Ubiquitous Colonic Ileal Metaplasia Consistent with the Diagnosis of Crohn’s Colitis among Indeterminate Colitis Cohorts

Main Article Content

Amosy E. M'Koma William A. Breaux Maya A. Bragg

Abstract

Background: Inadequate differentiated diagnostic features of predominantly colonic inflammatory bowel diseases i.e., ulcerative colitis and Crohn’s colitis, may lead to inexact diagnosis of “indeterminate colitis”. About 15% of indeterminate colitis patients are diagnosed at colonoscopy, in colonic biopsies, and/or at colectomy. Managing outcomes of indeterminate colitis, given its unpredictable clinical presentation, depends on future diagnosis of colitis, Crohn’s colitis or ulcerative colitis.


Objective: Overview the diagnostic efficacy of ectopic colonic ileal metaplasia and human α-defens 5 (DEFA5 alias HD5) for accurate delineation of indeterminate colitis into authentic Crohn’s colitis and/ or ulcerative colitis.


Design: We describe a targeted protein for potentially differentiating indeterminate colitis into an accurate clinical subtype diagnosis of inflammatory bowel diseases i.e., ulcerative colitis and Crohn’s colitis.


Patients: Twenty-one patients with the clinically inexact diagnosis of indeterminate colitis were followed, reassessed and data analyzed.


Main outcome measures: We observed that (i) some patients had their original diagnosis changed from indeterminate colitis to either ulcerative colitis or Crohn’s colitis; and (ii) human α-defensin 5 is aberrantly overexpressed in Crohn’s colitis.


Results: Fifteen of the twenty-one (71.4%) patients with indeterminate colitis had their inconclusive diagnosis changed; nine patients changed to ulcerative colitis and six to Crohn’s colitis. In human colon surgical samples, Human α-defensin-5 was significantly upregulated in Crohn’s colitis. In addition, Human α-defensin 5 processing enzyme, matrix metalloptotease-7 was inversely expressed compared to Human α- Defensin 5.


Limitation: Due to the sequence homology of the α-defensin class of proteins, preceding efforts to raise antibodies (Abs) against DEFA5 have limitations to produce adequate specificity. The Abs used in previous assays recognizes the α-defensins, active α-defensins 5 and inactive pro- α-defensins 5. Monoclonal antibodies (mAbs) to determine specificity and sensitivity of α-defensins 5, which is diagnostic of CC disease, and NOT other α-defensins is the limitation to overcome.


Conclusion: It is feasible to differentiate ulcerative colitis from Crohn’s colitis among patients with inexact diagnosis of indeterminate colitis using Human α-defensin 5 as a molecular biosignature delineator.

Keywords: inflammatory bowel disease, indeterminate colitis, Ulcerative colitis, Crohn’s colitis, Human alpha-defensin 5

Article Details

How to Cite
M'KOMA, Amosy E.; BREAUX, William A.; BRAGG, Maya A.. Ubiquitous Colonic Ileal Metaplasia Consistent with the Diagnosis of Crohn’s Colitis among Indeterminate Colitis Cohorts. Medical Research Archives, [S.l.], v. 11, n. 8, aug. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4188>. Date accessed: 22 apr. 2024. doi: https://doi.org/10.18103/mra.v11i8.4188.
Section
Research Articles

References

1. Burakoff R. Indeterminate colitis: clinical spectrum of disease. J Clin Gastroenterol. 2004;38(5 Suppl 1):S41-3. DOI: 10.1097/01.mcg.0000123991.13937.7e.
2. Carvalho RS, Abadom V, Dilworth HP, Thompson R, Oliva-Hemker M, Cuffari C. Indeterminate colitis: a significant subgroup of pediatric IBD. Inflammatory bowel diseases. 2006;12(4):258-62. DOI: 10.1097/01.MIB.0000215093.62245.b9.
3. M'Koma AE, Seeley EH, Washington MK, Schwartz DA, Muldoon RL, Herline AJ, Wise PE, Caprioli RM. Proteomic profiling of mucosal and submucosal colonic tissues yields protein signatures that differentiate the inflammatory colitides. Inflamm Bowel Dis. 2011;17(4):875-83. DOI: 10.1002/ibd.21442.
4. Seeley EH, Washington MK, Caprioli RM, M'Koma AE. Proteomic patterns of colonic mucosal tissues delineate Crohn's colitis and ulcerative colitis. Proteomics Clin Appl. 2013;7(7-8):541-9. DOI: 10.1002/prca.201200107.
5. Williams AD, Korolkova OY, Sakwe AM, Geiger TM, James SD, Muldoon RL, et al. Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease. PloS one. 2017;12(8):e0179710. DOI: 10.1371/journal.pone.0179710.
6. M'Koma AE, Wise PE, Muldoon RL, Schwartz DA, Washington MK, Herline AJ. Evolution of the restorative proctocolectomy and its effects on gastrointestinal hormones. Int J Colorectal Dis. 2007;22(10):1143-63. DOI: 10.1007/s00384-007-0331-x.
7. Shen B, Remzi FH, Brzezinski A, Lopez R, Bennett AE, Lavery IC, et al. Risk factors for pouch failure in patients with different phenotypes of Crohn's disease of the pouch. Inflammatory bowel diseases. 2008;14(7):942-8. DOI: 10.1002/ibd.20409
8. Shen B, Remzi FH, Lavery IC, Lashner BA, Fazio VW. A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy. Clin Gastroenterol Hepatol. 2008;6(2):145-58. DOI: 10.1016/j.cgh.2007.11.006.
9. Ricardo AP, Kayal M, Plietz MC, Khaitov S, Sylla P, Dubinsky MC, et al. Predictors of pouch failure: A tertiary care inflammatory bowel disease centre experience. Colorectal Dis. 2023. DOI: 10.1111/codi.16589.
10. Shen B. Crohn's disease of the ileal pouch: reality, diagnosis, and management. Inflammatory bowel diseases. 2009;15(2):284-94. DOI: 10.1002/ibd.20661
11. Malaty HM, Mehta S, Abraham B, Garnett EA, Ferry GD. The natural course of inflammatory bowel disease-indeterminate from childhood to adulthood: within a 25 year period. Clin Exp Gastroenterol. 2013;6:115-21. DOI: 10.2147/CEG.S44700
12. Malaty HM, Fan X, Opekun AR, Thibodeaux C, Ferry GD. Rising incidence of inflammatory bowel disease among children: a 12-year study. J Pediatr Gastroenterol Nutr. 2010;50(1):27-31. DOI: 10.1097/MPG.0b013e3181b99baa.
13. Keighley MR. The final diagnosis in pouch patients for presumed ulcerative colitis may change to Crohn's disease: patients should be warned of the consequences. Acta Chir Iugosl. 2000;47(4 Suppl 1):27-31. PMID: 11432239
14. Lawrance IC, Fiocchi C, Chakravarti S. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet. 2001;10(5):445-56. DOI: 10.1093/hmg/10.5.445.
15. Wang C, Shen M, Gohain N, Tolbert WD, Chen F, Zhang N, et al. Design of a potent antibiotic peptide based on the active region of human defensin 5. J Med Chem. 2015;58(7):3083-93. DOI: 10.1021/jm501824a.
16. Chileveru HR, Lim SA, Chairatana P, Wommack AJ, Chiang IL, Nolan EM. Visualizing attack of Escherichia coli by the antimicrobial peptide human defensin 5. Biochemistry. 2015;54(9):1767-77. DOI: 10.1021/bi501483q.
17. Wilson CL, Schmidt AP, Pirila E, Valore EV, Ferri N, Sorsa T, et al. Differential Processing of {alpha}- and {beta}-Defensin Precursors by Matrix Metalloproteinase-7 (MMP-7). J Biol Chem. 2009;284(13):8301-11. DOI: 10.1074/jbc.M809744200.
18. Vandenbroucke RE, Vanlaere I, Van Hauwermeiren F, Van Wonterghem E, Wilson C, Libert C. Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation. Mucosal Immunol. 2014;7(3):579-88. DOI: 10.1038/mi.2013.76.
19. Mastroianni JR, Costales JK, Zaksheske J, Selsted ME, Salzman NH, Ouellette AJ. Alternative luminal activation mechanisms for paneth cell alpha-defensins. J Biol Chem. 2012;287(14):11205-12. DOI: 10.1074/jbc.M111.333559.
20. Puri KS, Suresh KR, Gogtay NJ, Thatte UM. Declaration of Helsinki, 2008: implications for stakeholders in research. J Postgrad Med. 2009;55(2):131-4. DOI: 10.4103/0022-3859.52846.
21. Cook MG, Dixon MF. An analysis of the reliability of detection and diagnostic value of various pathological features in Crohn's disease and ulcerative colitis. Gut. 1973;14(4):255-62. DOI: 10.1136/gut.14.4.255.
22. Antonatos C, Panoutsopoulou M, Georgakilas GK, Evangelou E, Vasilopoulos Y. Gene Expression Meta-Analysis of Potential Shared and Unique Pathways between Autoimmune Diseases under Anti-TNFalpha Therapy. Genes (Basel). 2022;13(5). DOI: 10.3390/genes13050776.
23. Schaudy E, Lietard J, Somoza MM. Enzymatic Synthesis of High-Density RNA Microarrays. Curr Protoc. 2023;3(2):e667. DOI: 10.1002/cpz1.667.
24. Novianti PW, Jong VL, Roes KC, Eijkemans MJ. Factors affecting the accuracy of a class prediction model in gene expression data. BMC Bioinformatics. 2015;16:199. DOI: 10.1186/s12859-015-0610-4.
25. Atanassova A, Georgieva A. Circulating miRNA-16 in inflammatory bowel disease and some clinical correlations - a cohort study in Bulgarian patients. Eur Rev Med Pharmacol Sci. 2022;26(17):6310-5. DOI: 10.26355/eurrev_202209_29655.
26. Schaefer JS, Attumi T, Opekun AR, Abraham B, Hou J, Shelby H, et al. MicroRNA signatures differentiate Crohn's disease from ulcerative colitis. BMC immunology. 2015;16:5. DOI: 10.1186/s12865-015-0069-0.
27. Williams AD, Sakwe AM, D Smoot DT, Washington MK, Ballard BR, Geiger TM, M'Koma AE. Indeterminate Colitis Precision into Crohn's Colitis and Ulcerative Colitis Using Molecular Biometrics. Dis Colon Rectum 2016;59(5):E92-E93.
28. Myers JN, Schaffer MW, Korolkova OY, Williams AD, Gangula PR, M'Koma AE. Implications of the Colonic Deposition of Free Hemoglobin-alpha Chain: A Previously Unknown Tissue By-product in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2014;20(9):1530-47. DOI: 10.1097/MIB.0000000000000144.
29. Gmyr V, Bonner C, Lukowiak B, Pawlowski V, Dellaleau N, Belaich S, et al. Automated digital image analysis of islet cell mass using Nikon's inverted eclipse Ti microscope and software to improve engraftment may help to advance the therapeutic efficacy and accessibility of islet transplantation across centers. Cell Transplant. 2015;24(1):1-9. DOI: 10.3727/096368913X667493.
30. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, et al. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. Bmj. 2015;351:h5527. DOI: 10.1373/clinchem.2015.246280.
31. Ricciuto A, Fish JR, Tomalty DE, Carman N, Crowley E, Popalis C, et al. Diagnostic delay in Canadian children with inflammatory bowel disease is more common in Crohn's disease and associated with decreased height. Arch Dis Child. 2018;103(4):319-26. doi: 10.1136/archdischild-2017-313060.
32. Ricciuto A, Mack DR, Huynh HQ, Jacobson K, Otley AR, deBruyn J, et al. Diagnostic Delay Is Associated With Complicated Disease and Growth Impairment in Paediatric Crohn's Disease. J Crohns Colitis. 2021;15(3):419-31. DOI: 10.1093/ecco-jcc/jjaa197.
33. Jackson KL, Stocchi L, Duraes L, Rencuzogullari A, Bennett AE, Remzi FH. Long-Term Outcomes in Indeterminate Colitis Patients Undergoing Ileal Pouch-Anal Anastomosis: Function, Quality of Life, and Complications. J Gastrointest Surg. 2017;21(1):56-61. DOI: 10.1007/s11605-016-3306-9.
34. Novacek G, Grochenig HP, Haas T, Wenzl H, Steiner P, Koch R, et al. Diagnostic delay in patients with inflammatory bowel disease in Austria. Wien Klin Wochenschr. 2019;131(5-6):104-12. DOI: 10.1007/s00508-019-1451-3.
35. North American Society for Pediatric Gastroenterology H, Nutrition, Colitis Foundation of A, Bousvaros A, Antonioli DA, Colletti RB, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr. 2007;44(5):653-74. DOI: 10.1097/MPG.0b013e31805563f3
36. Murrell ZA, Melmed GY, Ippoliti A, Vasiliauskas EA, Dubinsky M, Targan SR, et al. A prospective evaluation of the long-term outcome of ileal pouch-anal anastomosis in patients with inflammatory bowel disease-unclassified and indeterminate colitis. Dis Colon Rectum. 2009;52(5):872-8. DOI: 10.1007/DCR.0b013e31819f5d4c.
37. Melton GB, Kiran RP, Fazio VW, He J, Shen B, Goldblum JR, et al. Do preoperative factors predict subsequent diagnosis of Crohn's disease after ileal pouch-anal anastomosis for ulcerative or indeterminate colitis? Colorectal Dis. 2010;12(10):1026-32. DOI: 10.1111/j.1463-1318.2009.02014.x.
38. Sagar PM, Dozois RR, Wolff BG. Long-term results of ileal pouch-anal anastomosis in patients with Crohn's disease. Dis Colon Rectum. 1996;39(8):893-8. DOI: 10.1007/BF02053988.
39. Rana T, Korolkova OY, Rachakonda G, Williams AD, Hawkins AT, James SD, et al. Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn's colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease. PloS one. 2021;16(3):e0246393. DOI: 10.1371/journal.pone.0246393. eCollection 2021.
40. Lightner AL, Jia X, Zaghiyan K, Fleshner PR. IPAA in Known Preoperative Crohn's Disease: A Systematic Review. Dis Colon Rectum. 2021;64(3):355-64. DOI: 10.1097/DCR.0000000000001918.
41. Lavryk OA, Stocchi L, Shawki S, Aiello A, Church JM, Steele SR, et al. Redo IPAA After a Failed Pouch In Patients With Crohn's Disease: Is It Worth Trying? Dis Colon Rectum. 2020;63(6):823-30. DOI: 10.1097/DCR.0000000000001644.
42. Ananthakrishnan AN, Kwon J, Raffals L, Sands B, Stenson WF, McGovern D, et al. Variation in treatment of patients with inflammatory bowel diseases at major referral centers in the United States. Clin Gastroenterol Hepatol. 2015;13(6):1197-200. DOI: 10.1016/j.cgh.2014.11.020.
43. Tremaine WJ. Is indeterminate colitis determinable? Curr Gastroenterol Rep. 2012;14(2):162-5. DOI: 10.1007/s11894-012-0244-x.
44. Brown CJ, Maclean AR, Cohen Z, Macrae HM, O'Connor BI, McLeod RS. Crohn's disease and indeterminate colitis and the ileal pouch-anal anastomosis: outcomes and patterns of failure. Dis Colon Rectum. 2005;48(8):1542-9. DOI: 10.1007/s10350-005-0059-z.
45. Conrad K, Roggenbuck D, Laass MW. Diagnosis and classification of ulcerative colitis. Autoimmun Rev. 2014;13(4-5):463-6. DOI: 10.1016/j.autrev.2014.01.028.
46. Laass MW, Roggenbuck D, Conrad K. Diagnosis and classification of Crohn's disease. Autoimmun Rev. 2014;13(4-5):467-71. DOI: 10.1016/j.autrev.2014.01.029.
47. Tremaine WJ. Review article: Indeterminate colitis--definition, diagnosis and management. Aliment Pharmacol Ther. 2007;25(1):13-7. DOI: 10.1111/j.1365-2036.2006.03159.x.
48. Jevon GP, Madhur R. Endoscopic and histologic findings in pediatric inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2010;6(3):174-80. PMID: 20567564
49. Nosti PA, Stahl TJ, Sokol AI. Surgical repair of rectovaginal fistulas in patients with Crohn's disease. Eur J Obstet Gynecol Reprod Biol. 2013;171(1):166-70. DOI: 10.1016/j.ejogrb.2013.08.011.
50. Nielsen OH, Rogler G, Hahnloser D, Thomsen OO. Diagnosis and management of fistulizing Crohn's disease. Nat Clin Pract Gastroenterol Hepatol. 2009;6(2):92-106. DOI: 10.1038/ncpgasthep1340.
51. M'Koma AE. Serum biochemical evaluation of patients with functional pouches ten to 20 years after restorative proctocolectomy. Int J Colorectal Dis. 2006;21(7):711-20. DOI: 10.1007/s00384-005-0076-3.
52. M'Koma AE. Observation on essential biochemical data profile in connection with restorative proctocolectomy in humans. Vitamin B12 and fat absorption cited. Dissertation Thesis. 2001:1-126. URI: http://hdl.handle.net/10616/38656
53. Lee H, Westerhoff M, Shen B, Liu X. Clinical Aspects of Idiopathic Inflammatory Bowel Disease: A Review for Pathologists. Arch Pathol Lab Med. 2016;140(5):413-28. DOI: 10.5858/arpa.2015-0305-RA.
54. M'Koma AE. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics. World J gastrointest surg. 2014;6(11):208-19. DOI: 10.4240/wjgs.v6.i11.208.
55. Feakins RM. Ulcerative colitis or Crohn's disease? Pitfalls and problems. Histopathology. 2014;64(3):317-35. DOI: 10.1111/his.12263.
56. Wagner-Bartak NA, Levine MS, Rubesin SE, Laufer I, Rombeau JL, Lichtenstein GR. Crohn's disease in the ileal pouch after total colectomy for ulcerative colitis: findings on pouch enemas in six patients. AJR Am J Roentgenol. 2005;184(6):1843-7. DOI: 10.2214/ajr.184.6.01841843
57. Price AB. Overlap in the spectrum of non-specific inflammatory bowel disease--'colitis indeterminate'. J Clin Pathol. 1978;31(6):567-77. DOI: 10.1136/jcp.31.6.567.
58. Mortellaro VE, Green J, Islam S, Bass JA, Fike FB, St Peter SD. Occurrence of Crohn's disease in children after total colectomy for ulcerative colitis. J Surg Res. 2011;170(1):38-40. DOI: 10.1016/j.jss.2011.02.011.
59. Tulchinsky H, Hawley PR, Nicholls J. Long-term failure after restorative proctocolectomy for ulcerative colitis. Ann Surg. 2003;238(2):229-34. DOI: 10.1097/01.sla.0000082121.84763.4c.
60. Tan HT, Morton D, Connolly AB, Pringle W, White M, Keighley MR. Quality of life after pouch excision. Br J Surg. 1998;85(2):249-51. DOI:10.1046/j.1365-2168.1998.00582.x.61
61. Meucci G, Bortoli A, Riccioli FA, Girelli CM, Radaelli F, Rivolta R, et al.Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in northern Italy. GSMII (Gruppo di Studio per le Malattie Infiammatorie Intestinali). Eur J Gastroenterol Hepatol. 1999;11(8):909-13. PMID: 10514127
62. Jong VL, Novianti PW, Roes KC, Eijkemans MJ. Selecting a classification function for class prediction with gene expression data. Bioinformatics. 2016, 15;32(12):1814-22. DOI: 10.1093/bioinformatics/btw034.
63. Deutsch AA, McLeod RS, Cullen J, Cohen Z. Results of the pelvic-pouch procedure in patients with Crohn's disease. Dis Colon Rectum. 1991;34(6):475-7. DOI: 10.1007/BF02049932.
64. Grobler SP, Hosie KB, Affie E, Thompson H, Keighley MR. Outcome of restorative proctocolectomy when the diagnosis is suggestive of Crohn's disease. Gut. 1993;34(10):1384-8. DOI: 10.1136/gut.34.10.1384.
65. Mylonakis E, Allan RN, Keighley MR. How does pouch construction for a final diagnosis of Crohn's disease compare with ileoproctostomy for established Crohn's proctocolitis? Dis Colon Rectum. 2001;44(8):1137-42. DOI: 10.1007/BF02234634.
66. Das P, Smith JJ, Tekkis PP, Heriot AG, Antropoli M, John Nicholls R. Quality of life after indefinite diversion/pouch excision in ileal pouch failure patients. Colorectal Dis. 2007;9(8):718-24. DOI: 10.1111/j.1463-1318.2007.01216.x.
67. Fornaro R, Caratto M, Barbruni G, Fornaro F, Salerno A, Giovinazzo D, et al. Surgical and medical treatment in patients with Acute Severe Ulcerative Colitis. J Dig Dis. 2015;16(10):558-67. DOI: 10.1111/1751-2980.12278.
68. Ikeuchi H, Nakano H, Uchino M, Nakamura M, Noda M, Yanagi H, et al. Safety of one-stage restorative proctocolectomy for ulcerative colitis. Dis Colon Rectum. 2005;48(8):1550-5. DOI: 10.1007/s10350-005-0083-z.
69. Le Q, Melmed G, Dubinsky M, McGovern D, Vasiliauskas EA, Murrell Z, et al. Surgical outcome of ileal pouch-anal anastomosis when used intentionally for well-defined Crohn's disease. Inflamm Bowel Dis. 2013;19(1):30-6. DOI: 10.1002/ibd.22955.
70. Cohan JN, Ozanne EM, Sewell JL, Hofer RK, Mahadevan U, Varma MG, et al. A Novel Decision Aid for Surgical Patients with Ulcerative Colitis: Results of a Pilot Study. Dis Colon Rectum. 2016;59(6):520-8. DOI: 10.1097/DCR.0000000000000572.
71. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347(6):417-29. DOI: 10.1056/NEJMra020831.
72. Corfield AP, Wallace HM, Probert CS. The molecular biology of inflammatory bowel diseases. Biochem Soc Trans. 2011;39(4):1057-60. DOI: 10.1042/BST0391057.
73. Courth LF, Ostaff MJ, Mailander-Sanchez D, Malek NP, Stange EF, Wehkamp J. Crohn's disease-derived monocytes fail to induce Paneth cell defensins. Proc Natl Acad Sci U S A. 2015;112(45):14000-5. DOI: 10.1073/pnas.1510084112.
74. MKoma AE, inventor; Meharry Medical College, assignee. Methods for diagnosing and treating inflammatory bowel disease. United States of America Patent 11,427,852. 2022. https://patents.google.com/patent/US11427852B2/en
75. M'Koma AE, Sakwe, AM, inventors; Meharry Medical College, assignee. Targeted HD5 antibody and assay methods for diagnosing and treating inflammatory bowel disease. United States of America Patent App 16/622,259. 2021. https://patents.google.com/patent/WO2018237064A1/en
76. M'Koma AE, Sakwe AM, Blum DL, Hawkins AT, Alexander LD, Hildreth JE. eP713 - Clones 1A8 and 4FD Targeted anti-DEFA5 mAbs Sensitive and Specific Immunereactive Bioassays for IBD Diagnostics. American Society of Colon and Rectal Surgeons (ASCRS) Annual Scientific Meeting, Seattle Convention Center, June 3-6, 2023. https://www.eventscribe.net/2023/ASCRS23/fsPopup.asp?efp=UUFJSE5KTVExOTE2Ng&PresentationID=1186777&rnd=0.2277816&mode=presin