Gut microbiota in immunosuppressive therapy in patients after allogeneic hemoietic stem cell transplantation
https://doi.org/10.51523/2708-6011.2025-22-1-05
Abstract
Objective. To make associations between the composition of the gut microbiota and the dosage of immunosuppressive drugs in patients after allogeneic hematopoietic stem cell transplantation.
Materials and methods. In this study, we studied the composition of the gut microbiota using the V3-V4 sequencing method of the 16S rRNA gene in 36 patients after allogeneic hematopoietic stem cell transplantation with various types of immunosuppression.
Results. Use of Tacrolimus significantly reduced the abundance of bacteria like Bacteroidetes and particularly Bacteroidaceae family in stool samples compared to cyclosporine A; patients with higher Akkermansia abundance more often required immunosuppression dose reduction to maintain target serum levels, as confirmed by two multivariate methods, while patients with higher Faecalibacterium, Oscillibacter, and Hungatella density had a higher median cyclosporine A dose to maintain therapeutic concentrations.
Conclusion. Additional studies are necessary to identify the relationship between gut microbiome and immunosuppressant drugs taking into account variable concentrations of calcineurin inhibitors, potential adverse events associated with insufficient or excessive serum drug levels, and the associations found between patients’ gut microbiome abundance and immunosuppressant dose
Supporting agencies: Republican budget; Extra-budgetary funds of the Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology
About the Authors
M. A. Uss
Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology
Belarus
Belarus
Mikhail A. Uss - Haematologist (Head) at the Hematology Department of Bone Marrow Transplantation No. 2.
Minsk
I. O. Stoma
Gomel State Medical University
Belarus
Belarus
Igor O. Stoma - Doctor of Medical Sciences, Professor.
Gomel
N. F. Milanovich
Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology
Belarus
Belarus
Natalya F. Milanovich - Candidate of Medical Sciences, Head of the Hematology Department of Bone Marrow Transplantation No. 3.
Minsk
T. N. Gubanova
Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology
Belarus
Belarus
Tatyana N. Gubanova - Researcher at the Scientific Department.
Minsk
A. L. Uss
Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology
Belarus
Belarus
Anatoly L. Uss - Doctor of Medical Sciences, Professor, Deputy Director for Hematology.
Minsk
A. A. Kovalev
Gomel State Medical University
Belarus
Belarus
Alexey A. Kovalev - Senior Lecturer at the Department of Medical and Biological Physics.
Gomel
References
1. Tourret J, Willing BP, Dion S, MacPherson J, Denamur E, Finlay BB. Immunosuppressive treatment alters secretion of ileal antimicrobial peptides and gut microbiota, and favors subsequent colonization by uropathogenic Escherichia coli. Transplantation. 2017;101:74-82. DOI: https://doi.org/10.1097/TP.0000000000001492
2. Wu T, Yang L, Jiang J, Ni Y, Zhu J, Zheng X, Wang Q, Lu X, Fu Z. Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats. Life Sci. 2018 Jan 1;192:173-182. DOI: https://doi.org/10.1016/j.lfs.2017.11.049
3. He Z, Kong X, Shao T, Zhang Y, Wen C. Alterations of the Gut Microbiota Associated With Promoting Efficacy of Prednisone by Bromofuranone in MRL/lpr Mice. Front Microbiol. 2019 May 1;10:978. DOI: https://doi.org/10.3389/fmicb.2019.00978
4. Huang EY, Inoue T, Leone VA, Dalal S, Touw K, Wang Y, Musch MW, Theriault B, Higuchi K, Donovan S, Gilbert J, Chang EB. Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. Inflamm Bowel Dis. 2015 May;21(5):963-972. DOI: https://doi.org/10.1097/MIB.0000000000000332
5. Bunker JJ, Flynn TM, Koval JC, Shaw DG, Meisel M, McDonald BD, Ishizuka IE, Dent AL, Wilson PC, Jabri B, Antonopoulos DA, Bendelac A. Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A. Immunity. 2015 Sep 15;43(3):541-553. DOI: https://doi.org/10.1016/j.immuni.2015.08.007
6. Muniz LR, Knosp C, Yeretssian G. Intestinal antimicrobial peptides during homeostasis, infection, and disease. Front Immunol. 2012;3:310. DOI: https://doi.org/10.3389/fimmu.2012.00310
7. Alverdy J, Aoys E. The effect of glucocorticoid administration on bacterial translocation. Evidence for an acquired mucosal immunodeficient state. Ann Surg. 1991;214:719-723. DOI: https://doi.org/10.1097/00000658-199112000-00012
8. Bhat M, Pasini E, Copeland J, Angeli M, Husain S, Kumar D, et al. Impact of immunosuppression on the metagenomic composition of the intestinal microbiome: a systems biology approach to post-transplant diabetes. Sci Rep. 2017; 7:10277. DOI: https://doi.org/10.1038/s41598-017-10471-2
9. Zhang Z, Liu L, Tang H Jiao W, Zeng S, Xu Y, et al. Immunosuppressive effect of the gut microbiome altered by high-dose tacrolimus in mice. Am J Transplant. 2018;18:1646-1656. DOI: https://doi.org/10.1111/ajt.14661
10. Toral M, Romero M, Rodríguez-Nogales A, Jiménez R, Robles-Vera I, Algieri F, et al. Lactobacillus fermentum improves tacrolimus-induced hypertension by restoring vascular redox state and improving eNOS coupling. Mol Nutr Food Res. 2018;62:1800033. DOI: https://doi.org/10.1002/mnfr.201800033
11. Jiang J-W, Ren Z-G, Lu H-F, Zhang H, Li A, Cui GY, et al. Optimal immunosuppressor induces stable gut microbiota after liver transplantation. World J Gastroenterol. 2018;24:3871-3883. DOI: https://doi.org/10.3748/wjg.v24.i34.3871
12. Jia J, Tian X, Jiang J. et al. Structural shifts in the intestinal microbiota of rats treated with cyclosporine A after orthotropic liver transplantation. Front Med. 2019;13:451-460.
13. Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf. 2001;24(9):645-663. DOI: https://doi.org/10.2165/00002018-200124090-00002
14. Flannigan KL, Taylor MR, Pereira SK, Rodriguez-Arguello J, Moffat AW, Alston L, et al. An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil. J Heart Lung Transplant. 2018;37:1047-1059. DOI: https://doi.org/10.1016/j.healun.2018.05.002
15. Taylor MR, Flannigan KL, Rahim H, Mohamud A, Lewis IA, Hirota SA, et al. Vancomycin relieves mycophenolate mofetil–induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity. Sci Adv. 2019; 5: eaax2358. DOI: https://doi.org/10.1126/sciadv.aax2358
16. Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019;570:462-467. DOI: https://doi.org/10.1038/s41586-019-1291-3
17. Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One. 2015 Mar 27;10(3):e0122399. DOI: https://doi.org/10.1371/journal.pone.0122399
18. Guo Y, Crnkovic CM, Won KJ, Yang X, Lee JR, Orjala J, et al. Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites. Drug Metab Dispos. 2019;47:194-202. DOI: https://doi.org/10.1124/dmd.118.084772
19. Guo Y, Lee H, Edusei E, Albakry S, Jeong H, Lee J.R. Blood Profiles of Gut Bacterial Tacrolimus Metabolite in Kidney Transplant Recipients. Transplant. Direct. 2020;6:601. DOI: https://doi.org/10.1097/TXD.0000000000001052
20. Degraeve AL, Haufroid V, Loriot A, Gatto L, Andries V, Vereecke L, Elens L, Bindels LB. Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1. Microbiome. 2023 Jul 6;11(1):138. DOI: https://doi.org/10.1186/s40168-023-01578-y
21. Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, et al. Clinical pharmacokinetics of tacrolimus. Clinical pharmacokinetics. 1995;29(6):404-430. DOI: https://doi.org/10.2165/00003088-199529060-00003
22. Gabarre P, Loens C, Tamzali Y, Barrou B, Jaisser F, Tourret J. Immunosuppressive Therapy after Solid Organ Transplantation and the Gut Microbiota: Bidirectional Interactions with Clinical 23. Consequences. Am J Transplant. 2022;22:1014-1030. DOI: https://doi.org/10.1111/ajt.16836
23. Jinping Zhou, Rui Zhang, Li P, Huang X, Wei Y, et al. Effects of intestinal microbiota on pharmacokinetics of cyclosporine in rats. Front Microbiol. 2022 Nov 22;13:1032290. DOI: https://doi.org/10.3389/fmicb.2022.1032290
24. RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA. [date of access 2025 January 28]. Available from: http://www.rstudio.com/
25. R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. [date of access 2025 January 28]. Available from: https://www.R-project.org/
Review
For citations:
Uss M.A., Stoma I.O., Milanovich N.F., Gubanova T.N., Uss A.L., Kovalev A.A. Gut microbiota in immunosuppressive therapy in patients after allogeneic hemoietic stem cell transplantation. Health and Ecology Issues. 2025;22(1):39-49. (In Russ.) https://doi.org/10.51523/2708-6011.2025-22-1-05
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