Identification of Immune-Related Diagnostic Genes and Subtypes of Active Ulcerative Colitis
-
Tianlong Tang
,
Xinquan Zan
,
Fei Liu
,
Xiao Shi
,
Qiaoming Zhi
,
Ye Han
Abstract
Ulcerative colitis (UC) is a chronic immune-mediated disease with a growing global burden. In this study, bioinformatics analysis and machine learning methods were employed to screen the potential immune microenvironment-related feature genes.
We identified 4 immune-related genes that are consistently dysregulated in UC and correlate with immune infiltration, including APOBEC3B (Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3B), CXCL11, PLA2G2A, and TMEM173. Their diagnostic performance was verified in an external cohort and in our clinical samples.
Then, the proportion of ambiguous clustering (PAC) successfully classified UC patients into 2 molecular subtypes, including subtype 1 (metabolism-related subtype) and subtype 2 (immune-related subtype). The single sample gene set enrichment analysis (ssGSEA) algorithm revealed that subtype 2, with a higher score, of the majority of immune cells presented a worse inflammatory response.
In addition, we assessed scores of partial novel drugs querying the cMAP database and found that the efficacy of clinical small-molecule compounds presented different results across UC subtypes. These findings identify biomarkers, establish a concise immune-based classification of UC, and support subtype-guided therapy.
1. Yu YR, Rodriguez JR. Clinical presentation of Crohn's, ulcerative colitis, and indeterminate colitis: Symptoms, extraintestinal manifestations, and disease phenotypes. Semin Pediatr Surg. 2017;26(6):349-55.
2. Gu Y, Zhao H, Zheng L, Zhou C, Han Y, Wu A, et al. Non-coding RNAs and colitis-associated cancer: Mechanisms and clinical applications. Clin Transl Med. 2023;13(5):e1253.
3. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):1756-70.
4. Porter RJ, Kalla R, Ho GT. Ulcerative colitis: Recent advances in the understanding of disease pathogenesis. F1000Res. 2020;9:
5. Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev. 2017;16(4):416-26.
6. Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol. 2018;30(1):1-10.
7. Camilleri M, Madsen K, Spiller R, Greenwood-Van MB, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroent Motil. 2012;24(6):503-12.
8. Minton K. Intestinal barrier protection. Nat Rev Immunol. 2022;22(3):144-5.
9. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14(3):141-53.
10. Maldonado-Contreras AL, McCormick BA. Intestinal epithelial cells and their role in innate mucosal immunity. Cell Tissue Res. 2011;343(1):5-12.
11. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014;13(1):3-10.
12. Kmiec Z, Cyman M, Slebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci-Poland. 2017;62(1):1-16.
13. Hanzel J, Hulshoff MS, Grootjans J, D'Haens G. Emerging therapies for ulcerative colitis. Expert Rev Clin Immu. 2022;18(5):513-24.
14. Ashton JJ, Green Z, Kolimarala V, Beattie RM. Inflammatory bowel disease: long-term therapeutic challenges. Expert Rev Gastroent. 2019;13(11):1049-63.
15. Tran V, Limketkai BN, Sauk JS. IBD in the Elderly: Management Challenges and Therapeutic Considerations. Curr Gastroenterol Rep. 2019;21(11):60.
16. Ferretti F, Cannatelli R, Maconi G, Ardizzone S. Therapeutic Management of Adults with Inflammatory Bowel Disease and Malignancies: A Clinical Challenge. Cancers. 2023;15(2):
17. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
18. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453-7.
19. Engebretsen S, Bohlin J. Statistical predictions with glmnet. Clin Epigenetics. 2019;11(1):123.
20. Gui J, Li H. Penalized Cox regression analysis in the high-dimensional and low-sample-size settings, with applications to microarray gene expression data. Bioinformatics. 2005;21(13):3001-8.
21. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.
22. Kim S. Margin-maximised redundancy-minimised SVM-RFE for diagnostic classification of mammograms. Int J Data Min Bioin. 2014;10(4):374-90.
23. Li W, Yin Y, Quan X, Zhang H. Gene Expression Value Prediction Based on XGBoost Algorithm. Front Genet. 2019;10:1077.
24. Degenhardt F, Seifert S, Szymczak S. Evaluation of variable selection methods for random forests and omics data sets. Brief Bioinform. 2019;20(2):492-503.
25. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade. Cell Rep. 2017;18(1):248-62.
26. Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.
27. Le Berre C, Ananthakrishnan AN, Danese S, Singh S, Peyrin-Biroulet L. Ulcerative Colitis and Crohn's Disease Have Similar Burden and Goals for Treatment. Clin Gastroenterol H. 2020;18(1):14-23.
28. Wei SC, Sollano J, Hui YT, Yu W, Santos EP, Llamado L, et al. Epidemiology, burden of disease, and unmet needs in the treatment of ulcerative colitis in Asia. Expert Rev Gastroent. 2021;15(3):275-89.
29. Seyedian SS, Nokhostin F, Malamir MD. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life. 2019;12(2):113-22.
30. Kaenkumchorn T, Wahbeh G. Ulcerative Colitis: Making the Diagnosis. Gastroenterol Clin N. 2020;49(4):655-69.
31. Sakurai T, Saruta M. Positioning and Usefulness of Biomarkers in Inflammatory Bowel Disease. Digestion. 2023;104(1):30-41.
32. Liu D, Saikam V, Skrada KA, Merlin D, Iyer SS. Inflammatory bowel disease biomarkers. Med Res Rev. 2022;42(5):1856-87.
33. Van der Goten J, Vanhove W, Lemaire K, Van Lommel L, Machiels K, Wollants WJ, et al. Integrated miRNA and mRNA expression profiling in inflamed colon of patients with ulcerative colitis. Plos One. 2014;9(12):e116117.
34. Zhou J, Liu J, Gao Y, Shen L, Li S, Chen S. miRNA-Based Potential Biomarkers and New Molecular Insights in Ulcerative Colitis. Front Pharmacol. 2021;12:707776.
35. Wan D, Wang S, Xu Z, Zan X, Liu F, Han Y, et al. PRKAR2A-derived circular RNAs promote the malignant transformation of colitis and distinguish patients with colitis-associated colorectal cancer. Clin Transl Med. 2022;12(2):e683.
36. Lu J, Wang Z, Maimaiti M, Hui W, Abudourexiti A, Gao F. Identification of diagnostic signatures in ulcerative colitis patients via bioinformatic analysis integrated with machine learning. Hum Cell. 2022;35(1):179-88.
37. Mohammed VN, Samaan M, Mosli MH, Parker CE, MacDonald JK, Nelson SA, et al. Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Db Syst Rev. 2018;1(1):CD011450.
38. Pai RK, Jairath V, Vande CN, Rieder F, Parker CE, Lauwers GY. The emerging role of histologic disease activity assessment in ulcerative colitis. Gastrointest Endosc. 2018;88(6):887-98.
39. Pabla BS, Schwartz DA. Assessing Severity of Disease in Patients with Ulcerative Colitis. Gastroenterol Clin N. 2020;49(4):671-88.
40. Ahluwalia B, Moraes L, Magnusson MK, Ohman L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroentero. 2018;53(4):379-89.
41. Furey TS, Sethupathy P, Sheikh SZ. Redefining the IBDs using genome-scale molecular phenotyping. Nat Rev Gastro Hepat. 2019;16(5):296-311.
42. Bhattacharya A, Osterman MT. Biologic Therapy for Ulcerative Colitis. Gastroenterol Clin N. 2020;49(4):717-29.
43. Caballol B, Gudino V, Panes J, Salas A. Ulcerative colitis: shedding light on emerging agents and strategies in preclinical and early clinical development. Expert Opin Inv Drug. 2021;30(9):931-46.
44. Lasa JS, Olivera PA, Danese S, Peyrin-Biroulet L. Efficacy and safety of biologics and small molecule drugs for patients with moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis. Lancet Gastroenterol. 2022;7(2):161-70.
45. Shaaban AA, Abdelhamid AM, Shaker ME, Cavalu S, Maghiar AM, Alsayegh AA, et al. Combining the HSP90 inhibitor TAS-116 with metformin effectively degrades the NLRP3 and attenuates inflammasome activation in rats: A new management paradigm for ulcerative colitis. Biomed Pharmacother. 2022;153:113247.
46. Feng YJ, Li YY. The role of p38 mitogen-activated protein kinase in the pathogenesis of inflammatory bowel disease. J Digest Dis. 2011;12(5):327-32.
47. Elkholy SE, Maher SA, Abd EN, Elsayed HA, Hassan WA, Abdelmaogood A, et al. The immunomodulatory effects of probiotics and azithromycin in dextran sodium sulfate-induced ulcerative colitis in rats via TLR4-NF-kappaB and p38-MAPK pathway. Biomed Pharmacother. 2023;165:115005.
48. Zhou A, Zhang S, Yang C, Liao N, Zhang Y. Dandelion root extracts abolish MAPK pathways to ameliorate experimental mouse ulcerative colitis. Adv Clin Exp Med. 2022;31(5):529-38.
49. Qian L, Hu S, Zhao H, Han Y, Dai C, Zan X, et al. The Diagnostic Significance of SLC26A2 and Its Potential Role in Ulcerative Colitis. Biomedicines. 2025;13(2):461.
2. Gu Y, Zhao H, Zheng L, Zhou C, Han Y, Wu A, et al. Non-coding RNAs and colitis-associated cancer: Mechanisms and clinical applications. Clin Transl Med. 2023;13(5):e1253.
3. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):1756-70.
4. Porter RJ, Kalla R, Ho GT. Ulcerative colitis: Recent advances in the understanding of disease pathogenesis. F1000Res. 2020;9:
5. Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev. 2017;16(4):416-26.
6. Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol. 2018;30(1):1-10.
7. Camilleri M, Madsen K, Spiller R, Greenwood-Van MB, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroent Motil. 2012;24(6):503-12.
8. Minton K. Intestinal barrier protection. Nat Rev Immunol. 2022;22(3):144-5.
9. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14(3):141-53.
10. Maldonado-Contreras AL, McCormick BA. Intestinal epithelial cells and their role in innate mucosal immunity. Cell Tissue Res. 2011;343(1):5-12.
11. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014;13(1):3-10.
12. Kmiec Z, Cyman M, Slebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci-Poland. 2017;62(1):1-16.
13. Hanzel J, Hulshoff MS, Grootjans J, D'Haens G. Emerging therapies for ulcerative colitis. Expert Rev Clin Immu. 2022;18(5):513-24.
14. Ashton JJ, Green Z, Kolimarala V, Beattie RM. Inflammatory bowel disease: long-term therapeutic challenges. Expert Rev Gastroent. 2019;13(11):1049-63.
15. Tran V, Limketkai BN, Sauk JS. IBD in the Elderly: Management Challenges and Therapeutic Considerations. Curr Gastroenterol Rep. 2019;21(11):60.
16. Ferretti F, Cannatelli R, Maconi G, Ardizzone S. Therapeutic Management of Adults with Inflammatory Bowel Disease and Malignancies: A Clinical Challenge. Cancers. 2023;15(2):
17. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
18. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453-7.
19. Engebretsen S, Bohlin J. Statistical predictions with glmnet. Clin Epigenetics. 2019;11(1):123.
20. Gui J, Li H. Penalized Cox regression analysis in the high-dimensional and low-sample-size settings, with applications to microarray gene expression data. Bioinformatics. 2005;21(13):3001-8.
21. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.
22. Kim S. Margin-maximised redundancy-minimised SVM-RFE for diagnostic classification of mammograms. Int J Data Min Bioin. 2014;10(4):374-90.
23. Li W, Yin Y, Quan X, Zhang H. Gene Expression Value Prediction Based on XGBoost Algorithm. Front Genet. 2019;10:1077.
24. Degenhardt F, Seifert S, Szymczak S. Evaluation of variable selection methods for random forests and omics data sets. Brief Bioinform. 2019;20(2):492-503.
25. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade. Cell Rep. 2017;18(1):248-62.
26. Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.
27. Le Berre C, Ananthakrishnan AN, Danese S, Singh S, Peyrin-Biroulet L. Ulcerative Colitis and Crohn's Disease Have Similar Burden and Goals for Treatment. Clin Gastroenterol H. 2020;18(1):14-23.
28. Wei SC, Sollano J, Hui YT, Yu W, Santos EP, Llamado L, et al. Epidemiology, burden of disease, and unmet needs in the treatment of ulcerative colitis in Asia. Expert Rev Gastroent. 2021;15(3):275-89.
29. Seyedian SS, Nokhostin F, Malamir MD. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life. 2019;12(2):113-22.
30. Kaenkumchorn T, Wahbeh G. Ulcerative Colitis: Making the Diagnosis. Gastroenterol Clin N. 2020;49(4):655-69.
31. Sakurai T, Saruta M. Positioning and Usefulness of Biomarkers in Inflammatory Bowel Disease. Digestion. 2023;104(1):30-41.
32. Liu D, Saikam V, Skrada KA, Merlin D, Iyer SS. Inflammatory bowel disease biomarkers. Med Res Rev. 2022;42(5):1856-87.
33. Van der Goten J, Vanhove W, Lemaire K, Van Lommel L, Machiels K, Wollants WJ, et al. Integrated miRNA and mRNA expression profiling in inflamed colon of patients with ulcerative colitis. Plos One. 2014;9(12):e116117.
34. Zhou J, Liu J, Gao Y, Shen L, Li S, Chen S. miRNA-Based Potential Biomarkers and New Molecular Insights in Ulcerative Colitis. Front Pharmacol. 2021;12:707776.
35. Wan D, Wang S, Xu Z, Zan X, Liu F, Han Y, et al. PRKAR2A-derived circular RNAs promote the malignant transformation of colitis and distinguish patients with colitis-associated colorectal cancer. Clin Transl Med. 2022;12(2):e683.
36. Lu J, Wang Z, Maimaiti M, Hui W, Abudourexiti A, Gao F. Identification of diagnostic signatures in ulcerative colitis patients via bioinformatic analysis integrated with machine learning. Hum Cell. 2022;35(1):179-88.
37. Mohammed VN, Samaan M, Mosli MH, Parker CE, MacDonald JK, Nelson SA, et al. Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Db Syst Rev. 2018;1(1):CD011450.
38. Pai RK, Jairath V, Vande CN, Rieder F, Parker CE, Lauwers GY. The emerging role of histologic disease activity assessment in ulcerative colitis. Gastrointest Endosc. 2018;88(6):887-98.
39. Pabla BS, Schwartz DA. Assessing Severity of Disease in Patients with Ulcerative Colitis. Gastroenterol Clin N. 2020;49(4):671-88.
40. Ahluwalia B, Moraes L, Magnusson MK, Ohman L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroentero. 2018;53(4):379-89.
41. Furey TS, Sethupathy P, Sheikh SZ. Redefining the IBDs using genome-scale molecular phenotyping. Nat Rev Gastro Hepat. 2019;16(5):296-311.
42. Bhattacharya A, Osterman MT. Biologic Therapy for Ulcerative Colitis. Gastroenterol Clin N. 2020;49(4):717-29.
43. Caballol B, Gudino V, Panes J, Salas A. Ulcerative colitis: shedding light on emerging agents and strategies in preclinical and early clinical development. Expert Opin Inv Drug. 2021;30(9):931-46.
44. Lasa JS, Olivera PA, Danese S, Peyrin-Biroulet L. Efficacy and safety of biologics and small molecule drugs for patients with moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis. Lancet Gastroenterol. 2022;7(2):161-70.
45. Shaaban AA, Abdelhamid AM, Shaker ME, Cavalu S, Maghiar AM, Alsayegh AA, et al. Combining the HSP90 inhibitor TAS-116 with metformin effectively degrades the NLRP3 and attenuates inflammasome activation in rats: A new management paradigm for ulcerative colitis. Biomed Pharmacother. 2022;153:113247.
46. Feng YJ, Li YY. The role of p38 mitogen-activated protein kinase in the pathogenesis of inflammatory bowel disease. J Digest Dis. 2011;12(5):327-32.
47. Elkholy SE, Maher SA, Abd EN, Elsayed HA, Hassan WA, Abdelmaogood A, et al. The immunomodulatory effects of probiotics and azithromycin in dextran sodium sulfate-induced ulcerative colitis in rats via TLR4-NF-kappaB and p38-MAPK pathway. Biomed Pharmacother. 2023;165:115005.
48. Zhou A, Zhang S, Yang C, Liao N, Zhang Y. Dandelion root extracts abolish MAPK pathways to ameliorate experimental mouse ulcerative colitis. Adv Clin Exp Med. 2022;31(5):529-38.
49. Qian L, Hu S, Zhao H, Han Y, Dai C, Zan X, et al. The Diagnostic Significance of SLC26A2 and Its Potential Role in Ulcerative Colitis. Biomedicines. 2025;13(2):461.
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How to Cite
1.
Tang T, Zan X, Liu F, Shi X, Zhi Q, Han Y. Identification of Immune-Related Diagnostic Genes and Subtypes of Active Ulcerative Colitis. Iran J Allergy Asthma Immunol. 2025;:1-21.
