International Urogynecology Journal

, Volume 30, Issue 3, pp 363–370 | Cite as

The potential role of folate metabolism in interstitial cystitis

  • Carolyn D. KeagyEmail author
Review Article


The topic of interstitial cystitis (IC), also known as painful bladder syndrome (PBS), and folate/one carbon metabolism has previously been unaddressed in research. This narrative review highlights a potential connection for those with mast cell-related IC and histamine-mediated pain that is explored through four conceptual sections. The first section focuses on the nature of mast cell involvement and histamine-mediated pain in some interstitial cystitis patients. The second section reviews the literature on folate status in wider allergic conditions. The third section addresses the role of folate and methylation in general in histamine excretion. Finally, folate metabolism and vascular function are addressed because of the vascular abnormalities present in some IC bladders.


Interstitial cystitis Painful bladder syndrome Folate Histamine Allergy Vascular endothelial growth factor 


Compliance with ethical standards

Conflicts of interest

This work is unfunded, and entirely authored by C. Keagy, with no conflicts of interest.


  1. 1.
    Logadottir Y, Fall M, Kåbjörn-Gustafsson C, Peeker R. Clinical characteristics differ considerably between phenotypes of bladder pain syndrome/interstitial cystitis. Scand J Urol Nephrol. 2012;46(5):365–70. Scholar
  2. 2.
    FitzGerald MP, Payne CK, Lukacz ES, et al. Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. J Urol. 2012;187(6):2113–8. Scholar
  3. 3.
    Cervigni M. Interstitial cystitis/bladder pain syndrome and glycosaminoglycans replacement therapy. Translat Androl Urol. 2015;4(6):638–42. Scholar
  4. 4.
    Rudick CN, Bryce PJ, Guichelaar LA, Berry RE, Klumpp DJ. Mast cell-derived histamine mediates cystitis pain. PLoS One. 2008;3(5):e2096. Scholar
  5. 5.
    Chen HM, Lin CC, Kang CS, Lee CT, Lin HC, Chung SD. Bladder pain syndrome/interstitial cystitis increase the risk of coronary heart disease. Neurourol Urodyn. 2014;33(5):511–5. Scholar
  6. 6.
    Chung SD, Xirasagar S, Lin CC, Ling W, Li HC, Lin HC. Increased risk of ischemic stroke among women with bladder pain syndrome/interstitial cystitis: a cohort study from Taiwan. Neurourol Urodyn. 2015;34(1):44–9. Scholar
  7. 7.
    Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology. 1997;49 ((5):52–7. Scholar
  8. 8.
    Dinis S, de Oliveira JT, Pinto R, Cruz F, Buffington CAT, Dinis P. From bladder to systemic syndrome: concept and treatment evolution of interstitial cystitis. Int J Women’s Health. 2015;7:735–44. Scholar
  9. 9.
    Lee J, Doggweiler-Wiygul R, Kim S, Hill BD, Yoo TJ. Is interstitial cystitis an allergic disorder?: a case of interstitial cystitis treated successfully with anti-IgE. Int J Urol. 2006;13(5):631–4. Scholar
  10. 10.
    Jhang JF, Hsu YH, Jiang YH, Kuo HC. The role of immunoglobulin E in the pathogenesis of ketamine related cystitis and ulcerative interstitial cystitis: an immunohistochemical study. Pain Phys. 2016;19(4):E581–7.Google Scholar
  11. 11.
    Boucher W, El-Mansoury M, Pang X, Sant GR, Theoharides TC. Elevated mast cell tryptase in the urine of patients with interstitial cystitis. Br J Urol. 1995;76(1):94–100. Scholar
  12. 12.
    Letourneau R, Pang X, Sant GR, Theoharides TC. Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis. Br J Urol. 1996;77(1):41–54. Scholar
  13. 13.
    Bicer F, Altuntas CZ, Izgi K, et al. Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model. Am J Physiol Renal Physiol. 2015;308(2):F103–13. Scholar
  14. 14.
    Spanos C, Pang X, Ligris K, et al. Stress-induced bladder mast cell activation: implications for interstitial cystitis. J Urol. 1997;157(2):669–72. Scholar
  15. 15.
    Theoharides TC, Sant GR, El-Mansoury M, Letourneau R, Ucci AA Jr, Meares EM Jr. Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. J Urol. 1995;153(3):629–36. Scholar
  16. 16.
    Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001;57(6, Suppl 1):47–55. Scholar
  17. 17.
    Yamada T, Murayama T, Mita H, Akiyama K. Subtypes of bladder mast cells in interstitial cystitis. Int J Urol. 2001;7(8):292–7. Scholar
  18. 18.
    Sant GR, Kempuraj D, Marchand JE, Theoharides TC. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology. 2007;69(4 Suppl):34–40. doi: Scholar
  19. 19.
    Martin Jensen M, Jia W, Schults AJ, Ye X, Prestwich GD, Oottamasathien S. IL-33 mast cell axis is central in LL-37 induced bladder inflammation and pain in a murine interstitial cystitis model. Cytokine. 2018;110:420–27. Scholar
  20. 20.
    Malik ST, Birch BR, Voegeli D, et al. Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies? J Clin Pathol. 2018;71(9):840–44.PubMedGoogle Scholar
  21. 21.
    Regauer S. Mast cell activation syndrome in pain syndromes bladder pain syndrome/interstitial cystitis and vulvodynia. Translat Androl Urol. 2016;5(3):396–7. Scholar
  22. 22.
    Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011;4(1):10. Scholar
  23. 23.
    Ratner V. Mast cell activation syndrome. Translat Androl Urol. 2015;4(5):587–8. Scholar
  24. 24.
    Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin N Am. 2006;26(3):465–85. doi: Scholar
  25. 25.
    Husemoen LL, Toft U, Fenger M, Jorgensen T, Johansen N, Linneberg A. The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy? Int J Epidemiol. 2006;35(4):954–61. Scholar
  26. 26.
    Haberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child. 2009;94(3):180–4. Scholar
  27. 27.
    Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;170(12):1486–93. Scholar
  28. 28.
    Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015;101(6):1286–94. Scholar
  29. 29.
    Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol. 2004;159(5):423–43. Scholar
  30. 30.
    Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185–96. Scholar
  31. 31.
    Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98(5):1272–81. Scholar
  32. 32.
    Brown SB, Reeves KW, Bertone-Johnson ER. Maternal folate exposure in pregnancy and childhood asthma and allergy: a systematic review. Nutr Rev. 2014;72(1):55–64.PubMedGoogle Scholar
  33. 33.
    Wang T, Zhang H-P, Zhang X, Liang Z-A, Ji Y-L, Wang G. Is folate status a risk factor for asthma or other allergic diseases? Allergy Asthma Immunol Res. 2015;7(6):538–46.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Magdelijns FJH, Mommers M, Penders J, Smits L, Thijs C. Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. Pediatrics. 2011;128(1):e135–44. Scholar
  35. 35.
    McGowan EC, Hong X, Selhub J, et al. The association between folate/folic acid metabolites and the development of food allergy (FA) in children. J Allergy Clin Immunol. 2018;141(2, Supplement):AB86. Scholar
  36. 36.
    Yang L, Jiang L, Bi M, et al. High dose of maternal folic acid supplementation is associated to infant asthma. Food Chem Toxicol. 2015;75:88–93. Scholar
  37. 37.
    Zetstra-van der Woude PA, De Walle HEK, Hoek A, et al. Maternal high-dose folic acid during pregnancy and asthma medication in the offspring. Pharmacoepidemiol Drug Saf. 2014;23(10):1059–65. Scholar
  38. 38.
    Blatter J, Han YY, Forno E, Brehm J, Bodnar L, Celedon JC. Folate and asthma. Am J Respir Crit Care Med. 2013;188(1):12–7. Scholar
  39. 39.
    Blatter J, Brehm JM, Sordillo J, et al. Folate deficiency, atopy, and severe asthma exacerbations in Puerto Rican children. Ann Am Thor Soc. 2016;13(2):223–30. Scholar
  40. 40.
    Montrose L, Ward TJ, Semmens EO, Cho YH, Brown B, Noonan CW. Dietary intake is associated with respiratory health outcomes and DNA methylation in children with asthma. Allergy Asthma Clin Immunol. 2017;13:12. Scholar
  41. 41.
    Thuesen BH, Husemoen LLN, Ovesen L, et al. Atopy, asthma, and lung function in relation to folate and vitamin B12 in adults. Allergy. 2010;65(11):1446–54. Scholar
  42. 42.
    Matsui EC, Matsui W. Higher serum folate levels are associated with a lower risk of atopy and wheeze. J Allergy Clin Immunol. 2009;123(6):1253–1259.e1252. Scholar
  43. 43.
    Farres MN, Shahin RY, Melek NA, El-Kabarity RH, Arafa NA. Study of folate status among Egyptian asthmatics. Intern Med. 2011;50(3):205–11. Scholar
  44. 44.
    Gustafsson A, Forshell G. Studies on the enzymic methylation of histamine. Acta Chem Scand. 1964;18:2069–76.Google Scholar
  45. 45.
    Schayer RW, Karjala S. Ring N methylation; a major route of histamine metabolism. J Biol Chem. 1956;221(1):307–14.PubMedGoogle Scholar
  46. 46.
    Granerus G. Urinary excretion of histamine, methylhistamine and methylimidazoleacetic acids in man under standardized dietary conditions. Scand J Clin Lab Invest. 1968;104:59–68.Google Scholar
  47. 47.
    Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging. 2002;6(1):39–42.PubMedGoogle Scholar
  48. 48.
    Brown DD, Tomchick R, Axelrod J. The distribution and properties of a histamine-methylating enzyme. J Biol Chem. 1959;234:2948–50.PubMedGoogle Scholar
  49. 49.
    Duch DS, Edelstein MP, Nichol CA. Inhibition of histamine-metabolizing enzymes and elevation of histamine levels in tissues by lipid-soluble anticancer folate antagonists. Mol Pharmacol. 1980;18(1):100.PubMedGoogle Scholar
  50. 50.
    Ishizaka T, Hirata F, Ishizaka K, Axelrod J. Stimulation of phospholipid methylation, Ca2+ influx, and histamine release by bridging of IgE receptors on rat mast cells. Proc Natl Acad Sci. 1980;77(4):1903–6.PubMedGoogle Scholar
  51. 51.
    Hirata F, Axelrod J, Crews FT. Concanavalin a stimulates phospholipid methylation and phosphatidylserine decarboxylation in rat mast cells. Proc Natl Acad Sci U S A. 1979;76(10):4813–6.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Sharma S, Litonjua A. Asthma, allergy, and responses to methyl donor supplements and nutrients. J Allergy Clin Immunol. 2014;133(5):1246–54. Scholar
  53. 53.
    Manzotti G, Breda D, Di Gioacchino M, Burastero SE. Serum diamine oxidase activity in patients with histamine intolerance. Int J Immunopathol Pharmacol. 2016;29(1):105–11. Scholar
  54. 54.
    Wagner N, Dirk D, Peveling-Oberhag A, et al. A popular myth—low-histamine diet improves chronic spontaneous urticaria—fact or fiction? J Eur Acad Dermatol Venereol. 2017;31(4):650–5. Scholar
  55. 55.
    Saban R. Angiogenic factors, bladder neuroplasticity and interstitial cystitis—new pathobiological insights. Transl Androl Urol. 2015;4(5):555–62. Scholar
  56. 56.
    Peng CH, Jhang JF, Shie JH, Kuo HC. Down regulation of vascular endothelial growth factor is associated with decreased inflammation after intravesical OnabotulinumtoxinA injections combined with hydrodistention for patients with interstitial cystitis—clinical results and immunohistochemistry analysis. Urology. 2013;82(6):1452.e1451–6. Scholar
  57. 57.
    Rosamilia A, Cann L, Dwyer P, Scurry J, Rogers P. Bladder microvasculature in women with interstitial cystitis. J Urol. 1999;161(6):1865–70.PubMedGoogle Scholar
  58. 58.
    Yamada T, Nishimura M, Mita H. Increased number of apoptotic endothelial cells in bladder of interstitial cystitis patients. World J Urol. 2007;25(4):407–13. Scholar
  59. 59.
    Roybal CN, Yang S, Sun CW, et al. Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem. 2004;279(15):14844–52. Scholar
  60. 60.
    Maeda M, Yamamoto I, Fujio Y, Azuma J. Homocysteine induces vascular endothelial growth factor expression in differentiated THP-1 macrophages. Biochim Biophys Acta Gen Subj. 2003;1623(1):41–6. Scholar
  61. 61.
    Herrmann M, Taban-Shomal O, Hübner U, Böhm M, Herrmann W. A review of homocysteine and heart failure. Eur J Heart Fail. 2006;8(6):571–6. Scholar
  62. 62.
    Singh AP, Singh M, Balakumar P. Effect of mast cell stabilizers in hyperhomocysteinemia-induced cardiac hypertrophy in rats. J Cardiovasc Pharmacol. 2008;51(6):596–604. Scholar
  63. 63.
    Joseph J, Kennedy RH, Devi S, Wang J, Joseph L, Hauer-Jensen M. Protective role of mast cells in homocysteine-induced cardiac remodeling. Am J Physiol Heart Circ Physiol. 2005;288(5):H2541–5. Scholar
  64. 64.
    Spence JD. Homocysteine lowering for stroke prevention: unravelling the complexity of the evidence. Int J Stroke. 2016;11(7):744–7. Scholar
  65. 65.
    Clejan S, Japa S, Clemetson C, Hasabnis SS, David O, Talano JV. Blood histamine is associated with coronary artery disease, cardiac events and severity of inflammation and atherosclerosis. J Cell Mol Med. 2002;6(4):583–92.PubMedGoogle Scholar
  66. 66.
    Zdravkovic V, Pantovic S, Rosic G, et al. Histamine blood concentration in ischemic heart disease patients. J Biomed Biotechnol. 2011;2011:8. Scholar
  67. 67.
    Frye R, Sequeira J, Quadros E, James S, Rossignol D. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013;18(3):369.PubMedGoogle Scholar
  68. 68.
    Ramaekers VT, Rothenberg SP, Sequeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005;352(19):1985–91.PubMedGoogle Scholar

Copyright information

© The International Urogynecological Association 2018

Authors and Affiliations

  1. 1.Kaiser PermanenteBerkeleyUSA

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