ORIGINAL ARTICLE

The distribution of intestinal flora after hematopoietic stem cell transplantation in children

Lin Tong

orcid.org/0000-0002-1102-7327

Department of Hematology Oncology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China

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Yan Meng,

Yan Meng

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Luying Zhang,

Luying Zhang

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Jie Yu,

Jie Yu

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Ying Dou,

Corresponding Author

Ying Dou

[email protected]

Correspondence

Ying Dou, Department of Hematology Oncology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing 400014, China.

Email: [email protected]

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Lin Tong,

Lin Tong

orcid.org/0000-0002-1102-7327

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Yan Meng,

Yan Meng

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Luying Zhang,

Luying Zhang

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Jie Yu,

Jie Yu

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Ying Dou,

Corresponding Author

Ying Dou

[email protected]

Correspondence

Email: [email protected]

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First published: 26 December 2023

https://doi.org/10.1111/petr.14678

Citations: 2

Lin Tong and Yan Meng contributed to this work equally and should be regarded as co-first authors.

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Abstract

Background

This prospective study aimed to comprehensively understand the changes in intestinal flora at different stages after hematopoietic stem cell transplantation (HSCT) in pediatric patients and to analyze the effect of intestinal flora on acute graft versus host disease (aGVHD), especially on gastrointestinal graft versus host disease (GI GVHD).

Methods

A total of 32 children with primary diseases of primary immunodeficiency disease (PID) and thalassemia were included. 16S sequencing was used to characterize the microbiota layout at three time points peri-transplant including pre-transplant, Day +3, and Day +30.

Results

By comparing the intestinal flora of children with GI GVHD and those without GI GVHD, it suggests that in children with GI GVHD, the distribution of intestinal flora after transplantation was more variable and more chaotic (chao1 index, Friedman test, p = .029). Besides, Veillonella and Ruminococcaceae were more abundant before transplantation, Bifidobacteriaceae and Bacillales were more abundant after transplantation. Comparing children with PID and thalassemia, it was found that the destruction of gut microbiota diversity was more significant in children with thalassemia after transplantation. The comparison of children with 0-I° aGVHD and II-III° aGVHD indicates that children with II-III° aGVHD had more Bilophila before transplantation than children with 0-I° aGVHD. Additionally, exploratory analyses to evaluate correlations between clinical characteristics (medications, immune cell recovery, etc.) and microbiome features were also performed.

Conclusions

This study has synthetically shown the distribution of intestinal flora after allo-HSCT, and some characteristic bacteria at different stages that may serve as potential biomarkers were screened out additionally, perhaps providing clues for the prevention and treatment of the disease.

CONFLICT OF INTEREST STATEMENT

All authors declare no conflict of interest.

Open Research

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supporting Information

REFERENCES

1Daillere R, Vetizou M, Waldschmitt N, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity. 2016; 45(4): 931-943.
10.1016/j.immuni.2016.09.009
CAS PubMed Web of Science® Google Scholar
2Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med. 2014; 6(220): 211r-220r.
10.1126/scitranslmed.3008051
Web of Science® Google Scholar
3Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014; 157(1): 121-141.
10.1016/j.cell.2014.03.011
CAS PubMed Web of Science® Google Scholar
4Round JL, Lee SM, Li J, et al. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011; 332(6032): 974-977.
10.1126/science.1206095
CAS PubMed Web of Science® Google Scholar
5Eriguchi Y, Takashima S, Oka H, et al. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood. 2012; 120(1): 223-231.
10.1182/blood-2011-12-401166
CAS PubMed Web of Science® Google Scholar
6Shono Y, van den Brink M. Gut microbiota injury in allogeneic hematopoietic stem cell transplantation. Nat Rev Cancer. 2018; 18(5): 283-295.
10.1038/nrc.2018.10
CAS PubMed Web of Science® Google Scholar
7Holler E, Butzhammer P, Schmid K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014; 20(5): 640-645.
10.1016/j.bbmt.2014.01.030
PubMed Web of Science® Google Scholar
8Peled JU, Hanash AM, Jenq RR. Role of the intestinal mucosa in acute gastrointestinal GVHD. Blood. 2016; 128(20): 2395-2402.
10.1182/blood-2016-06-716738
CAS PubMed Web of Science® Google Scholar
9Lin D, Hu B, Li P, Zhao Y, Xu Y, Wu D. Roles of the intestinal microbiota and microbial metabolites in acute GVHD. Exp Hematol Oncol. 2021; 10(1): 49.
10.1186/s40164-021-00240-3
PubMed Web of Science® Google Scholar
10Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014; 124(7): 1174-1182.
10.1182/blood-2014-02-554725
CAS PubMed Web of Science® Google Scholar
11Mathewson ND, Jenq R, Mathew AV, et al. Gut microbiome–derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016; 17(5): 505-513.
10.1038/ni.3400
CAS PubMed Web of Science® Google Scholar
12Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012; 209(5): 903-911.
10.1084/jem.20112408
CAS PubMed Web of Science® Google Scholar
13Jenq RR, Taur Y, Devlin SM, et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015; 21(8): 1373-1383.
10.1016/j.bbmt.2015.04.016
PubMed Web of Science® Google Scholar
14Peled JU, Devlin SM, Staffas A, et al. Intestinal microbiota and relapse after hematopoietic-cell transplantation. J Clin Oncol. 2017; 35(15): 1650-1659.
10.1200/JCO.2016.70.3348
PubMed Web of Science® Google Scholar
15Taur Y, Xavier JB, Lipuma L, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012; 55(7): 905-914.
10.1093/cid/cis580
CAS PubMed Web of Science® Google Scholar
16Derrien M, Alvarez A, de Vos WM. The gut microbiota in the first decade of life. Trends Microbiol. 2019; 27(12): 997-1010.
10.1016/j.tim.2019.08.001
CAS PubMed Web of Science® Google Scholar
17Biagi E, Zama D, Rampelli S, et al. Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders. BMC Med Genomics. 2019; 12(1): 49.
10.1186/s12920-019-0494-7
PubMed Web of Science® Google Scholar
18Biagi E, Zama D, Nastasi C, et al. Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT. Bone Marrow Transplant. 2015; 50(7): 992-998.
10.1038/bmt.2015.16
CAS PubMed Web of Science® Google Scholar
19Lähteenmäki K, Wacklin P, Taskinen M, et al. Hematopoietic stem cell transplantation induces severe dysbiosis in intestinal microbiota of paediatric ALL patients. Bone Marrow Transplant. 2017; 52(10): 1479-1482.
10.1038/bmt.2017.168
CAS PubMed Web of Science® Google Scholar
20Köhler N, Zeiser R. Intestinal microbiota influence immune tolerance post allogeneic hematopoietic cell transplantation and intestinal GVHD. Front Immunol. 2019; 9: 3179.
10.3389/fimmu.2018.03179
PubMed Web of Science® Google Scholar
21Shallis RM, Terry CM, Lim SH. Changes in intestinal microbiota and their effects on allogeneic stem cell transplantation. Am J Hematol. 2018; 93(1): 122-128.
10.1002/ajh.24896
PubMed Web of Science® Google Scholar
22Gu Z, Xiong Q, Wang L, et al. The impact of intestinal microbiota in antithymocyte globulin-based myeloablative allogeneic hematopoietic cell transplantation. Cancer. 2022; 128(7): 1402-1410.
10.1002/cncr.34091
CAS PubMed Web of Science® Google Scholar
23Peled JU, Gomes ALC, Devlin SM, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl J Med. 2020; 382(9): 822-834.
10.1056/NEJMoa1900623
CAS PubMed Web of Science® Google Scholar
24Tkachev V, Kaminski J, Potter EL, et al. Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8+ T cells drive gastrointestinal acute graft-versus-host disease. Sci Transl Med. 2021; 13(576):eabc0227.
10.1126/scitranslmed.abc0227
CAS PubMed Web of Science® Google Scholar
25Jarosch S, Köhlen J, Ghimire S, et al. Multimodal immune cell phenotyping in GI biopsies reveals microbiome-related T cell modulations in human GvHD. Cell Rep Med. 2023; 4(7):101125.
10.1016/j.xcrm.2023.101125
CAS PubMed Google Scholar
26Staffas A, Burgos Da Silva M, van den Brink MR. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood. 2017; 129(8): 927-933.
10.1182/blood-2016-09-691394
CAS PubMed Web of Science® Google Scholar
27Kinnebrew MA, Ubeda C, Zenewicz LA, Smith N, Flavell RA, Pamer EG. Bacterial Flagellin stimulates toll-like receptor 5-dependent defense against vancomycin-resistant enterococcus infection. J Infect Dis. 2010; 201(4): 534-543.
10.1086/650203
CAS PubMed Web of Science® Google Scholar
28Arias CA, Murray BE. The rise of the enterococcus: beyond vancomycin resistance. Nat Rev Microbiol. 2012; 10(4): 266-278.
10.1038/nrmicro2761
CAS PubMed Web of Science® Google Scholar
29Kouidhi S, Souai N, Zidi O, et al. High throughput analysis reveals changes in gut microbiota and specific fecal Metabolomic signature in hematopoietic stem cell transplant patients. Microorganisms. 2021; 9(9): 1845.
10.3390/microorganisms9091845
CAS PubMed Web of Science® Google Scholar
30Devaux CA, Million M, Raoult D. The Butyrogenic and lactic bacteria of the gut microbiota determine the outcome of allogenic hematopoietic cell transplant. Front Microbiol. 2020; 11: 1642.
10.3389/fmicb.2020.01642
PubMed Web of Science® Google Scholar
31Ingham AC, Kielsen K, Cilieborg MS, et al. Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation. Microbiome. 2019; 7(1): 131.
10.1186/s40168-019-0745-z
PubMed Web of Science® Google Scholar
32Han L, Jin H, Zhou L, et al. Intestinal microbiota at engraftment influence acute graft-versus-host disease via the Treg/Th17 balance in Allo-HSCT recipients. Front Immunol. 2018; 9: 669.
10.3389/fimmu.2018.00669
PubMed Web of Science® Google Scholar
33Schluter J, Peled JU, Taylor BP, et al. The gut microbiota is associated with immune cell dynamics in humans. Nature. 2020; 588(7837): 303-307.
10.1038/s41586-020-2971-8
CAS PubMed Web of Science® Google Scholar
34Weber D, Hiergeist A, Weber M, et al. Detrimental effect of broad-spectrum antibiotics on intestinal microbiome diversity in patients after allogeneic stem cell transplantation: lack of commensal sparing antibiotics. Clin Infect Dis. 2019; 68(8): 1303-1310.
10.1093/cid/ciy711
CAS PubMed Web of Science® Google Scholar
35Defilipp Z, Peled JU, Li S, et al. Third-party fecal microbiota transplantation following Allo-HCT reconstitutes microbiome diversity. Blood Adv. 2018; 2(7): 745-753.
10.1182/bloodadvances.2018017731
CAS PubMed Web of Science® Google Scholar
36Zhao Y, Li X, Zhou Y, et al. Safety and efficacy of fecal microbiota transplantation for grade IV steroid refractory GI-GvHD patients: interim results from FMT2017002 trial. Front Immunol. 2021; 12:678476.
10.3389/fimmu.2021.678476
CAS PubMed Web of Science® Google Scholar
37Ouyang J, Isnard S, Lin J, et al. Treating from the inside out: relevance of fecal microbiota transplantation to counteract gut damage in GVHD and HIV infection. Front Med (Lausanne). 2020; 7: 421.
10.3389/fmed.2020.00421
PubMed Web of Science® Google Scholar
38Ciernikova S, Kasperova B, Drgona L, Smolkova B, Stevurkova V, Mego M. Targeting the gut microbiome: an emerging trend in hematopoietic stem cell transplantation. Blood Rev. 2021; 48:100790.
10.1016/j.blre.2020.100790
CAS PubMed Web of Science® Google Scholar
39Kakihana K, Fujioka Y, Suda W, et al. Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut. Blood. 2016; 128(16): 2083-2088.
10.1182/blood-2016-05-717652
CAS PubMed Web of Science® Google Scholar
40Hayase E, Hashimoto D, Nakamura K, et al. R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease. J Exp Med. 2017; 214(12): 3507-3518.
10.1084/jem.20170418
CAS PubMed Web of Science® Google Scholar
41Zhao D, Kim Y, Jeong S, et al. Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease. J Clin Invest. 2018; 128(11): 4970-4979.
10.1172/JCI99261
PubMed Web of Science® Google Scholar
42Svahn BM, Remberger M, Heijbel M, et al. Case-control comparison of at-home and hospital care for allogeneic hematopoietic stem-cell transplantation: the role of oral nutrition. Transplantation. 2008; 85(7): 1000-1007.
10.1097/TP.0b013e31816a3267
PubMed Web of Science® Google Scholar
43Seguy D, Berthon C, Micol JB, et al. Enteral feeding and early outcomes of patients undergoing allogeneic stem cell transplantation following myeloablative conditioning. Transplantation. 2006; 82(6): 835-839.
10.1097/01.tp.0000229419.73428.ff
PubMed Web of Science® Google Scholar

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Volume28, Issue1

February 2024

e14678

The distribution of intestinal flora after hematopoietic stem cell transplantation in children

Abstract

Background

Methods

Results

Conclusions

CONFLICT OF INTEREST STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

References

Information

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The distribution of intestinal flora after hematopoietic stem cell transplantation in children

Abstract

Background

Methods

Results

Conclusions

CONFLICT OF INTEREST STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

References

Related

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