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IBS: an epigenetic perspective

Nature Reviews Gastroenterology & Hepatology volume 7, pages 465–471 (2010)Cite this article

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Abstract

IBS is a common and debilitating disorder. The pathophysiology of IBS is poorly understood and is currently viewed as a biopsychosocial disorder with symptoms mediated via the brain–gut axis. Epidemiological studies of IBS point to risk factors such as familial clustering, sexual abuse and other forms of childhood trauma, low birth weight and gastrointestinal infection. Epigenetics focuses on the complex and dynamic interaction between the DNA sequence, DNA modifications and environmental factors, all of which combine to produce the phenotype. Studies in animal models of early stress and in humans who have experienced childhood trauma or abuse suggest that these events can lead to long-lasting epigenetic changes in the glucocorticoid receptor gene brought about by hypermethylation of a key regulatory component. Animal studies also indicate that the microbiota has a pivotal role in programming the core stress system, the hypothalamic–pituitary–adrenal axis and the immune system through epigenetic mechanisms. In this Perspectives, an epigenetic model of IBS is presented that incorporates many of the current findings regarding IBS, including proinflammatory markers, neuroendocrine alterations and links with both psychosocial stress and stress related to infection. We conclude that applying epigenetic methodology to this common and disabling disorder may help unravel its complex pathophysiology and lead to more effective treatments.

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Figure 1: Epigenetic mechanisms of histone modification and RNA-induced silencing.
Figure 2: Mechanism of generational transfer of environmentally induced genetic alterations.
Figure 3: Epigenetic model of IBS.

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References

  1. Hungin, A. P., Whorwell, P. J., Tack, J. & Mearin, F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects. Aliment. Pharmacol. Ther. 17, 643–650 (2003).

    Article  CAS  Google Scholar 

  2. Quigley, E. M. Current concepts of the irritable bowel syndrome. Scand. J. Gastroenterol. Suppl. 1–8 (2003).

    Article  CAS  Google Scholar 

  3. Lydiard, R. B. Irritable bowel syndrome, anxiety, and depression: what are the links? J. Clin. Psychiatry 62 (Suppl. 8), 38–45 (2001).

    PubMed  Google Scholar 

  4. Lee, S. et al. Irritable bowel syndrome is strongly associated with generalized anxiety disorder: a community study. Aliment. Pharmacol. Ther. 30, 643–651 (2009).

    Article  CAS  Google Scholar 

  5. Drossman, D. A. Presidential address: Gastrointestinal illness and the biopsychosocial model. Psychosom. Med. 60, 258–267 (1998).

    Article  CAS  Google Scholar 

  6. Clarke, G., Quigley, E. M., Cryan, J. F. & Dinan, T. G. Irritable bowel syndrome: towards biomarker identification. Trends Mol. Med. 15, 478–489 (2009).

    Article  CAS  Google Scholar 

  7. Grundmann, O. & Yoon, S. L. Irritable bowel syndrome: Epidemiology, diagnosis and treatment: An update for health-care practitioners. J. Gastroenterol. Hepatol. 25, 691–699 (2010).

    Article  Google Scholar 

  8. Whorwell, P. J., McCallum, M., Creed, F. H. & Roberts, C. T. Non-colonic features of irritable bowel syndrome. Gut 27, 37–40 (1986).

    Article  CAS  Google Scholar 

  9. Locke, G. R. 3rd et al. Familial association in adults with functional gastrointestinal disorders. Mayo Clin. Proc. 75, 907–912 (2000).

    Article  Google Scholar 

  10. Kalantar, J. S. et al. Familial aggregation of irritable bowel syndrome: a prospective study. Gut 52, 1703–1707 (2003).

    Article  CAS  Google Scholar 

  11. Saito, Y. A., Petersen, G. M., Locke, G. R. 3rd & Talley, N. J. The genetics of irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 3, 1057–1065 (2005).

    Article  CAS  Google Scholar 

  12. Kanazawa, M. et al. Patients and nonconsulters with irritable bowel syndrome reporting a parental history of bowel problems have more impaired psychological distress. Dig. Dis. Sci. 49, 1046–1053 (2004).

    Article  Google Scholar 

  13. Galton, F. Inquiries into Human Faculty and its Development (AMS Press, New York, 1973).

    Google Scholar 

  14. Morris-Yates, A. et al. Evidence of a genetic contribution to functional bowel disorder. Am. J. Gastroenterol. 93, 1311–1317 (1998).

    Article  CAS  Google Scholar 

  15. Levy, R. L. et al. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology 121, 799–804 (2001).

    Article  CAS  Google Scholar 

  16. Gottesman, I. I. & Shields, J. A. Critical review of recent adoption, twin and family studies of schizophrenia: Behavioural genetics perspectives. Schizophr. Bull. 2, 360–401 (1976).

    Article  CAS  Google Scholar 

  17. Mohammed, I. et al. Genetic influences in irritable bowel syndrome: a twin study. Am. J. Gastroenterol. 100, 1340–1344 (2005).

    Article  Google Scholar 

  18. Bengtson, M. B., Ronning, T., Vatn, M. H. & Harris, J. R. Irritable bowel syndrome in twins: genes and environment. Gut 55, 1754–1759 (2006).

    Article  Google Scholar 

  19. Hotoleanu, C., Popp, R., Trifa, A. P., Nedelcu, L. & Dumitrascu, D. L. Genetic determinants of irritable bowel syndrome. World J. Gastroenterol. 14, 6636–6640 (2008).

    Article  CAS  Google Scholar 

  20. Yeo, A. et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut 53, 1452–1458 (2004).

    Article  CAS  Google Scholar 

  21. Kim, H. J., Camilleri, M. & Carlson, P. J. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Gut 53, 829–837 (2004).

    Article  CAS  Google Scholar 

  22. Cremonini, F., Camilleri, M. & McKinzie, S. Effect of CCK-1 antagonist, dexloxiglumide, in female patients with irritable bowel syndrome: a pharmacodynamic and pharmacogenomic study. Am. J. Gastroenterol. 100, 652–663 (2005).

    Article  CAS  Google Scholar 

  23. Ohman, L. & Simren, M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat. Rev. Gastroenterol. Hepatol. 7, 163–173 (2010).

    Article  Google Scholar 

  24. Camilleri, M. Genetics and irritable bowel syndrome: from genomics to intermediate phenotype and pharmacogenetics. Dig. Dis. Sci. 54, 2318–2324 (2009).

    Article  CAS  Google Scholar 

  25. Haque, F. N., Gottesman, I. I. & Wong, A. H. Not really identical: epigenetic differences in monozygotic twins and implications for twin studies in psychiatry. Am. J. Med. Genet. 151C, 136–141 (2009).

    Article  CAS  Google Scholar 

  26. Tang, W. Y. & Ho, S. M. Epigenetic reprogramming and imprinting in origins of disease. Rev. Endocr. Metab. Disord. 8, 173–182 (2007).

    Article  Google Scholar 

  27. Mehler, M. F. Epigenetics and the nervous system. Ann. Neurol. 64, 602–617 (2008).

    Article  CAS  Google Scholar 

  28. Mehler, M. F. Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog. Neurobiol. 86, 305–341 (2008).

    Article  CAS  Google Scholar 

  29. Mehler, M. F. & Mattick, J. S. Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease. Physiol. Rev. 87, 799–823 (2007).

    Article  CAS  Google Scholar 

  30. Farh, K. K. et al. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310, 1817–1821 (2005).

    Article  CAS  Google Scholar 

  31. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  CAS  Google Scholar 

  32. Hobert, O. Gene regulation by transcription factors and microRNAs. Science 319, 1785–1786 (2008).

    Article  CAS  Google Scholar 

  33. Valencia-Sanchez, M. A., Liu, J., Hannon, G. J. & Parker, R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515–524 (2006).

    Article  CAS  Google Scholar 

  34. Dinan, T. G. MicroRNAs as a target for novel antipsychotics: a systematic review of an emerging field. Int. J. Neuropsychopharmacol. 13, 395–404 (2010).

    Article  CAS  Google Scholar 

  35. Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).

    Article  CAS  Google Scholar 

  36. Oh, G. & Petronis, A. Environmental studies of schizophrenia through the prism of epigenetics. Schizophr. Bull. 34, 1122–1129 (2008).

    Article  Google Scholar 

  37. Baccarelli, A. & Bollati, V. Epigenetics and environmental chemicals. Curr. Opin. Pediatr. 21, 243–251 (2009).

    Article  Google Scholar 

  38. Pembrey, M. et al. Sex specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2005).

    Article  Google Scholar 

  39. Kaati, G., Bygren, L. O., Pembrey, M. & Sjostrom, M. Transgenerational response to nutrition, early life circumstances and longevity. Eur. J. Hum. Genet. 15, 784–790 (2007).

    Article  CAS  Google Scholar 

  40. Stermer, E., Ber, H. & Levy, N. Chronic functional gastrointestinal symptoms in Holocaust survivors. Am. J. Gastroenterol. 86, 417–422 (2008).

    Google Scholar 

  41. Yehuda, R., Bell, A., Bierer, L. M. & Schmeidler, J. Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. J. Psychiatr. Res. 42, 1104–1111 (2008).

    Article  Google Scholar 

  42. Yehuda, R. & Bierer, L. M. The relevance of epigenetics to PTSD: implications for the DSM-V. J. Trauma Stress doi:10.1002/jts.20448.

    Article  Google Scholar 

  43. Klooker, T. K. et al. Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study. Am. J. Gastroenterol. 104, 2250–2256 (2009).

    Article  Google Scholar 

  44. Delvaux, M., Denis, P. & Allemand, H. Sexual abuse is more frequently reported by IBS patients than by patients with organic digestive diseases or controls. Results of a multicentre inquiry. French Club of Digestive Motility. Eur. J. Gastroenterol. Hepatol. 9, 345–352 (1997).

    Article  CAS  Google Scholar 

  45. Walker, E. A., Katon, W. J., Roy-Byrne, P. P., Jemelka, R. P. & Russo, J. Histories of sexual victimization in patients with irritable bowel syndrome or inflammatory bowel disease. Am. J. Psychiatry 150, 1502–1506 (1993).

    Article  CAS  Google Scholar 

  46. O'Mahony, S. M. et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol. Psychiatry 65, 263–267 (2009).

    Article  Google Scholar 

  47. Weaver, S. A., Diorio, J. & Meaney, M. J. Maternal separation leads to persistent reductions in pain sensitivity in female rats. J. Pain 8, 962–969 (2007).

    Article  Google Scholar 

  48. McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12, 342–348 (2009).

    Article  CAS  Google Scholar 

  49. McGowan, P. O. et al. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE 3, e2085 (2008).

    Article  Google Scholar 

  50. Cameron, N. M. et al. Epigenetic programming of phenotypic variations in reproductive strategies in the rat through maternal care. J. Neuroendocrinol. 20, 795–801 (2008).

    Article  CAS  Google Scholar 

  51. Meaney, M. J., Szyf, M. & Seckl, J. R. Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol. Med. 13, 269–277 (2007).

    Article  CAS  Google Scholar 

  52. Murgatroyd, C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat. Neurosci. 12, 1559–1566 (2009).

    Article  CAS  Google Scholar 

  53. Talley, N. J. Serotoninergic neuroenteric modulators. Lancet 358, 2061–2068 (2001).

    Article  CAS  Google Scholar 

  54. Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004).

    Article  CAS  Google Scholar 

  55. Shanahan, F. Gut microbes: from bugs to drugs. Am. J. Gastroenterol. 105, 275–279 (2010).

    Article  Google Scholar 

  56. O'Mahony, C. et al. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NFκB activation. PLoS Pathog. 4, e1000112 (2008).

    Article  Google Scholar 

  57. McKernan, D. P. et al. Toll-like receptor mRNA expression is selectively increased in the colonic mucosa of two animal models relevant to irritable bowel syndrome. PLoS ONE 4, e8226 (2010).

    Article  Google Scholar 

  58. Kallio, P. et al. Dietary carbohydrate modification induces alterations in gene expression in abdominal subcutaneous adipose tissue in persons with the metabolic syndrome: the FUNGENUT Study. Am. J. Clin. Nutr. 85, 1417–1427 (2007).

    Article  CAS  Google Scholar 

  59. O'Mahony, L. et al. A randomized, placebo-controlled, double-blind comparison of the probiotic bacteria lactobacillus and bifidobacterium in irritable bowel syndrome (IBS): symptom responses and relationship to cytokine profiles. Gastroenterology 128, 541–551 (2005).

    Article  Google Scholar 

  60. Kapeller, J. et al. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum. Mol. Genet. 17, 2967–2977 (2008).

    Article  CAS  Google Scholar 

  61. Zhou, Q., Souba, W. W., Croce, C. M. & Verne, G. N. MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome. Gut 59, 775–784 (2010).

    Article  CAS  Google Scholar 

  62. Fitzgerald, P. et al. Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2, 3-dioxygenase activation in a male cohort. BMC Gastroenterol. 9, 6 (2009).

    Article  Google Scholar 

  63. Fitzgerald, P. et al. Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity. Neurogastroenterol. Motil. 20, 1291–1297 (2008).

    Article  CAS  Google Scholar 

  64. Dinan, T. G. et al. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: Plasma cytokines as a potential biomarker? Gastroenterology 130, 304–311 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are supported in part by Science Foundation Ireland in the form of a center grant (Alimentary Pharmabiotic Center), by the Health Research Board of Ireland, and the Higher Education Authority of Ireland. They are also in receipt of research funding from the pharmaceutical company GSK.

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Authors and Affiliations

  1. Alimentary Pharmabiotic Center, University College Cork, College Road, Cork, Ireland

    Timothy G. Dinan, John Cryan, Fergus Shanahan & Eamonn M. M. Quigley

  2. Department of Medicine, Trinity College, College Green, 2, Dublin, Ireland

    P. W. Napoleon Keeling

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Correspondence to Timothy G. Dinan.

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Dinan, T., Cryan, J., Shanahan, F. et al. IBS: an epigenetic perspective. Nat Rev Gastroenterol Hepatol 7, 465–471 (2010). https://doi.org/10.1038/nrgastro.2010.99

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