Microbiome: An Emerging New Frontier in Graft-Versus-Host Disease

  • Reena Kumari
  • Senthilnathan Palaniyandi
  • Gerhard Carl Hildebrandt


Hematopoietic cell transplantation is an intensive therapy used to treat high-risk hematological malignant disorders and other life-threatening hematological and genetic diseases. Graft-versus-host disease (GVHD) presents a barrier to its wider application. A conditioning regimen and medications given to patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) are capable of disturbing the homeostatic crosstalk between the microbiome and the host immune system and of leading to dysbiosis. Intestinal inflammation in the context of GVHD is associated with loss in microbial diversity that could serve as an independent predictor of mortality. Successful gastrointestinal decontamination using high doses of non-absorbable antibiotics likely affect allo-HCT outcomes leading to significantly less acute GVHD (aGVHD). Butyrate-producing Clostridia directly result in the increased presence of regulatory T cells in the gut, which are protective in GVHD development. Beyond the microbiome, Candida, a member of the mycobiome, colonization in the gut has been considered as a risk factor in pathophysiology of aGVHD and reduction in GVHD is observed with antifungal prophylaxis with fluconazole. Reduced number of goblet cells and Paneth cells have been shown to associate with GVHD and has a significant impact on the micro- and mycobiome density and their composition. Lower levels of 3-indoxyl sulfate at initial stages after allo-HCT are related with worse GVHD outcomes and increased mortality. Increased understanding of the vital role of the gut microbiome in GVHD can give directions to move the field towards the development of improved innovative approaches for preventing or treating GVHD following allo-HCT.


Microbiome Hematopoietic cell transplantation Graft-versus-host disease Dysbiosis 


Compliance with ethical standards

Conflict of interest

There is no conflict of interest.


  1. 1.
    Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–230.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS. Application of metagenomics in the human gut microbiome. World J Gastroenterol. 2015;21:803–814.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol. 2011;23:473–480.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Gomez C, Chanez P. The lung microbiome: the perfect culprit for COPD exacerbations? Eur Respir J. 2016;47:1034–1036.CrossRefPubMedGoogle Scholar
  5. 5.
    Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Ann Rev Immunol. 2010;28:573–621.CrossRefGoogle Scholar
  6. 6.
    Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol. 2006;43:3–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet (London, England). 2009;373:1550–1561.CrossRefGoogle Scholar
  8. 8.
    Teshima T, Reddy P, Zeiser R. Acute Graft-versus-Host Disease: Novel Biological Insights. Biol Blood Marrow Transpl. 2016;22:11–16.CrossRefGoogle Scholar
  9. 9.
    Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124:1174–1182.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen Y, Zhao Y, Cheng Q, Wu D, Liu H. The role of intestinal microbiota in acute graft-versus-host disease. J Immunol Res. 2015;2015:145859.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Mathewson N, Reddy P. Sugar polymers exacerbate lung GVHD. Blood. 2015;125:2883–2884.CrossRefPubMedGoogle Scholar
  12. 12.
    Peled JU, Devlin SM, Staffas A, et al. Intestinal microbiota and relapse after hematopoietic-cell transplantation. J Clin Oncol. 2017;35:1650–1659.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Andermann T, Peled J, Ho C, et al. Microbiome-host interactions in hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2018;24:1322–1340.CrossRefPubMedGoogle Scholar
  14. 14.
    Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012;209:903–911.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jenq RR, Taur Y, Devlin SM, et al. Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:1373–1383.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tawara I, Liu C, Tamaki H, et al. Influence of donor microbiota on the severity of experimental graft-versus-host-disease. Biol Blood Marrow Transplant. 2013;19:164–168.CrossRefPubMedGoogle Scholar
  17. 17.
    Knight P, Campbell BJ, Rhodes JM. Host-bacteria interaction in inflammatory bowel disease. Br Med Bull. 2008;88:95–113.CrossRefPubMedGoogle Scholar
  18. 18.
    Holler 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;20:640–645.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Junghanss C, Marr KA, Carter RA, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant. 2002;8:512–520.CrossRefPubMedGoogle Scholar
  20. 20.
    Kamboj M, Chung D, Seo SK, et al. The changing epidemiology of vancomycin-resistant Enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Biol Blood Marrow Transplant. 2010;16:1576–1581.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Taur 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;55:905–914.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ponce DM, Gomes A, Dierov D, et al. High intestinal microbiota diversity is associated with sparing of the lower GI tract in acute Gvhd patients. Biol Blood Marrow Transplant. 2018;24:S66–S67.CrossRefGoogle Scholar
  23. 23.
    Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487–1496.CrossRefPubMedGoogle Scholar
  24. 24.
    Yan H, Baldridge MT. Hematopoiesis and the bacterial microbiome. Blood. 2018;132:559–564.PubMedGoogle Scholar
  25. 25.
    Iwamura C, Bouladoux N, Belkaid Y, Sher A, Jankovic D. Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood. 2017;129:171–176.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kumari RPS, Hildebrandt GC. The human microbiome in hematologic malignancies. Hematol Transfus Int J. 2016;2:3.Google Scholar
  27. 27.
    Gerbitz A, Schultz M, Wilke A, et al. Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. Blood. 2004;103:4365–4367.CrossRefPubMedGoogle Scholar
  28. 28.
    Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129:729–739.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Palaniyandi S, Radhakrishnan SV, Karlsson FJ, et al. Murine cytomegalovirus immediate-early 1 gene expression correlates with increased GVHD after allogeneic hematopoietic cell transplantation in recipients reactivating from latent infection. PLoS ONE. 2018;8:e61841.CrossRefGoogle Scholar
  30. 30.
    Gratama JW, Sinnige LG, Weijers TF, et al. Marrow donor immunity to herpes simplex virus: association with acute graft-versus-host disease. Exp Hematol. 1987;15:735–740.PubMedGoogle Scholar
  31. 31.
    Arthur RR, Shah KV, Charache P, Saral R. BK and JC virus infections in recipients of bone marrow transplants. J Infect Dis. 1988;158:563–569.CrossRefPubMedGoogle Scholar
  32. 32.
    Williams WB, Liao HX, Moody MA, et al. HIV-1 VACCINES: Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies. Science (New York, N.Y.). 2015;349:aab1253.CrossRefGoogle Scholar
  33. 33.
    Oh JZ, Ravindran R, Chassaing B, et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity. 2014;41:478–492.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pfeiffer JK, Virgin HW. Viral immunity: transkingdom control of viral infection and immunity in the mammalian intestine. Science (New York, N.Y.). 2016;351:aad5872.CrossRefGoogle Scholar
  35. 35.
    Kane M, Case LK, Kopaskie K, et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science (New York, N.Y.). 2011;334:245–249.CrossRefGoogle Scholar
  36. 36.
    Kuss SK, Best GT, Etheredge CA, et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science (New York, N.Y.). 2011;334:249–252.CrossRefGoogle Scholar
  37. 37.
    Robinson CM, Jesudhasan PR, Pfeiffer JK. Bacterial lipopolysaccharide binding enhances virion stability and promotes environmental fitness of an enteric virus. Cell Host Microbe. 2014;15:36–46.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Uchiyama R, Chassaing B, Zhang B, Gewirtz AT. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J Infect Dis. 2014;210:171–182.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Roddie C, Paul JP, Benjamin R, et al. Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: a previously unrecognized cause of morbidity. Clin Infect Dis. 2009;49:1061–1068.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hassan IA, Chopra R, Swindell R, Mutton KJ. Respiratory viral infections after bone marrow/peripheral stem-cell transplantation: the Christie hospital experience. Bone Marrow Transplant. 2003;32:73–77.CrossRefPubMedGoogle Scholar
  41. 41.
    van der Velden WJ, Plantinga TS, Feuth T, Donnelly JP, Netea MG, Blijlevens NM. The incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status. Clin Immunol (Orlando, FL). 2010;136:302–306.CrossRefGoogle Scholar
  42. 42.
    van der Velden WJFM, Plantinga T, Feuth T, Donnelly P, Netea M, Blijlevens NNA. No impact of dectin-1 polymorphism Y238X on the outcome of hematopoietic stem cell transplantation, but a role for Candida in acute graft-versus-host disease. Blood. 2009;114:4498.Google Scholar
  43. 43.
    Safdar A. Strategies to enhance immune function in hematopoietic transplantation recipients who have fungal infections. Bone Marrow Transplant. 2006;38:327–337.CrossRefPubMedGoogle Scholar
  44. 44.
    Beck O, Topp MS, Koehl U, et al. Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus. Blood. 2006;107:2562–2569.CrossRefPubMedGoogle Scholar
  45. 45.
    Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:909–917.CrossRefPubMedGoogle Scholar
  46. 46.
    Morgan J, Wannemuehler KA, Marr KA, et al. Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol. 2005;43:S49–S58.CrossRefPubMedGoogle Scholar
  47. 47.
    Ribaud P, Chastang C, Latge JP, et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis. 1999;28:322–330.CrossRefPubMedGoogle Scholar
  48. 48.
    Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191:1350–1360.CrossRefPubMedGoogle Scholar
  49. 49.
    Weber D, Oefner PJ, Dettmer K, et al. Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51:1087–1092.CrossRefPubMedGoogle Scholar
  50. 50.
    Steck N, Hoffmann M, Sava IG, et al. Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology. 2011;141:959–971.CrossRefPubMedGoogle Scholar
  51. 51.
    Stein-Thoeringer C, Peled JU, Lazrak A, et al. Domination of the gut microbiota with Enterococcus species early after allogeneic bone marrow transplantation is an important contributor to the development of acute graft-versus-host disease (GHVD) in mouse and man. Biol Blood Marrow Transplant. 2018;24:S40–S41.CrossRefGoogle Scholar
  52. 52.
    Vossen JM, Guiot HF, Lankester AC, et al. Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation. PLoS ONE. 2014;9:e105706.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Chakrabarti S, Lees A, Jones SG, Milligan DW. Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality. Bone Marrow Transplant. 2000;26:871–876.CrossRefPubMedGoogle Scholar
  54. 54.
    Kinnebrew MA, Lee YJ, Jenq RR, et al. Early Clostridium difficile infection during allogeneic hematopoietic stem cell transplantation. PLoS ONE. 2014;9:e90158.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Borody TJ. “Floor Power”—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol. 2000;95:3028–3029.PubMedGoogle Scholar
  56. 56.
    van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415.CrossRefPubMedGoogle Scholar
  57. 57.
    van Lier YF, de Groot PF, Nur E, et al. Fecal microbiota transplantation as safe and successful therapy for intestinal graft-versus-host disease. Blood. 2017;130:1986.Google Scholar
  58. 58.
    Kumari R, Ahuja V, Paul J. Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India. World J Gastroenterol. 2013;19:3404–3414.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Kumari RVN, Paul J. Potential contribution of microbiome in neurodegenerative diseases: Alzheimer’s disease. Inflamm Cell Signal. 2017;4:58.Google Scholar
  60. 60.
    Reddy P, Sun Y, Toubai T, et al. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Investig. 2008;118:2562–2573.PubMedGoogle Scholar
  61. 61.
    Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17:1519–1528.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Romick-Rosendale L, Haslam D, Lane A, et al. Short chain fatty acids are reduced after hematopoietic stem cell transplant in humans and are associated with modifications of the gut microbiome. Biol Blood Marrow Transplant. 2018;24:S87–S88.CrossRefGoogle Scholar
  63. 63.
    Mathewson 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;17:505–513.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500:232–236.CrossRefGoogle Scholar
  65. 65.
    Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–450.CrossRefPubMedGoogle Scholar
  66. 66.
    Dant TA, Lin KL, Bruce DW, et al. T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD. Blood. 2017;130:348–359.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Edinger M, Powrie F, Chakraverty R. Regulatory mechanisms in graft-versus-host responses. Biol Blood Marrow Transplant. 2009;15:2–6.CrossRefPubMedGoogle Scholar
  68. 68.
    Berstad A, Raa J, Valeur J. Indole - the scent of a healthy ‘inner soil’. Microb Ecol Health Dis. 2015;26:27997.PubMedGoogle Scholar
  69. 69.
    Weber D, Jenq RR, Peled JU, et al. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:845–852.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Rayes A, Morrow AL, Payton LR, Lake KE, Lane A, Davies SM. A genetic modifier of the gut microbiome influences the risk of graft-versus-host disease and bacteremia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:418–422.CrossRefPubMedGoogle Scholar
  71. 71.
    Wacklin P, Tuimala J, Nikkila J, et al. Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status. PLoS ONE. 2014;9:e94863.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Wacklin P, Makivuokko H, Alakulppi N, et al. Secretor genotype (FUT2 gene) is strongly associated with the composition of Bifidobacteria in the human intestine. PLoS ONE. 2011;6:e20113.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Pelaseyed T, Bergstrom JH, Gustafsson JK, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;260:8–20.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Penack O, Henke E, Suh D, et al. Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. J Natl Cancer Inst. 2010;102:894–908.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012;489:231–241.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Eriguchi 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;120:223–231.CrossRefPubMedGoogle Scholar
  77. 77.
    Levine JE, Huber E, Hammer ST, et al. Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood. 2013;122:1505–1509.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Cerf-Bensussan N, Gaboriau-Routhiau V. The immune system and the gut microbiota: friends or foes? Nat Rev Immunol. 2010;10:735–744.CrossRefPubMedGoogle Scholar
  79. 79.
    Crawford PA, Gordon JI. Microbial regulation of intestinal radiosensitivity. Proc Natl Acad Sci USA. 2005;102:13254–13259.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Reena Kumari
    • 1
  • Senthilnathan Palaniyandi
    • 1
  • Gerhard Carl Hildebrandt
    • 1
    • 2
  1. 1.Division of Hematology & Blood and Marrow Transplantation, Markey Cancer CenterUniversity of KentuckyLexingtonUSA
  2. 2.Department of Microbiology, Immunology & Molecular GeneticsUniversity of KentuckyLexingtonUSA

Personalised recommendations