zdorПроблемы здоровья и экологииHealth and Ecology Issues2220-09672708-6011Gomel State Medical University10.51523/2708-6011.2025-22-1-05zdor-2822Research ArticleЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНА И БИОЛОГИЯEXPERIMENTAL MEDICINE AND BIOLOGYМикробиом кишечника при иммуносупрессивной терапии у пациентов после аллогенной трансплантации гемоэтических стволовых клетокGut microbiota in immunosuppressive therapy in patients after allogeneic hemoietic stem cell transplantationhttps://orcid.org/0009-0002-9550-1117УссМ. А.UssM. A.

Усс Михаил Анатольевич - врач-гематолог (заведующий) гематологического отделения трансплантации костного мозга № 2.

Минск

Mikhail A. Uss - Haematologist (Head) at the Hematology Department of Bone Marrow Transplantation No. 2.

Minsk

mikhail.uss@mail.ruhttps://orcid.org/0000-0003-0483-7329СтомаИ. О.StomaI. O.

Стома Игорь Олегович - д.м.н., профессор, ректор.

Гомель

Igor O. Stoma - Doctor of Medical Sciences, Professor.

Gomel

gsmu@gsmu.byhttps://orcid.org/0009-0009-7249-8198МилановичН. Ф.MilanovichN. F.

Миланович Наталья Феодосьевна - к.м.н., врач-гематолог (заведующий) гематологического отделения трансплантации костного мозга № 3.

Минск

Natalya F. Milanovich - Candidate of Medical Sciences, Head of the Hematology Department of Bone Marrow Transplantation No. 3.

Minsk

nataly.milanovich@gmail.comГубановаТ. Н.GubanovaT. N.

Губанова Татьяна Николаевна - научный сотрудник научного отдела.

Минск

Tatyana N. Gubanova - Researcher at the Scientific Department.

Minsk

УссА. Л.UssA. L.

Усс Анатолий Леонидович - д.м.н., профессор, заместитель директора по гематологии.

Минск

Anatoly L. Uss - Doctor of Medical Sciences, Professor, Deputy Director for Hematology.

Minsk

bmtc@mail.ruhttps://orcid.org/0000-0001-9148-487XКовалевА. А.KovalevA. A.

Ковалев Алексей Алексеевич - старший преподаватель кафедры медицинской и биологической физики.

Гомель

Alexey A. Kovalev - Senior Lecturer at the Department of Medical and Biological Physics.

Gomel

kovalev.data.analysis.gsmu@yandex.byМинский научно-практический центр хирургии, трансплантологии и гематологииMinsk Scientific and Practical Center for Surgery, Transplantology and HematologyГомельский государственный медицинский университетGomel State Medical University2025290320252213949Copyright © Усс М.А., Стома И.О., Миланович Н.Ф., Губанова Т.Н., Усс А.Л., Ковалев А.А., 20252025Усс М.А., Стома И.О., Миланович Н.Ф., Губанова Т.Н., Усс А.Л., Ковалев А.А.Uss M.A., Stoma I.O., Milanovich N.F., Gubanova T.N., Uss A.L., Kovalev A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.gsmu.by/jour/article/view/2822Цель исследования

Цель исследования. Провести ассоциации между составом микробиома кишечника и дозированием иммуносупрессивных препаратов у пациентов после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК).

Материалы и методы

Материалы и методы. В настоящем исследовании методом секвенирования V3–V4 участков гена 16S рРНК нами был изучен состав микробиома кишечника 36 пациентов после алло-ТГСК при различных вариантах иммуносупрессии.

Результаты

Результаты. Прием такролимуса приводил к значимому снижению представленности бактерий типа Bacteroidetes и в особенности семейства Bacteroidaceae в образцах стула в отличие от циклоспорина А; пациентам с более высокой плотностью микробов рода Akkermansia чаще требовалась редукция дозы иммуносупрессии для поддержания целевого уровня в сыворотке крови, что было подтверждено двумя многомерными методами, а у пациентов с большей представленностью видов Faecalibacterium, Oscillibacter и Hungatella медиана дозы циклоспорина А для поддержания терапевтической концентрации была больше.

Заключение

Заключение. С учетом вариабельных концентраций ингибиторов кальциневрина, возможных нежелательных явлений, связанных с недостаточным либо избыточным уровнем препаратов в сыворотке крови, а также полученными ассоциациями между микробиомом кишечника пациентов и дозой иммуносупрессоров, необходимы дополнительные исследования для выявления взаимосвязи кишечного микробиома и иммуносупрессивных препаратов.

Objective

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

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

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

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

трансплантация гемопоэтических стволовых клетокмикробиом кишечникаиммуносупрессивная терапияHematopoietic stem cell transplantationgut microbiotaimmunosuppressive therapyРеспубликанский бюджет; Внебюджетные средства ГУ «Минский научно-практический центр хирургии, трансплантологии и гематологии»Republican budget; Extra-budgetary funds of the Minsk Scientific and Practical Center for Surgery, Transplantology and HematologyReferencesTourret 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.0000000000001492Tourret 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.0000000000001492Wu 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.2017.11.049Wu 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.2017.11.049He 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.2019.00978He 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.2019.00978Huang 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.0000000000000332Huang 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.0000000000000332Bunker 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.2015.08.007Bunker 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.2015.08.007Muniz 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.2012.00310Muniz 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.2012.00310Alverdy 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/10.1097/00000658-199112000-00012Alverdy 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/10.1097/00000658-199112000-00012Bhat 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/s41598-017-10471-2Bhat 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/s41598-017-10471-2Zhang 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.14661Zhang 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.14661Toral 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.201800033Toral 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.201800033Jiang 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.i34.3871Jiang 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.i34.3871Jia 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.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.Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf. 2001;24(9):645-663. DOI: https://doi.org/10.2165/00002018-200124090-00002Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf. 2001;24(9):645-663. DOI: https://doi.org/10.2165/00002018-200124090-00002Flannigan 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.2018.05.002Flannigan 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.2018.05.002Taylor 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.aax2358Taylor 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.aax2358Zimmermann 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/s41586-019-1291-3Zimmermann 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/s41586-019-1291-3Lee 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.0122399Lee 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.0122399Guo 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.118.084772Guo 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.118.084772Guo 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.0000000000001052Guo 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.0000000000001052Degraeve 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-yDegraeve 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-yVenkataramanan 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/10.2165/00003088-199529060-00003Venkataramanan 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/10.2165/00003088-199529060-00003Gabarre 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.16836Gabarre 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.16836Jinping 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.2022.1032290Jinping 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.2022.1032290RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA. [date of access 2025 January 28]. Available from: http://www.rstudio.com/RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA. [date of access 2025 January 28]. Available from: http://www.rstudio.com/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/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/

The authors declare that there are no conflicts of interest present.