, Volume 36, Issue 4, pp 855–861 | Cite as

Increased Fecal Levels of Chromogranin A, Chromogranin B, and Secretoneurin in Collagenous Colitis

  • Michael Wagner
  • Mats Stridsberg
  • Christer G. B. Peterson
  • Per Sangfelt
  • Maria Lampinen
  • Marie Carlson


Interactions between the enteric nervous system and the immune system are suggested to play an important role in the pathophysiology of inflammatory bowel disease (IBD). This study aims to determine if chromogranin A (CgA), chromogranin B (CgB), and secretoneurin (SN) are detectable in feces (F) from patients with collagenous colitis (CC) and to compare the levels found in patients with ulcerative colitis (UC) and Crohn’s disease (CD) before and during treatment. Patients with CC (n = 12) were studied before and after 3, 7, 28, and 56 days of treatment. Patients with IBD (UC, n = 21; CD, n = 11) were studied before and after 28 and 56 days of treatment. Clinical data were recorded, and fecal samples were collected at each occasion. F-CgA, F-CgB, and F-SN were measured by RIA. Eleven patients with CC, 21 with UC, and 10 with CD achieved remission. On inclusion, CC patients had higher levels of F-CgA, F-CgB, and F-SN than patients with IBD and controls. Patients with IBD expressed markedly lower levels of F-SN than controls. During treatment, F-SN in CC patients decreased to control levels but remained low in IBD patients. No change was found in F-CgA or F-CgB in any of the groups. In conclusion, CgA, CgB, and SN are detectable in feces, and CC patients express higher values than patients with IBD and controls. During treatment, F-SN decreased to control levels in CC. These findings suggest that the enteric nervous system is clearly involved in the pathophysiology of CC.


collagenous colitis inflammatory bowel disease chromogranin A chromogranin B secretoneurin fecal samples 



Collagenous colitis


Crohn’s disease


Chromogranin A


Chromogranin B




Enteric nervous system


Fecal calprotectin


Healthy control subjects


Inflammatory bowel disease






Nonsteroid anti-inflammatory drugs






Ulcerative colitis


Vascular endothelial growth factor



This study was supported by grants from the Swedish Research Council–Medicine, the Hedlunds Foundation, and from the Medical Faculty, Uppsala University, Uppsala, Sweden. We acknowledge the skillful technical assistance of Inger Olsson and the practical support from Ingrid Stolt.

Conflict of interest



  1. 1.
    Collins, S.M. 1996. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 111(6): 1683–1699.PubMedCrossRefGoogle Scholar
  2. 2.
    Goyal, R.K., and I. Hirano. 1996. The enteric nervous system. The New England Journal of Medicine 334(17): 1106–1115.PubMedCrossRefGoogle Scholar
  3. 3.
    Gross, K.J., and C. Pothoulakis. 2007. Role of neuropeptides in inflammatory bowel disease. Inflammatory Bowel Diseases 13(7): 918–932.PubMedCrossRefGoogle Scholar
  4. 4.
    Levite, M., and Y. Chowers. 2001. Nerve-driven immunity: neuropeptides regulate cytokine secretion of T cells and intestinal epithelial cells in a direct, powerful and contextual manner. Annals of Oncology 12(Suppl 2): S19–S25.PubMedCrossRefGoogle Scholar
  5. 5.
    Castagliuolo, I., A.C. Keates, B. Qiu, et al. 1997. Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proceedings of the National Academy of Sciences of the United States of America 94(9): 4788–4793.PubMedCrossRefGoogle Scholar
  6. 6.
    Liu, L., F. Shang, and I. Markus. 2002. Roles of substance P receptors in human colon circular muscle: alterations in diverticular disease. The Journal of Pharmacology and Experimental Therapeutics 302(2): 627–635.PubMedCrossRefGoogle Scholar
  7. 7.
    Mantyh, C.R., T.S. Gates, R.P. Zimmerman, et al. 1988. Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease. Proceedings of the National Academy of Sciences of the United States of America 85(9): 3235–3239.PubMedCrossRefGoogle Scholar
  8. 8.
    Renzi, D., B. Pellegrini, F. Tonelli, et al. 2000. Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine. The American Journal of Pathology 157(5): 1511–1522.PubMedCrossRefGoogle Scholar
  9. 9.
    Granberg, D., M. Stridsberg, R. Seensalu, et al. 1999. Plasma chromogranin A in patients with multiple endocrine neoplasia type 1. The Journal of Clinical Endocrinology and Metabolism 84(8): 2712–2717.PubMedCrossRefGoogle Scholar
  10. 10.
    Sciola, V., S. Massironi, D. Conte, et al. 2009. Plasma chromogranin A in patients with inflammatory bowel disease. Inflammatory Bowel Diseases 15(6): 867–871.PubMedCrossRefGoogle Scholar
  11. 11.
    Spadaro, A., A. Ajello, C. Morace, et al. 2005. Serum chromogranin-A in hepatocellular carcinoma: diagnostic utility and limits. World Journal of Gastroenterology 11(13): 1987–1990.PubMedGoogle Scholar
  12. 12.
    Briolat, J., S.D. Wu, S.K. Mahata, et al. 2005. New antimicrobial activity for the catecholamine release-inhibitory peptide from chromogranin A. Cellular and Molecular Life Sciences 62(3): 377–385.PubMedCrossRefGoogle Scholar
  13. 13.
    Lugardon, K., R. Raffner, Y. Goumon, et al. 2000. Antibacterial and antifungal activities of vasostatin-1, the N-terminal fragment of chromogranin A. The Journal of Biological Chemistry 275(15): 10745–10753.PubMedCrossRefGoogle Scholar
  14. 14.
    Russell, J., P. Gee, S.M. Liu, et al. 1994. Inhibition of parathyroid hormone secretion by amino-terminal chromogranin peptides. Endocrinology 135(1): 337–342.PubMedCrossRefGoogle Scholar
  15. 15.
    Strub, J.M., P. Garcia-Sablone, K. Lonning, et al. 1995. Processing of chromogranin B in bovine adrenal medulla. Identification of secretolytin, the endogenous C-terminal fragment of residues 614-626 with antibacterial activity. European Journal of Biochemistry/FEBS 229(2): 356–368.PubMedCrossRefGoogle Scholar
  16. 16.
    Stridsberg, M., B. Eriksson, B. Fellstrom, et al. 2007. Measurements of chromogranin B can serve as a complement to chromogranin A. Regulatory Peptides 139(1–3): 80–83.PubMedCrossRefGoogle Scholar
  17. 17.
    Stridsberg, M., and E.S. Husebye. 1997. Chromogranin A and chromogranin B are sensitive circulating markers for phaeochromocytoma. European Journal of Endocrinology/European Federation of Endocrine Societies 136(1): 67–73.PubMedCrossRefGoogle Scholar
  18. 18.
    Stridsberg, M., K. Oberg, Q. Li, et al. 1995. Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. The Journal of Endocrinology 144(1): 49–59.PubMedCrossRefGoogle Scholar
  19. 19.
    Kirchmair, R., R. Hogue-Angeletti, J. Gutierrez, et al. 1993. Secretoneurin–a neuropeptide generated in brain, adrenal medulla and other endocrine tissues by proteolytic processing of secretogranin II (chromogranin C). Neuroscience 53(2): 359–365.PubMedCrossRefGoogle Scholar
  20. 20.
    Schurmann, G., A.E. Bishop, P. Facer, et al. 1995. Secretoneurin: a new peptide in the human enteric nervous system. Histochemistry and Cell Biology 104(1): 11–19.PubMedCrossRefGoogle Scholar
  21. 21.
    Dunzendorfer, S., P. Schratzberger, N. Reinisch, et al. 1998. Secretoneurin, a novel neuropeptide, is a potent chemoattractant for human eosinophils. Blood 91(5): 1527–1532.PubMedGoogle Scholar
  22. 22.
    Schratzberger, P., N. Reinisch, C.M. Kahler, et al. 1996. Deactivation of chemotaxis of human neutrophils by priming with secretogranin II-derived secretoneurin. Regulatory Peptides 63(2–3): 65–71.PubMedCrossRefGoogle Scholar
  23. 23.
    Furness, J.B., C. Jones, K. Nurgali, et al. 2004. Intrinsic primary afferent neurons and nerve circuits within the intestine. Progress in Neurobiology 72(2): 143–164.PubMedCrossRefGoogle Scholar
  24. 24.
    Fujimiya, M., K. Okumiya, and A. Kuwahara. 1997. Immunoelectron microscopic study of the luminal release of serotonin from rat enterochromaffin cells induced by high intraluminal pressure. Histochemistry and Cell Biology 108(2): 105–113.PubMedCrossRefGoogle Scholar
  25. 25.
    Okumiya, K., and M. Fujimiya. 1999. Immunoelectron microscopic study of the luminal release of chromogranin A from rat enterochromaffin cells. Histochemistry and Cell Biology 111(4): 253–257.PubMedCrossRefGoogle Scholar
  26. 26.
    Peterson, C.G., P. Sangfelt, M. Wagner, et al. 2007. Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis. Scandinavian Journal of Clinical and Laboratory Investigation 67(8): 810–820.PubMedCrossRefGoogle Scholar
  27. 27.
    Wagner, M., C.G. Peterson, P. Ridefelt, et al. 2008. Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease. World Journal of Gastroenterology 14(36): 5584–5589. discussion 8.PubMedCrossRefGoogle Scholar
  28. 28.
    Wagner, M., C.G. Peterson, I. Stolt, et al. 2011. Fecal eosinophil cationic protein as a marker of active disease and treatment outcome in collagenous colitis: a pilot study. Scandinavian Journal of Gastroenterology 46(7–8): 849–854.PubMedCrossRefGoogle Scholar
  29. 29.
    Peterson, C.G., E. Eklund, Y. Taha, et al. 2002. A new method for the quantification of neutrophil and eosinophil cationic proteins in feces: establishment of normal levels and clinical application in patients with inflammatory bowel disease. The American Journal of Gastroenterology 97(7): 1755–1762.PubMedCrossRefGoogle Scholar
  30. 30.
    Stridsberg, M., B. Eriksson, and E.T. Janson. 2008. Measurements of secretogranins II, III, V and proconvertases 1/3 and 2 in plasma from patients with neuroendocrine tumours. Regulatory Peptides 148(1–3): 95–98.PubMedCrossRefGoogle Scholar
  31. 31.
    Wagner, M., M. Lampinen, P. Sangfelt, et al. 2010. Budesonide treatment of patients with collagenous colitis restores normal eosinophil and T-cell activity in the colon. Inflammatory Bowel Diseases 16(7): 1118–1126.PubMedCrossRefGoogle Scholar
  32. 32.
    Munch, A., J.D. Soderholm, A. Ost, et al. 2009. Increased transmucosal uptake of E. coli K12 in collagenous colitis persists after budesonide treatment. The American Journal of Gastroenterology 104(3): 679–685.PubMedCrossRefGoogle Scholar
  33. 33.
    Bürgel, N., C. Bojarski, J. Mankerts, et al. 2002. Mechanism of diarrhea in collagenous colitis. Gastroenterology 123(2): 433–443.PubMedCrossRefGoogle Scholar
  34. 34.
    Aoki, S., M. Watanabe, H. Hasegawa, et al. 2004. Rectal carcinoid arising in ulcerative colitis associated with rectal adenocarcinoma. Journal of Gastroenterology 39(7): 697–698.PubMedCrossRefGoogle Scholar
  35. 35.
    El-Salhy, M., A. Danielsson, R. Stenling, et al. 1997. Colonic endocrine cells in inflammatory bowel disease. Journal of Internal Medicine 242(5): 413–419.PubMedCrossRefGoogle Scholar
  36. 36.
    Matsumoto, T., Y. Jo, R. Mibu, et al. 2003. Multiple microcarcinoids in a patient with long standing ulcerative colitis. Journal of Clinical Pathology 56(12): 963–965.PubMedCrossRefGoogle Scholar
  37. 37.
    Miller, R.R., and H.W. Sumner. 1982. Argyrophilic cell hyperplasia and an atypical carcinoid tumor in chronic ulcerative colitis. Cancer 50(12): 2920–2925.PubMedCrossRefGoogle Scholar
  38. 38.
    Rybakova, M.G., A.V. Botina, and O.I. Solov’eva. 2005. Immunomorphological characteristics of mucosal and endocrine cells of the colon in patients with chronic ulcerative colitis. Arkhiv Patologii 67(2): 30–33.PubMedGoogle Scholar
  39. 39.
    Stewart, C.J., T. Matsumoto, Y. Jo, et al. 2005. Multifocal microcarcinoid tumours in ulcerative colitis. Journal of Clinical Pathology 58(1): 111–112. author reply 1112.PubMedCrossRefGoogle Scholar
  40. 40.
    Elliott, S.N., and J.L. Wallace. 1998. Neutrophil-mediated gastrointestinal injury. Canadian Journal of Gastroenterology=Journal Canadien de Gastroenterologie 12(8): 559–568.PubMedGoogle Scholar
  41. 41.
    Panes, J., and D.N. Granger. 1998. Leukocyte–endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease. Gastroenterology 114(5): 1066–1090.PubMedCrossRefGoogle Scholar
  42. 42.
    Langhorst, J., S. Elsenbruch, T. Mueller, et al. 2005. Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity in ulcerative colitis. Inflammatory Bowel Diseases 11(12): 1085–1091.PubMedCrossRefGoogle Scholar
  43. 43.
    Roseth, A.G., E. Aadland, J. Jahnsen, et al. 1997. Assessment of disease activity in ulcerative colitis by faecal calprotectin, a novel granulocyte marker protein. Digestion 58(2): 176–180.PubMedCrossRefGoogle Scholar
  44. 44.
    Tibble, J., K. Teahon, B. Thjodleifsson, et al. 2000. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut 47(4): 506–513.PubMedCrossRefGoogle Scholar
  45. 45.
    Korsgren, M., J.S. Erjefalt, J. Hinterholzl, et al. 2003. Neural expression and increased lavage fluid levels of secretoneurin in seasonal allergic rhinitis. American Journal of Respiratory and Critical Care Medicine 167(11): 1504–1508.PubMedCrossRefGoogle Scholar
  46. 46.
    Korsgren, M., R. Fischer-Colbrie, M. Andersson, et al. 2005. Secretoneurin is released into human airways by topical histamine but not capsaicin. Allergy 60(4): 459–463.PubMedCrossRefGoogle Scholar
  47. 47.
    O’Brien, L.M., E. Fitzpatrick, A.W. Baird, et al. 2008. Eosinophil-nerve interactions and neuronal plasticity in rat gut associated lymphoid tissue (GALT) in response to enteric parasitism. Journal of Neuroimmunology 197(1): 1–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Stead, R.H. 1992. Innervation of mucosal immune cells in the gastrointestinal tract. Regional Immunology 4(2): 91–99.PubMedGoogle Scholar
  49. 49.
    Costello, R.W., B.H. Schofield, G.M. Kephart, et al. 1997. Localization of eosinophils to airway nerves and effect on neuronal M2 muscarinic receptor function. The American Journal of Physiology 273(1 Pt 1): L93–L103.PubMedGoogle Scholar
  50. 50.
    Flejou, J.F., J.A. Grimaud, G. Molas, et al. 1984. Collagenous colitis. Ultrastructural study and collagen immunotyping of four cases. Archives of Pathology & Laboratory Medicine 108(12): 977–982.Google Scholar
  51. 51.
    Widgren, S., R. Jlidi, and J.N. Cox. 1988. Collagenous colitis: histologic, morphometric, immunohistochemical and ultrastructural studies. Report of 21 cases. Virchows Archiv 413(4): 287–296.PubMedCrossRefGoogle Scholar
  52. 52.
    Kingham, J.G., D.A. Levison, B.C. Morson, et al. 1986. Collagenous colitis. Gut 27(5): 570–577.PubMedCrossRefGoogle Scholar
  53. 53.
    Teglbjaerg, P.S., and E.H. Thaysen. 1982. Collagenous colitis: an ultrastructural study of a case. Gastroenterology 82(3): 561–563.PubMedGoogle Scholar
  54. 54.
    Yan, S., X. Wang, H. Chai, et al. 2006. Secretoneurin increases monolayer permeability in human coronary artery endothelial cells. Surgery 140(2): 243–251.PubMedCrossRefGoogle Scholar
  55. 55.
    Kirchmair, R., R. Gander, M. Egger, et al. 2004. The neuropeptide secretoneurin acts as a direct angiogenic cytokine in vitro and in vivo. Circulation 109(6): 777–783.PubMedCrossRefGoogle Scholar
  56. 56.
    Taha, Y., Y. Raab, A. Larsson, et al. 2004. Vascular endothelial growth factor (VEGF)—a possible mediator of inflammation and mucosal permeability in patients with collagenous colitis. Digestive Diseases and Sciences 49(1): 109–115.PubMedCrossRefGoogle Scholar
  57. 57.
    Taha, Y., Y. Raab, M. Carlson, et al. 2006. Steroids reduce local inflammatory mediator secretion and mucosal permeability in collagenous colitis patients. World Journal of Gastroenterology 12(43): 7012–7018.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Michael Wagner
    • 1
  • Mats Stridsberg
    • 2
  • Christer G. B. Peterson
    • 1
  • Per Sangfelt
    • 1
  • Maria Lampinen
    • 1
  • Marie Carlson
    • 1
  1. 1.Department of Medical Sciences, Gastroenterology Research GroupUppsala UniversityUppsalaSweden
  2. 2.Department of Clinical ChemistryUppsala UniversityUppsalaSweden

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