Co-administration of 1,25-dihydroxyvitamin D3 and infliximab improves colitis in mice by modulating Treg differentiation

Document Type : Original Article

Authors

1 Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, China, 230022

2 Department of Gastroenterology, Anhui Children’s Hospital, 39 Wangjiang East road, Hefei, China, 230051

10.22038/ijbms.2024.74640.16209

Abstract

Objective(s): The combination of TNF-α inhibitors and vitamin D in colitis remains to be elucidated. In the present study, we revealed the benefit of infliximab (IFX) and vitamin D in a mouse model of Ulcerative colitis (UC). 
Materials and Methods: A dextran sulfate sodium-induced colitis model was used. The therapeutic effect of the combination was evaluated by symptom and histopathology analysis. The synergistic mechanism was explored by detecting the regulatory effect of the combined therapy on Regulatory T cell (Treg) differentiation.
Results: IFX and 1,25-dihydroxyvitamin D3 (VitD3) synergistically prevented the development of colitis by improving clinical signs, pathological and hematological manifestation, and inhibiting intestinal inflammation (decreasing TNF-α, IL-1β, and IL-6). Coadministration of IFX (2.5 mg/kg) with VitD3 or IFX (5.0 mg/kg) with VitD3 was more effective than administration of IFX (2.5 mg/kg, 5.0 mg/kg). There was no difference in therapeutic effect between IFX (5.0 mg/kg) and VitD3+ IFX (2.5 mg/kg) groups or between the VitD3+IFX (5.0 mg/kg) and VitD3+ Azathioprine (AZA) groups. VitD3 or combination therapy showed more powerful regulation of splenetic Treg differentiation and IL-10 production than IFX alone. Moreover, VitD3 alone or in combination induced higher levels of Foxp3 and IL-10 than IFX in colon tissue. In ulcerative colitis patients, serum VitD3 levels positively correlated with Treg levels.
Conclusion: VitD3 and IFX synergistically inhibit colitis based on their powerful regulation of Treg differentiation. VitD3 combined with IFX is an alternative therapy for patients who are intolerant to standard   doses of IFX or combination of IFX and AZA.

Keywords

Main Subjects

References

1. Du L, Ha C. Epidemiology and pathogenesis of ulcerative colitis. Gastroenterol Clin North Am 2020;49:643-654.
2. Segal JP, LeBlanc JF, Hart AL. Ulcerative colitis: an update. Clin Med (Lond) 2021;21:135-139.
3. Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB, et al. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int J Mol Sci 2021; 22: 2719. 
4. Bhattacharya A, Osterman MT. Biologic therapy for ulcerative colitis. Gastroenterol Clin North Am 2020;49:717-729. 
5. Bradley GM, Oliva-Hemker M. Infliximab for the treatment of pediatric ulcerative colitis. Expert Rev Gastroenterol Hepatol 2012;6:659-665. 
6. D’Haens GR, Panaccione R, Higgins PD, Vermeire S, Gassull M, Chowers Y, et al. The london position statement of the World Congress of Gastroenterology on biological therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011;106:199-212. 
7. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther 2011;33:987-995. 
8. Lambrescak E, Vaysse T, Allez M, Ungar B, Gleizes A, Hacein-Bey S, et al. Duration of combination therapy and risk of treatment failure in patients with inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2021;45:101503. 
9. Bots S, Gecse K, Barclay M, D’Haens G. Combination immunosuppression in IBD. Inflamm Bowel Dis 2018;24:539-545. 
10. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients 2013;5:2502-2521. 
11. Battistini C, Ballan R, Herkenhoff ME, Saad SMI, Sun J. Vitamin D modulates intestinal microbiota in inflammatory bowel diseases. Int J Mol Sci 2020 ;22:362.
12. Zhao H, Zhang H, Wu H, Li H, Liu L, Guo J,et al. Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol 2012;12:57.
13. Fletcher J, Cooper SC, Ghosh S, Hewison M. The role of Vitamin D in inflammatory bowel disease: mechanism to management. Nutrients 2019;11:1019. 
14. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al. European Crohn’s and Colitis Organisation [ECCO]. Third European Evidence-based consensus on diagnosis and management of ulcerative colitis. Part 1: Definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders. J Crohns Colitis 2017;11:649-670.
15. Li J, Ren S, Li M, Bi J, Yang G, Li E. Paeoniflorin protects against dextran sulfate sodium (DSS)-induced colitis in mice through inhibition of inflammation and eosinophil infiltration. Int Immunopharmacol 2021;97:107667.
16. Han DH, Kim WK, Lee C, Park S, Lee K, Jang SJ, et al. Co-administration of Lactobacillus gasseri KBL697 and tumor necrosis factor-alpha inhibitor infliximab improves colitis in mice. Sci Rep 2022;12:9640. 
17. Negi S, Saini S, Tandel N, Sahu K, Mishra RPN, Tyagi RK.Translating treg therapy for inflammatory bowel disease in humanized mice. Cells 2021;10:1847.  
18. Ono M. Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes. Immunology 2020;160:24- 37.
19. Arieira C, Dias de Castro F, Cúrdia Gonçalves T, Moreira MJ, Cotter J. Combination therapy in inflammatory bowel disease patients: do we need to maximize the dose of azathioprine? Scand J Gastroenterol 2020;55:920-923. 
20. Hendler SA, Cohen BL, Colombel JF, Sands BE, Mayer L, Agarwal S.High-dose infliximab therapy in Crohn’s disease: clinical experience, safety, and efficacy. J Crohns Colitis 2015;9:266-275. 
21. Privitera G, Pugliese D, Onali S, Petito V, Scaldaferri F, Gasbarrini A, et al.Combination therapy in inflammatory bowel disease-from traditional immunosuppressors towards the new paradigm of dual targeted therapy. Autoimmun Rev 2021;20:102832. 
22. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology 2018;155:337-346. 
23. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A.Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296:2832-2838. 
24. Law AD, Dutta U, Kochhar R, Vaishnavi C, Kumar S, Noor T, et al.Vitamin D deficiency in adult patients with ulcerative colitis: prevalence and relationship with disease severity, extent, and duration. Indian J Gastroenterol 2019;38:6-14. 
25. Garg M, Hendy P, Ding JN, Shaw S, Hold G, Hart A. The Effect of Vitamin D on intestinal inflammation and faecal microbiota in patients with ulcerative colitis. J Crohns Colitis 2018;12:963-972. 26. Urena-Torres P, Souberbielle JC. Pharmacologic role of vitamin D natural products. Curr Vasc Pharmacol 2014;12:278-285. 
27. Cao R, Ma Y, Li S, Shen D, Yang S, Wang X, et al. 1,25(OH)2 D3 alleviates DSS-induced ulcerative colitis via inhibiting NLRP3 inflammasome activation. J Leukoc Biol 2020;108:283-295. 
28. Wei X, Li X, Du J, Ge X, Sun Y, Li X, et al. Vitamin D deficiency exacerbates colonic inflammation due to activation of the local renin-angiotensin system in the colon. Dig Dis Sci 2021;66:3813-3821. 
29. Zhang H, Wu H, Liu L, Li H, Shih DQ, Zhang X.1,25-dihydroxyvitamin D3 regulates the development of chronic colitis by modulating both T helper (Th)1 and Th17 activation. APMIS 2015;123:490-501. 
30. Mohammadnia-Afrouzi M, Zavaran Hosseini A, Khalili A, Abediankenari S, Hosseini V, Maleki I. Decrease of CD4(+) CD25(+) CD127(low) FoxP3(+) regulatory T cells with impaired suppressive function in untreated ulcerative colitis patients. Autoimmunity 2015;48:556-561. 
31. Pedros C, Duguet F, Saoudi A, Chabod M.Disrupted regulatory T cell homeostasis in inflammatory bowel diseases. World J Gastroenterol 2016 ;22:974-995. 
32. Ribeiro VR, Romao-Veiga M, Nunes PR, Matias ML, Peracoli JC, Peracoli MTS.Vitamin D modulates the transcription factors of T cell subsets to anti-inflammatory and regulatory profiles in preeclampsia. Int Immunopharmacol 2021;101(Pt B):108366.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 9
September 2024
Pages 1172-1179

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