Exploration of key genes and mechanisms of depression aggravating Crohn disease based on bioinformatics_West China Medical Journal

Authors：

WANG Liangfang , CAO Yubin , DUAN Shihao ,  ZHANG Yan

Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHANG Yan, Email: hxzyan@163.com

Keywords：

Crohn disease; depression; biomarkers; immune cells; bioinformatics

DOI：

10.7507/1002-0179.202307032

Video：

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Objective To explore key genes and mechanisms of depression aggravating Crohn disease. Methods In March 2023, the Public Health Genomics and Precision Health Knowledge Base and Gene Expression Omnibus database were used to identify the overlapping differentially expressed genes between Crohn disease and depression and the key genes were screened by Metascape, STRING, Cytoscape, and protein interaction network analysis. The Gene Expression Omnibus database was used to analyze the correlations between key genes and clinical pathologies such as Crohn Disease Endoscopic Index of Severity and intestinal microvilli length. Results There were 137 overlapping differentially expressed genes between Crohn disease and depression, and 25 key genes were further screened out. Among them, CREB1, FKBP5, MAPT, NTSR1, OXTR, PROK2, POMC, HTR2B, and PPARGC1A genes were significantly correlated with multiple clinical parameters. The functions of PROK2 and PROK2-related genes were mainly enriched in neutrophil and granulocyte migration, neutrophil and granulocyte chemotaxis, etc. Conclusions There are 25 key genes, especially CREB1, FKBP5, MAPT, NTSR1, OXTR, PROK2, POMC, HTR2B, and PPARGC1A, that possibly contribute to the establishment and deterioration of Crohn disease caused by depressive disorder. Among these genes, PROK2 showes the possibility of regulating immune cell (neutrophils and CD8⁺ T cells) infiltration.

Citation： WANG Liangfang, CAO Yubin, DUAN Shihao, ZHANG Yan. Exploration of key genes and mechanisms of depression aggravating Crohn disease based on bioinformatics. West China Medical Journal, 2024, 39(1): 71-79. doi: 10.7507/1002-0179.202307032 Copy

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2.	Barberio B, Zamani M, Black CJ, et al. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol, 2021, 6(5): 359-370.
3.	Neuendorf R, Harding A, Stello N, et al. Depression and anxiety in patients with inflammatory bowel disease: a systematic review. J Psychosom Res, 2016, 87: 70-80.
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5.	Navabi S, Gorrepati VS, Yadav S, et al. Influences and impact of anxiety and depression in the setting of inflammatory bowel disease. Inflamm Bowel Dis, 2018, 24(11): 2303-2308.
6.	Dubinsky MC, Dotan I, Rubin DT, et al. Burden of comorbid anxiety and depression in patients with inflammatory bowel disease: a systematic literature review. Expert Rev Gastroenterol Hepatol, 2021, 15(9): 985-997.
7.	Frolkis AD, Vallerand IA, Shaheen AA, et al. Depression increases the risk of inflammatory bowel disease, which may be mitigated by the use of antidepressants in the treatment of depression. Gut, 2019, 68(9): 1606-1612.
8.	Ghia JE, Blennerhassett P, Deng Y, et al. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology, 2009, 136(7): 2280-2288.
9.	Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res, 2013, 41(Database issue): D991-D995.
10.	Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 2015, 43(Database issue): D447-D452.
11.	Simundic AM. Diagnostic accuracy—part 1: basic concepts: sensitivity and specificity, ROC analysis, STARD statement. Point of Care, 2012, 11(1).
12.	Racle J, de Jonge K, Baumgaertner P, et al. Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. Elife, 2017, 6: e26476.
13.	Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol, 2010, 28: 573-621.
14.	García-Alanís M, Quiroz-Casian L, Castañeda-González H, et al. Prevalence of mental disorder and impact on quality of life in inflammatory bowel disease. Gastroenterol Hepatol, 2021, 44(3): 206-213.
15.	Ananthakrishnan AN, Gainer VS, Perez RG, et al. Psychiatric co-morbidity is associated with increased risk of surgery in Crohn’s disease. Aliment Pharmacol Ther, 2013, 37(4): 445-454.
16.	Kochar B, Barnes EL, Long MD, et al. Depression is associated with more aggressive inflammatory bowel disease. Am J Gastroenterol, 2018, 113(1): 80-85.
17.	Baj A, Moro E, Bistoletti M, et al. Glutamatergic signaling along the microbiota-gut-brain axis. Int J Mol Sci, 2019, 20(6): 1482.
18.	Liñán-Rico A, Turco F, Ochoa-Cortes F, et al. Molecular signaling and dysfunction of the human reactive enteric glial cell phenotype: implications for GI infection, IBD, POI, neurological, motility, and GI disorders. Inflamm Bowel Dis, 2016, 22(8): 1812-1834.
19.	Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity, 2019, 50(4): 992-1006.
20.	Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut, 1989, 30(7): 983-989.
21.	VanDussen KL, Stojmirović A, Li K, et al. Abnormal small intestinal epithelial microvilli in patients with Crohn’s disease. Gastroenterology, 2018, 155(3): 815-828.
22.	Windgassen EB, Funtowicz L, Lunsford TN, et al. C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians. Postgrad Med, 2011, 123(1): 114-119.
23.	Zannas AS, Jia M, Hafner K, et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci U S A, 2019, 116(23): 11370-11379.
24.	D’Addabbo A, Palmieri O, Maglietta R, et al. Discovering genetic variants in Crohn’s disease by exploring genomic regions enriched of weak association signals. Dig Liver Dis, 2011, 43(8): 623-631.
25.	Gui X, Liu S, Yan Y, et al. Neurotensin receptor 1 overexpression in inflammatory bowel diseases and colitis-associated neoplasia. World J Gastroenterol, 2013, 19(28): 4504-4510.
26.	Bugni JM, Rabadi LA, Jubbal K, et al. The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer. Int J Cancer, 2012, 130(8): 1798-1805.
27.	Szeto A, Sun-Suslow N, Mendez AJ, et al. Regulation of the macrophage oxytocin receptor in response to inflammation. Am J Physiol Endocrinol Metab, 2017, 312(3): E183-E189.
28.	Tang Y, Shi Y, Gao Y, et al. Oxytocin system alleviates intestinal inflammation by regulating macrophages polarization in experimental colitis. Clin Sci (Lond), 2019, 133(18): 1977-1992.
29.	Getting SJ, Gibbs L, Clark AJ, et al. POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation. J Immunol, 1999, 162(12): 7446-7453.
30.	Catania A, Lonati C, Sordi A, et al. The melanocortin system in control of inflammation. Sci World J, 2010, 10: 1840-1853.
31.	de Las Casas-Engel M, Corbí AL. Serotonin modulation of macrophage polarization: inflammation and beyond. Adv Exp Med Biol, 2014, 824: 89-115.
32.	Lee YH, Song GG. Pathway analysis of a genome-wide association study of ileal Crohn’s disease. DNA Cell Biol, 2012, 31(10): 1549-1554.
33.	Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. J Immunol, 2010, 185(11): 6413-6419.
34.	Watson RP, Lilley E, Panesar M, et al. Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport. Neurogastroenterol Motil, 2012, 24(1): 65-75, e12.
35.	Chen ZA, Ma HH, Wang Y, et al. Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn’s disease based on three machine learning method. Sci Rep, 2023, 13(1): 2694.
36.	Li X, Lee EJ, Gawel DR, et al. Meta-analysis of expression profiling data indicates need for combinatorial biomarkers in pediatric ulcerative colitis. J Immunol Res, 2020, 2020: 8279619.
37.	Negri L, Ferrara N. The prokineticins: neuromodulators and mediators of inflammation and myeloid cell-dependent angiogenesis. Physiol Rev, 2018, 98(2): 1055-1082.
38.	Martucci C, Franchi S, Giannini E, et al. Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages. Br J Pharmacol, 2006, 147(2): 225-234.
39.	LeCouter J, Zlot C, Tejada M, et al. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci U S A, 2004, 101(48): 16813-16818.

1. de Souza HSP, Fiocchi C, Iliopoulos D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol, 2017, 14(12): 739-749.
2. Barberio B, Zamani M, Black CJ, et al. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol, 2021, 6(5): 359-370.
3. Neuendorf R, Harding A, Stello N, et al. Depression and anxiety in patients with inflammatory bowel disease: a systematic review. J Psychosom Res, 2016, 87: 70-80.
4. Fairbrass KM, Lovatt J, Barberio B, et al. Bidirectional brain-gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis. Gut, 2022, 71(9): 1773-1780.
5. Navabi S, Gorrepati VS, Yadav S, et al. Influences and impact of anxiety and depression in the setting of inflammatory bowel disease. Inflamm Bowel Dis, 2018, 24(11): 2303-2308.
6. Dubinsky MC, Dotan I, Rubin DT, et al. Burden of comorbid anxiety and depression in patients with inflammatory bowel disease: a systematic literature review. Expert Rev Gastroenterol Hepatol, 2021, 15(9): 985-997.
7. Frolkis AD, Vallerand IA, Shaheen AA, et al. Depression increases the risk of inflammatory bowel disease, which may be mitigated by the use of antidepressants in the treatment of depression. Gut, 2019, 68(9): 1606-1612.
8. Ghia JE, Blennerhassett P, Deng Y, et al. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology, 2009, 136(7): 2280-2288.
9. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res, 2013, 41(Database issue): D991-D995.
10. Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 2015, 43(Database issue): D447-D452.
11. Simundic AM. Diagnostic accuracy—part 1: basic concepts: sensitivity and specificity, ROC analysis, STARD statement. Point of Care, 2012, 11(1).
12. Racle J, de Jonge K, Baumgaertner P, et al. Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. Elife, 2017, 6: e26476.
13. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol, 2010, 28: 573-621.
14. García-Alanís M, Quiroz-Casian L, Castañeda-González H, et al. Prevalence of mental disorder and impact on quality of life in inflammatory bowel disease. Gastroenterol Hepatol, 2021, 44(3): 206-213.
15. Ananthakrishnan AN, Gainer VS, Perez RG, et al. Psychiatric co-morbidity is associated with increased risk of surgery in Crohn’s disease. Aliment Pharmacol Ther, 2013, 37(4): 445-454.
16. Kochar B, Barnes EL, Long MD, et al. Depression is associated with more aggressive inflammatory bowel disease. Am J Gastroenterol, 2018, 113(1): 80-85.
17. Baj A, Moro E, Bistoletti M, et al. Glutamatergic signaling along the microbiota-gut-brain axis. Int J Mol Sci, 2019, 20(6): 1482.
18. Liñán-Rico A, Turco F, Ochoa-Cortes F, et al. Molecular signaling and dysfunction of the human reactive enteric glial cell phenotype: implications for GI infection, IBD, POI, neurological, motility, and GI disorders. Inflamm Bowel Dis, 2016, 22(8): 1812-1834.
19. Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity, 2019, 50(4): 992-1006.
20. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut, 1989, 30(7): 983-989.
21. VanDussen KL, Stojmirović A, Li K, et al. Abnormal small intestinal epithelial microvilli in patients with Crohn’s disease. Gastroenterology, 2018, 155(3): 815-828.
22. Windgassen EB, Funtowicz L, Lunsford TN, et al. C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians. Postgrad Med, 2011, 123(1): 114-119.
23. Zannas AS, Jia M, Hafner K, et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci U S A, 2019, 116(23): 11370-11379.
24. D’Addabbo A, Palmieri O, Maglietta R, et al. Discovering genetic variants in Crohn’s disease by exploring genomic regions enriched of weak association signals. Dig Liver Dis, 2011, 43(8): 623-631.
25. Gui X, Liu S, Yan Y, et al. Neurotensin receptor 1 overexpression in inflammatory bowel diseases and colitis-associated neoplasia. World J Gastroenterol, 2013, 19(28): 4504-4510.
26. Bugni JM, Rabadi LA, Jubbal K, et al. The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer. Int J Cancer, 2012, 130(8): 1798-1805.
27. Szeto A, Sun-Suslow N, Mendez AJ, et al. Regulation of the macrophage oxytocin receptor in response to inflammation. Am J Physiol Endocrinol Metab, 2017, 312(3): E183-E189.
28. Tang Y, Shi Y, Gao Y, et al. Oxytocin system alleviates intestinal inflammation by regulating macrophages polarization in experimental colitis. Clin Sci (Lond), 2019, 133(18): 1977-1992.
29. Getting SJ, Gibbs L, Clark AJ, et al. POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation. J Immunol, 1999, 162(12): 7446-7453.
30. Catania A, Lonati C, Sordi A, et al. The melanocortin system in control of inflammation. Sci World J, 2010, 10: 1840-1853.
31. de Las Casas-Engel M, Corbí AL. Serotonin modulation of macrophage polarization: inflammation and beyond. Adv Exp Med Biol, 2014, 824: 89-115.
32. Lee YH, Song GG. Pathway analysis of a genome-wide association study of ileal Crohn’s disease. DNA Cell Biol, 2012, 31(10): 1549-1554.
33. Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. J Immunol, 2010, 185(11): 6413-6419.
34. Watson RP, Lilley E, Panesar M, et al. Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport. Neurogastroenterol Motil, 2012, 24(1): 65-75, e12.
35. Chen ZA, Ma HH, Wang Y, et al. Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn’s disease based on three machine learning method. Sci Rep, 2023, 13(1): 2694.
36. Li X, Lee EJ, Gawel DR, et al. Meta-analysis of expression profiling data indicates need for combinatorial biomarkers in pediatric ulcerative colitis. J Immunol Res, 2020, 2020: 8279619.
37. Negri L, Ferrara N. The prokineticins: neuromodulators and mediators of inflammation and myeloid cell-dependent angiogenesis. Physiol Rev, 2018, 98(2): 1055-1082.
38. Martucci C, Franchi S, Giannini E, et al. Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages. Br J Pharmacol, 2006, 147(2): 225-234.
39. LeCouter J, Zlot C, Tejada M, et al. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci U S A, 2004, 101(48): 16813-16818.

West China Medical Journal

Exploration of key genes and mechanisms of depression aggravating Crohn disease based on bioinformatics

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