzadeh H, Naji F, Afshar H, et al. Efficacy of duloxetine add on in treatment of inflammatory bowel disease patients: a double-blind controlled study. J Res Med Sci. 2015;20:595–601.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Goodhand JR, Greig FI, Koodun Y, et al. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm Bowel Dis. 2012;18:1232–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Sleep duration affects risk for ulcerative colitis: a prospective cohort study. Clin Gastroenterol Hepatol. 2014;12:1879–86.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Ananthakrishnan AN, Long MD, Martin CF, et al. Sleep disturbance and risk of active disease in patients with Crohn’s disease and ulcerative colitis. Clin Gastroenterol Hepatol. 2013;11:965–71.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Ali T, Madhoun MF, Orr WC, et al. Assessment of the relationship between quality of sleep and disease activity in inflammatory bowel disease patients. Inflamm Bowel Dis. 2013;19:2440–3.PubMedCrossRefGoogle Scholar
  138. 138.
    Esposito E, Mazzon E, Riccardi L, et al. Matrix metalloproteinase-9 and metalloproteinase-2 activity and expression is reduced by melatonin during experimental colitis. J Pineal Res. 2008;45:166–73.PubMedCrossRefGoogle Scholar
  139. 139.
    Mazzon E, Esposito E, Crisafulli C, et al. Melatonin modulates signal transduction pathways and apoptosis in experimental colitis. J Pineal Res. 2006;41:363–73.PubMedCrossRefGoogle Scholar
  140. 140.
    Esiringu F, Tugcu-Demiroz F, Acarturk F, et al. Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis. Drug Deliv. 2016;23:2318–26.PubMedGoogle Scholar
  141. 141.
    Ananthakrishnan AN, Higuchi LM, Huang ES, et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann Intern Med. 2012;156:350–9.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Long MD, Kappelman MD, Martin CF, et al. Role of nonsteroidal anti-inflammatory drugs in exacerbations of inflammatory bowel disease. J Clin Gastroenterol. 2016;50:152–6.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Takeuchi K, Smale S, Premchand P, et al. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006;4:196–202.PubMedCrossRefGoogle Scholar
  144. 144.
    Sandborn WJ, Stenson WF, Brynskov J, et al. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006;4:203–11.PubMedCrossRefGoogle Scholar
  145. 145.
    Andersson RE, Olaison G, Tysk C, et al. Appendectomy is followed by increased risk of Crohn’s disease. Gastroenterology. 2003;124:40–6.PubMedCrossRefGoogle Scholar
  146. 146.
    Kaplan GG, Jackson T, Sands BE, et al. The risk of developing Crohn’s disease after an appendectomy: a meta-analysis. Am J Gastroenterol. 2008;103:2925–31.PubMedCrossRefGoogle Scholar
  147. 147.
    Matsushita M, Uchida K, Okazaki K. Role of the appendix in the pathogenesis of ulcerative colitis. Inflammopharmacology. 2007;15:154–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Andersson RE, Olaison G, Tysk C, et al. Appendectomy and protection against ulcerative colitis. N Engl J Med. 2001;344:808–14.PubMedCrossRefGoogle Scholar
  149. 149.
    Naganuma M, Iizuka B, Torii A, et al. Appendectomy protects against the development of ulcerative colitis and reduces its recurrence: results of a multicenter case-controlled study in Japan. Am J Gastroenterol. 2001;96:1123–6.PubMedCrossRefGoogle Scholar
  150. 150.
    Rachmilewitz D, Karmeli F, Takabayashi K, et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology. 2002;122:1428–41.PubMedCrossRefGoogle Scholar
  151. 151.
    Matsushita M, Takakuwa H, Matsubayashi Y, et al. Appendix is a priming site in the development of ulcerative colitis. World J Gastroenterol. 2005;11:4869–74.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of appendicectomy on the course of ulcerative colitis. Gut. 2002;51:803–7.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Parian A, Limketkai B, Koh J, et al. Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis. Gut 2016.Google Scholar
  154. 154.
    Jarnerot G, Andersson M, Franzen L. Laparoscopic appendectomy in patients with refractory ulcerative colitis. Gastroenterology. 2001;120:1562–3.PubMedCrossRefGoogle Scholar
  155. 155.
    Gardenbroek TJ, Pinkney TD, Sahami S, et al. The ACCURE-trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicenter trial (NTR2883) and the ACCURE-UK trial: a randomised external pilot trial (ISRCTN56523019). BMC Surg. 2015;15:30.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Harper JW, Zisman TL. Interaction of obesity and inflammatory bowel disease. World J Gastroenterol. 2016;22:7868–81.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Khalili H, Ananthakrishnan AN, Konijeti GG, et al. Measures of obesity and risk of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2015;21:361–8.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Harpsoe MC, Basit S, Andersson M, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43:843–55.PubMedCrossRefGoogle Scholar
  159. 159.
    Endo Y, Yokote K, Nakayama T. The obesity-related pathology and Th17 cells. Cell Mol Life Sci 2016.Google Scholar
  160. 160.
    Van Der Sloot KW, Joshi AD, Bellavance DR, et al. Visceral adiposity, genetic susceptibility, and risk of complications among individuals with Crohn’s disease. Inflamm Bowel Dis. 2017;23:82–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Seminerio JL, Koutroubakis IE, Ramos-Rivers C, et al. Impact of obesity on the management and clinical course of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2015;21:2857–63.PubMedCrossRefGoogle Scholar
  162. 162.
    Cornish JA, Tan E, Simillis C, et al. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008;103:2394–400.PubMedCrossRefGoogle Scholar
  163. 163.
    Garcia Rodriguez LA, Gonzalez-Perez A, Johansson S, et al. Risk factors for inflammatory bowel disease in the general population. Aliment Pharmacol Ther. 2005;22:309–15.PubMedCrossRefGoogle Scholar
  164. 164.
    Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut. 2013;62:1153–9.PubMedCrossRefGoogle Scholar
  165. 165.
    Khalili H, Neovius M, Ekbom A, et al. Oral contraceptive use and risk of ulcerative colitis progression: a nationwide study. Am J Gastroenterol. 2016;111:1614–20.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Khalili H, Granath F, Smedby KE, et al. Association between long-term oral contraceptive use and risk of Crohn’s disease complications in a nationwide study. Gastroenterology. 2016;150:1561–1567 e1.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Kristin E. Burke
    • 1
  • Christine Boumitri
    • 2
  • Ashwin N. Ananthakrishnan
    • 1
    • 3
  1. 1.Division of GastroenterologyMassachusetts General HospitalBostonUSA
  2. 2.Division of GastroenterologyUniversity of Missouri-ColumbiaColumbiaUSA
  3. 3.Massachusetts General Hospital Crohn’s and Colitis CenterBostonUSA

Personalised recommendations