Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Host Disease

Potential protective effect of Helicobacter pylori on the development of gastrointestinal GvHD

Abstract

Previous reports ascribe a modulating capacity of the immune response to Helicobacter pylori (HP). Our hypothesis was to demonstrate in a prospective study that HP infection could have a protective effect against development of gastrointestinal GvHD in patients receiving allogeneic hematopoietic cell transplantation (HCT). Presence of HP before transplant was determined using C13 urea breath test. Seventy-nine patients receiving an allogeneic HCT were included and 93.7% of them received PBSC; in 51.9%, the donor was unrelated. Acute gastrointestinal GvHD was diagnosed in 51.9% (n=41). In the multivariable analysis, HP infection was associated with a lower frequency of gastrointestinal GvHD (odds ratio (OR)=0.19 (95% confidence interval (CI): 0.05–0.67); in contrast, an unrelated donor was associated with a higher frequency of gastrointestinal GvHD (odds ratio=5.4 (95% confidence interval: 1.6–18.2). One year overall survival (OS) was 74%. In the multivariate Cox proportional-hazards regression analysis, stages 0–II gastrointestinal GvHD (hazards ratio (HR)=0.19), reduced intensity conditioning (HR=0.04) and tacrolimus-sirolimus GvHD prophylaxis (HR=0.06) were all associated with a better OS. In summary, HP infection could have a role in decreasing gastrointestinal GvHD in patients receiving allogeneic HCT from peripheral blood including related and unrelated donors.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Welniak LA, Blazar BR, Murphy WJ . Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25: 139–170.

    Article  CAS  PubMed  Google Scholar 

  2. Holmberg L, Kikuchi K, Gooley TA, Adams KM, Hockenbery DM, Flowers ME et al. Gastrointestinal graft-versus-host disease in recipients of autologous hematopoietic stem cells: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 2006; 12: 226–234.

    Article  PubMed  Google Scholar 

  3. Leisenring WM, Martin PJ, Petersdorf EW, Regan AE, Aboulhosn N, Stern JM et al. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood 2006; 108: 749–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kuipers EJ, Pena AS, van Kamp G, Uyterlinde AM, Pals G, Pels NF et al. Seroconversion for Helicobacter pylori. Lancet 1993; 342: 328–331.

    Article  CAS  PubMed  Google Scholar 

  5. Malaty HM, El Kasabany A, Graham DY, Miller CC, Reddy SG, Srinivasan SR et al. Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to adulthood. Lancet 2002; 359: 931–935.

    Article  PubMed  Google Scholar 

  6. Go MF . Review article: natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16: 3–15.

    Article  PubMed  Google Scholar 

  7. Testerman TL, Morris J . Beyond the stomach: an updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment. World J Gastroenterol 2014; 20: 12781–12808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhou X, Wu J, Zhang G . Association between Helicobacter pylori and asthma: a meta-analysis. Eur J Gastroenterol Hepatol 2013; 25: 460–468.

    Article  CAS  PubMed  Google Scholar 

  9. Taye B, Enquselassie F, Tsegaye A, Medhin G, Davey G, Venn A . Is Helicobacter Pylori infection inversely associated with atopy? A systematic review and meta-analysis. Clin Exp Allergy 2015; 45: 882–890.

    Article  CAS  PubMed  Google Scholar 

  10. Hasni SA . Role of Helicobacter pylori infection in autoimmune diseases. Curr Opin Rheumatol 2012; 24: 429–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jones NL, Shannon PT, Cutz E, Yeger H, Sherman PM . Increase in proliferation and apoptosis of gastric epithelial cells early in the natural history of Helicobacter pylori infection. Am J Pathol 1997; 151: 1695–1703.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Moss SF, Calam J, Agarwal B, Wang S, Holt PR . Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 1996; 38: 498–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gisbert JP, Pajares JM . Review article: 13C-urea breath test in the diagnosis of Helicobacter pylori infection — a critical review. Aliment Pharmacol Ther 2004; 20: 1001–1017.

    Article  CAS  PubMed  Google Scholar 

  14. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT . Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995; 109: 136–141.

    Article  CAS  PubMed  Google Scholar 

  15. Velasco-Guardado A, Lopez-Corral L, Perez-Simon JA, Caballero-Velazquez T, Flores-Corral T, Caballero-Barrigon D et al. Helicobacter pylori infection and graft-versus-host disease. Biol Blood Marrow Transplant 2011; 17: 765–769.

    Article  PubMed  Google Scholar 

  16. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al1995 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15: 825–828.

    CAS  PubMed  Google Scholar 

  17. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  18. Cruz-Correa M, Poonawala A, Abraham SC, Wu TT, Zahurak M, Vogelsang G et al. Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease. Endoscopy 2002; 34: 808–813.

    Article  CAS  PubMed  Google Scholar 

  19. Washington K, Jagasia M . Pathology of graft-versus-host disease in the gastrointestinal tract. Hum Pathol 2009; 40: 909–917.

    Article  PubMed  Google Scholar 

  20. van der Velden WJ, Netea MG, de Haan AF, Huls GA, Donnelly JP, Blijlevens NM . Role of the mycobiome in human acute graft-versus-host disease. Biol Blood Marrow Transplant 2013; 19: 329–332.

    Article  CAS  PubMed  Google Scholar 

  21. Jenq R, Marcel RM . Identification of intestinal commensal bacteria protective against GVHD in mice and humans. Biol Blood Marrow Transplant 2014; 20: S22–S23.

    Article  Google Scholar 

  22. Gerbitz A, Schultz M, Wilke A, Linde HJ, Scholmerich J, Andreesen R et al. Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. Blood 2004; 103: 4365–4367.

    Article  CAS  PubMed  Google Scholar 

  23. Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014; 124: 1174–1182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Larussa T, Leone I, Suraci E, Nazionale I, Procopio T, Conforti F et al. Enhanced expression of indoleamine 2,3-dioxygenase in Helicobacter pylori-infected human gastric mucosa modulates Th1/Th2 pathway and interleukin 17 production. Helicobacter 2015; 20: 41–48.

    Article  CAS  PubMed  Google Scholar 

  25. Chen Y, Blaser MJ . Inverse associations of Helicobacter pylori with asthma and allergy. Arch Intern Med 2007; 167: 821–827.

    Article  PubMed  Google Scholar 

  26. Teshima T, Ordemann R, Reddy P, Gagin S, Liu C, Cooke KR et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 2002; 8: 575–581.

    Article  CAS  PubMed  Google Scholar 

  27. Xun CQ, Thompson JS, Jennings CD, Brown SA, Widmer MB . Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood 1994; 83: 2360–2367.

    CAS  PubMed  Google Scholar 

  28. Nestel FP, Price KS, Seemayer TA, Lapp WS . Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med 1992; 175: 405–413.

    Article  CAS  PubMed  Google Scholar 

  29. Koyama M, Kuns RD, Olver SD, Raffelt NC, Wilson YA, Don AL et al. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med 2011; 18: 135–142.

    Article  PubMed  Google Scholar 

  30. Tawara I, Koyama M, Liu C, Toubai T, Thomas D, Evers R et al. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res 2011; 17: 77–88.

    Article  CAS  PubMed  Google Scholar 

  31. Hill GR, Teshima T, Rebel VI, Krijanovski OI, Cooke KR, Brinson YS et al. The p55 TNF-alpha receptor plays a critical role in T cell alloreactivity. J Immunol 2000; 164: 656–663.

    Article  CAS  PubMed  Google Scholar 

  32. Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, Zhao G et al. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J Exp Med 2006; 203: 2021–2031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Markey KA, MacDonald KP, Hill GR . The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood 2014; 124: 354–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang Q, Yu C, Sun Y . The association between asthma and Helicobacter pylori: a meta-analysis. Helicobacter 2013; 18: 41–53.

    Article  PubMed  Google Scholar 

  35. Del Prete G, Chiumiento L, Amedei A, Piazza M, D'Elios MM, Codolo G et al. Immunosuppression of TH2 responses in Trichinella spiralis infection by Helicobacter pylori neutrophil-activating protein. J Allergy Clin Immunol 2008; 122: 908–913.

    Article  CAS  PubMed  Google Scholar 

  36. Codolo G, Mazzi P, Amedei A, Del Prete G, Berton G, D'Elios MM et al. The neutrophil-activating protein of Helicobacter pylori down-modulates Th2 inflammation in ovalbumin-induced allergic asthma. Cell Microbiol 2008; 10: 2355–2363.

    Article  CAS  PubMed  Google Scholar 

  37. Luther J, Dave M, Higgins PD, Kao JY . Association between Helicobacter pylori infection and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Inflamm Bowel Dis 2010; 16: 1077–1084.

    Article  PubMed  Google Scholar 

  38. Correia-Silva JF, Neto Victoria JM, Guimaraes AL, de Sa AR, Gomes CC, de Almeida HC et al. Helicobacter pylori in the oral mucosa of patients submitted to allogeneic haematopoietic stem cell transplantation. Braz Oral Res 2006; 20: 191–195.

    Article  Google Scholar 

  39. Au WY, Wong RW, Wong BC, Lie AK, Liang R, Leung AY et al. Reduced incidence of acute graft versus host disease (GVHD) of the gut in Chinese carriers of Helicobacter pylori during allogeneic bone marrow transplantation. Ann Hematol 2004; 83: 34–37.

    Article  CAS  PubMed  Google Scholar 

  40. Fuji S, Kapp M, Einsele H . Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Front Oncol 2014; 4: 89.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Martin PJ, McDonald GB, Sanders JE, Anasetti C, Appelbaum FR, Deeg HJ et al. Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2004; 10: 320–327.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Professor George B McDonald MD for reading and reviewing the paper as well as for his suggestions to improve the final version of paper. We thank the doctors and nurses of the Gastroenterology and Hematology Clinical Units as well as the Pathology Department for their collaboration/ help.

Author contributions

AVG wrote the manuscript and performed statistical analysis; AM-S compiled the clinical data; LL-C, LV-L and DC-B enrolled patients; OL-G and EL-P reviewed the clinical data; AVG, AM-S and ARP performed the endoscopies; OB-M performed histological analysis; ARP and DC-B reviewed the manuscript. All authors approved the final version of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Velasco-Guardado.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Velasco-Guardado, A., Mora-Soler, A., López-Corral, L. et al. Potential protective effect of Helicobacter pylori on the development of gastrointestinal GvHD. Bone Marrow Transplant 51, 819–824 (2016). https://doi.org/10.1038/bmt.2016.31

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2016.31

Search

Quick links