Abstract
Acute graft-versus-host disease (GvHD) of the gastrointestinal (GI) tract is still a major cause of severe morbidity and mortality following allogeneic stem cell transplantation (ASCT). The intestinal “microflora” has been in the focus of the pathophysiology of acute GI GvHD since many years. In 1974 van Bekkum and colleagues reported a possible role of microbiota as they observed that mice kept under germ-free conditions did not develop acute GI GvHD. Clinical studies showed a reduction of GvHD severity with total or selective gut decontamination and isolation which became standard for years. However, with deeper insights obtained by new molecular techniques, our understanding of the association between microbiota and GI GvHD has changed. During ASCT an early loss of intestinal microbiome diversity especially with regard to commensal Clostridiales and a shift toward an enteropathogenic flora was observed which associated with increased GvHD-related mortality. A major risk factor for the loss of commensal bacteria is the use of systemic broad-spectrum antibiotics for prophylaxis and therapy of neutropenic infections which occur frequently in ASCT patients. Both the kind of antibiotics and the timing of antibiotic treatment influence the outcome of patients after ASCT. The damage and destruction of Paneth cells by GvHD itself reduce antimicrobial peptides further aggravating intestinal dysbiosis during GvHD. These results indicate that microbiota manipulation could be a promising future approach not only for prophylaxis and treatment of acute GI GvHD but also for eradication of a colonization with multiple antibiotic-resistant pathogens to prevent infections or even to prevent relapse.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Ames, N. J., Sulima, P., Ngo, T., Barb, J., Munson, P. J., Paster, B. J., & Hart, T. C. (2012). A characterization of the oral microbiome in allogeneic stem cell transplant patients. PLoS One, 7(10), e47628. https://doi.org/10.1371/journal.pone.0047628. Epub 2012 Oct 29. PubMed PMID: 23144704; PubMed Central PMCID: PMC3483166.
Apostolova, P., & Zeiser, R. (2016). The role of purine metabolites as DAMPs in acute graft-versus-host disease. Frontiers in Immunology, 7, 439. eCollection 2016.
Beelen, D. W., Elmaagacli, A., Müller, K. D., Hirche, H., & Schaefer, U. W. (1999). Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: Final results and long-term follow-up of an open-label prospective randomized trial. Blood, 93(10), 3267–3275.
Bevins, C. L., Stange, E. F., & Wehkamp, J. (2009). Decreased Paneth cell defensin expression in ileal Crohn’s disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut, 58(6), 882–883. discussion 883–4. PubMed PMID: 19433600.
Bilinski, J., Grzesiowski, P., Sorensen, N., Madry, K., Muszynski, J., Robak, K., Wroblewska, M., Dzieciatkowski, T., Dulny, G., Dwilewicz-Trojaczek, J., Wiktor-Jedrzejczak, W., & Basak, G. W. (2017). Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: Results of a prospective, single-center study. Clinical Infectious Diseases, 65(3), 364–370. https://doi.org/10.1093/cid/cix252. PubMed PMID: 28369341.
Bilinski, J., Robak, K., Peric, Z., Marchel, H., Karakulska-Prystupiuk, E., Halaburda, K., Rusicka, P., Swoboda-Kopec, E., Wroblewska, M., Wiktor-Jedrzejczak, W., & Basak, G. W. (2016). Impact of gut colonization by antibiotic-resistant bacteria on the outcomes of allogeneic hematopoietic stem cell transplantation: A retrospective, single-center study. Biology of Blood and Marrow Transplantation, 22(6), 1087–1093. https://doi.org/10.1016/j.bbmt.2016.02.009. Epub 2016 Feb 18. PubMed PMID: 26900084.
Cooke, K. R., Gerbitz, A., Crawford, J. M., Teshima, T., Hill, G. R., Tesolin, A., Rossignol, D. P., & Ferrara, J. L. (2001). LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. The Journal of Clinical Investigation, 107(12), 1581–1589.
Cooke, K. R., Olkiewicz, K., Erickson, N., & Ferrara, J. L. (2002). The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. Journal of Endotoxin Research, 8(6), 441–448.
Doki, N., Suyama, M., Sasajima, S., Ota, J., Igarashi, A., Mimura, I., Morita, H., Fujioka, Y., Sugiyama, D., Nishikawa, H., Shimazu, Y., Suda, W., Takeshita, K., Atarashi, K., Hattori, M., Sato, E., Watakabe-Inamoto, K., Yoshioka, K., Najima, Y., Kobayashi, T., Kakihana, K., Takahashi, N., Sakamaki, H., Honda, K., & Ohashi, K. (2017). Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation. Annals of Hematology, 96(9), 1517–1523. https://doi.org/10.1007/s00277-017-3069-8. Epub 2017 Jul 21. PubMed PMID: 28733895.
Ekmekciu, I., von Klitzing, E., Fiebiger, U., Escher, U., Neumann, C., Bacher, P., Scheffold, A., Kühl, A. A., Bereswill, S., & Heimesaat, M. M. (2017). Immune responses to broad-spectrum antibiotic treatment and fecal microbiota transplantation in mice. Frontiers in Immunology, 8, 397. https://doi.org/10.3389/fimmu.2017.00397.
Eriguchi, Y., Nakamura, K., Hashimoto, D., Shimoda, S., Shimono, N., Akashi, K., Ayabe, T., & Teshima, T. (2015). Decreased secretion of Paneth cell α-defensins in graft-versus-host disease. Transplant Infectious Disease, 17(5), 702–706.
Eriguchi, Y., Takashima, S., Oka, H., Shimoji, S., Nakamura, K., Uryu, H., Shimoda, S., Iwasaki, H., Shimono, N., Ayabe, T., Akashi, K., & Teshima, T. (2012). Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins. Blood, 120(1), 223–231.
Eriguchi, Y., Uryu, H., Nakamura, K., Shimoji, S., Takashima, S., Iwasaki, H., Miyamoto, T., Shimono, N., Hashimoto, D., Akashi, K., Ayabe, T., & Teshima, T. (2013). Reciprocal expression of enteric antimicrobial proteins in intestinal graft-versus-host disease. Biology of Blood and Marrow Transplantation, 19(10), 1525–1529.
Ferrara, J. L., Harris, A. C., Greenson, J. K., Braun, T. M., Holler, E., Teshima, T., Levine, J. E., Choi, S. W., Huber, E., Landfried, K., Akashi, K., Vander Lugt, M., Reddy, P., Chin, A., Zhang, Q., Hanash, S., & Paczesny, S. (2011). Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood, 118(25), 6702–6708.
Ferrara, J. L., Levine, J. E., Reddy, P., & Holler, E. (2009). Graft-versus-host disease. Lancet, 373(9674), 1550–1561. https://doi.org/10.1016/S0140-6736(09)60237-3.
Gafter-Gvili, A., Fraser, A., Paul, M., van de Wetering, M., Kremer, L., & Leibovici, L. (2005). Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Systematic Review, (4), CD004386. Review. Update in: Cochrane Database Syst Rev. 2012;1:CD004386.
Gerbitz, A., Schultz, M., Wilke, A., Linde, H. J., Schölmerich, J., Andreesen, R., & Holler, E. (2004). Probiotic effects on experimental graft-versus-host disease: Let them eat yogurt. Blood, 103(11), 4365–4367.
Ghimire, S., Matos, C., Caioni, M., Weber, D., Peter, K., Holler, E., Kreutz, M., & Renner, K. (2018). Indoxyl 3-sulfate inhibits maturation and activation of human monocyte-derived dendritic cells. Immunobiology, 223(2), 239–245.
Golob, J. L., Pergam, S. A., Srinivasan, S., Fiedler, T. L., Liu, C., Garcia, K., Mielcarek, M., Ko, D., Aker, S., Marquis, S., Loeffelholz, T., Plantinga, A., Wu, M. C., Celustka, K., Morrison, A., Woodfield, M., & Fredricks, D. N. (2017). The stool microbiota at neutrophil recovery is predictive for severe acute graft versus host disease after hematopoietic cell transplantation. Clinical Infectious Diseases. https://doi.org/10.1093/cid/cix699. [Epub ahead of print] PubMed PMID: 29020185.
Gonzales, F., Bruno, B., Alarcón Fuentes, M., De Berranger, E., Guimber, D., Behal, H., Gandemer, V., Spiegel, A., Sirvent, A., Yakoub-Agha, I., Nelken, B., Duhamel, A., & Seguy, D. (2017). Better early outcome with enteral rather than parenteral nutrition in children undergoing MAC allo-SCT. Clinical Nutrition. https://doi.org/10.1016/j.clnu.2017.10.005. pii: S0261-5614(17)31365-1. [Epub ahead of print] PubMed PMID: 29097037.
Gooley, T. A., Chien, J. W., Pergam, S. A., Hingorani, S., Sorror, M. L., Boeckh, M., Martin, P. J., Sandmaier, B. M., Marr, K. A., Appelbaum, F. R., Storb, R., & McDonald, G. B. (2010). Reduced mortality after allogeneic hematopoietic-cell transplantation. The New England Journal of Medicine, 363(22), 2091–2101.
Gorshein, E., Wei, C., Ambrosy, S., Budney, S., Vivas, J., Shenkerman, A., Manago, J., McGrath, M. K., Tyno, A., Lin, Y., Patel, V., Gharibo, M., Schaar, D., Jenq, R. R., Khiabanian, H., & Strair, R. (2017). Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation. Clinical Transplantation, 31(5). https://doi.org/10.1111/ctr.12947. Epub 2017 Mar 31.
Hanash, A. M., Dudakov, J. A., Hua, G., O’Connor, M. H., Young, L. F., Singer, N. V., West, M. L., Jenq, R. R., Holland, A. M., Kappel, L. W., Ghosh, A., Tsai, J. J., Rao, U. K., Yim, N. L., Smith, O. M., Velardi, E., Hawryluk, E. B., Murphy, G. F., Liu, C., Fouser, L. A., Kolesnick, R., Blazar, B. R., & van den Brink, M. R. (2012). Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity, 37(2), 339–350.
Harris, B., Morjaria, S. M., Littmann, E. R., Geyer, A. I., Stover, D. E., Barker, J. N., Giralt, S. A., Taur, Y., & Pamer, E. G. (2016). Gut microbiota predict pulmonary infiltrates after allogeneic hematopoietic cell transplantation. American Journal of Respiratory and Critical Care Medicine, 194(4), 450–463.
Holler, E., Butzhammer, P., Schmid, K., Hundsrucker, C., Koestler, J., Peter, K., Zhu, W., Sporrer, D., Hehlgans, T., Kreutz, M., Holler, B., Wolff, D., Edinger, M., Andreesen, R., Levine, J. E., Ferrara, J. L., Gessner, A., Spang, R., & Oefner, P. J. (2014). 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. Biology of Blood and Marrow Transplantation, 20(5), 640–645.
Holler, E., Kolb, H. J., Möller, A., Kempeni, J., Liesenfeld, S., Pechumer, H., Lehmacher, W., Ruckdeschel, G., Gleixner, B., Riedner, C., et al. (1990). Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood, 75(4), 1011–1016. PubMed PMID: 2405918.
Holler, E., Rogler, G., Brenmoehl, J., Hahn, J., Herfarth, H., Greinix, H., Dickinson, A. M., Socié, G., Wolff, D., Fischer, G., Jackson, G., Rocha, V., Steiner, B., Eissner, G., Marienhagen, J., Schoelmerich, J., & Andreesen, R. (2006). Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: Effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood, 107(10), 4189–4193.
Jenq, R. R., Taur, Y., Devlin, S. M., Ponce, D. M., Goldberg, J. D., Ahr, K. F., Littmann, E. R., Ling, L., Gobourne, A. C., Miller, L. C., Docampo, M. D., Peled, J. U., Arpaia, N., Cross, J. R., Peets, T. K., Lumish, M. A., Shono, Y., Dudakov, J. A., Poeck, H., Hanash, A. M., Barker, J. N., Perales, M. A., Giralt, S. A., Pamer, E. G., & van den Brink, M. R. (2015). Intestinal blautia is associated with reduced death from graft-versus-host disease. Biology of Blood and Marrow Transplantation, 21(8), 1373–1383.
Jenq, R. R., Ubeda, C., Taur, Y., Menezes, C. C., Khanin, R., Dudakov, J. A., Liu, C., West, M. L., Singer, N. V., Equinda, M. J., Gobourne, A., Lipuma, L., Young, L. F., Smith, O. M., Ghosh, A., Hanash, A. M., Goldberg, J. D., Aoyama, K., Blazar, B. R., Pamer, E. G., & van den Brink, M. R. (2012). Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. The Journal of Experimental Medicine, 209(5), 903–911.
Kakihana, K., Fujioka, Y., Suda, W., Najima, Y., Kuwata, G., Sasajima, S., Mimura, I., Morita, H., Sugiyama, D., Nishikawa, H., Hattori, M., Hino, Y., Ikegawa, S., Yamamoto, K., Toya, T., Doki, N., Koizumi, K., Honda, K., & Ohashi, K. (2016). Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut. Blood, 128(16), 2083–2088.
Kaysen, A., Heintz-Buschart, A., Muller, E. E. L., Narayanasamy, S., Wampach, L., Laczny, C. C., Graf, N., Simon, A., Franke, K., Bittenbring, J., Wilmes, P., & Schneider, J. G. (2017). Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation. Translational Research, 186, 79–94.e1. https://doi.org/10.1016/j.trsl.2017.06.008. Epub 2017 Jun 20. PubMed PMID: 28686852.
Ladas, E. J., Bhatia, M., Chen, L., Sandler, E., Petrovic, A., Berman, D. M., Hamblin, F., Gates, M., Hawks, R., Sung, L., & Nieder, M. (2016). The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation. Bone Marrow Transplantation, 51(2), 262–266.
Lee, Y. J., Arguello, E. S., Jenq, R. R., Littmann, E., Kim, G. J., Miller, L. C., Ling, L., Figueroa, C., Robilotti, E., Perales, M. A., Barker, J. N., Giralt, S., van den Brink, M. R. M., Pamer, E. G., & Taur, Y. (2017). Protective factors in the intestinal microbiome against Clostridium difficile infection in recipients of allogeneic hematopoietic stem cell transplantation. The Journal of Infectious Diseases, 215(7), 1117–1123. https://doi.org/10.1093/infdis/jix011. PubMed PMID: 28498996; PubMed Central PMCID: PMC5426375.
Legoff, J., Resche-Rigon, M., Bouquet, J., Robin, M., Naccache, S. N., Mercier-Delarue, S., Federman, S., Samayoa, E., Rousseau, C., Piron, P., Kapel, N., Simon, F., Socié, G., & Chiu, C. Y. (2017). The eukaryotic gut virome in hematopoietic stem cell transplantation: New cluesin enteric graft-versus-host disease. Nature Medicine, 23(9), 1080–1085. https://doi.org/10.1038/nm.4380. Epub 2017 Jul 31. PubMed PMID: 28759053.
Levine, J. E., Huber, E., Hammer, S. T., Harris, A. C., Greenson, J. K., Braun, T. M., Ferrara, J. L., & Holler, E. (2013). Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood, 122(8), 1505–1509.
Liu, C., Frank, D. N., Horch, M., Chau, S., Ir, D., Horch, E. A., Tretina, K., van Besien, K., Lozupone, C. A., & Nguyen, V. H. (2017). Associations between acute gastrointestinal GvHD and the baseline gut microbiota of allogeneic hematopoietic stem cell transplant recipients and donors. Bone Marrow Transplantation. https://doi.org/10.1038/bmt.2017.200. [Epub ahead of print].
Mandalia, A., Ward, A., Tauxe, W., Kraft, C. S., & Dhere, T. (2016). Fecal transplant is as effective and safe in immunocompromised as non-immunocompromised patients for Clostridium difficile. International Journal of Colorectal Disease, 31(5), 1059–1060.
Manges, A. R., Steiner, T. S., & Wright, A. J. (2016). Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: A review. Infectious Diseases (London), 48(8), 587–592.
Mathewson, N. D., Jenq, R., Mathew, A. V., Koenigsknecht, M., Hanash, A., Toubai, T., Oravecz-Wilson, K., Wu, S. R., Sun, Y., Rossi, C., Fujiwara, H., Byun, J., Shono, Y., Lindemans, C., Calafiore, M., Schmidt, T. C., Honda, K., Young, V. B., Pennathur, S., van den Brink, M., & Reddy, P. (2016). Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nature Immunology, 17(5), 505–513.
Montassier, E., Al-Ghalith, G. A., Ward, T., Corvec, S., Gastinne, T., Potel, G., Moreau, P., de la Cochetiere, M. F., Batard, E., & Knights, D. (2016). Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. Genome Medicine, 8(1), 49. https://doi.org/10.1186/s13073-016-0301-4. Erratum in: Genome Med. 2016;8(1):61. PubMed PMID: 27121964; PubMed Central PMCID: PMC4848771.
Paczesny, S., Krijanovski, O. I., Braun, T. M., Choi, S. W., Clouthier, S. G., Kuick, R., Misek, D. E., Cooke, K. R., Kitko, C. L., Weyand, A., Bickley, D., Jones, D., Whitfield, J., Reddy, P., Levine, J. E., Hanash, S. M., & Ferrara, J. L. (2009). A biomarker panel for acute graft-versus-host disease. Blood, 113(2), 273–278.
Peled, J. U., Devlin, S. M., Staffas, A., Lumish, M., Khanin, R., Littmann, E. R., Ling, L., Kosuri, S., Maloy, M., Slingerland, J. B., Ahr, K. F., Porosnicu Rodriguez, K. A., Shono, Y., Slingerland, A. E., Docampo, M. D., Sung, A. D., Weber, D., Alousi, A. M., Gyurkocza, B., Ponce, D. M., Barker, J. N., Perales, M. A., Giralt, S. A., Taur, Y., Pamer, E. G., Jenq, R. R., & van den Brink, M. R. M. (2017). Intestinal microbiota and relapse after hematopoietic-cell transplantation. Journal of Clinical Oncology, 35(15), 1650–1659.
Peled, J. U., Jenq, R. R., Holler, E., & van den Brink, M. R. (2016). Role of gut flora after bone marrow transplantation. Nature Microbiology, 1, 16036. https://doi.org/10.1038/nmicrobiol.2016.36.
Penack, O., Smith, O. M., Cunningham-Bussel, A., Liu, X., Rao, U., Yim, N., Na, I. K., Holland, A. M., Ghosh, A., Lu, S. X., Jenq, R. R., Liu, C., Murphy, G. F., Brandl, K., & van den Brink, M. R. (2009). NOD2 regulates hematopoietic cell function during graft-versus-host disease. The Journal of Experimental Medicine, 206(10), 2101–2110. https://doi.org/10.1084/jem.20090623. Epub 2009 Sep 8. PubMed PMID: 19737867; PubMed Central PMCID: PMC2757869.
Pflug, N., Kluth, S., Vehreschild, J. J., Bahlo, J., Tacke, D., Biehl, L., Eichhorst, B., Fischer, K., Cramer, P., Fink, A. M., von Bergwelt-Baildon, M., Stilgenbauer, S., Hallek, M., Cornely, O. A., & Vehreschild, M. J. (2016). Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota. Oncoimmunology, 5(6), e1150399. https://doi.org/10.1080/2162402X.2016.1150399. eCollection 2016 Jun. PubMed PMID: 27471619; PubMed Central PMCID: PMC4938364.
Piguet, P. F., Grau, G. E., Allet, B., & Vassalli, P. (1987). Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. The Journal of Experimental Medicine, 166(5), 1280–1289.
Reddy, P., Sun, Y., Toubai, T., Duran-Struuck, R., Clouthier, S. G., Weisiger, E., Maeda, Y., Tawara, I., Krijanovski, O., Gatza, E., Liu, C., Malter, C., Mascagni, P., Dinarello, C. A., & Ferrara, J. L. (2008). Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. The Journal of Clinical Investigation, 118(7), 2562–2573. Review.
Riwes, M., & Reddy, P. (2017). Microbial metabolites and graft versus host disease. American Journal of Transplantation. https://doi.org/10.1111/ajt.14443. [Epub ahead of print] Review. PubMed PMID: 28742948.
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., Fidelle, M., Flament, C., Poirier-Colame, V., Opolon, P., Klein, C., Iribarren, K., Mondragón, L., Jacquelot, N., Qu, B., Ferrere, G., Clémenson, C., Mezquita, L., Masip, J. R., Naltet, C., Brosseau, S., Kaderbhai, C., Richard, C., Rizvi, H., Levenez, F., Galleron, N., Quinquis, B., Pons, N., Ryffel, B., Minard-Colin, V., Gonin, P., Soria, J. C., Deutsch, E., Loriot, Y., Ghiringhelli, F., Zalcman, G., Goldwasser, F., Escudier, B., Hellmann, M. D., Eggermont, A., Raoult, D., Albiges, L., Kroemer, G., & Zitvogel, L. (2017). Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. https://doi.org/10.1126/science.aan3706. pii: eaan3706. [Epub ahead of print] PubMed PMID: 29097494.
Routy, B., Letendre, C., Enot, D., Chénard-Poirier, M., Mehraj, V., Séguin, N. C., Guenda, K., Gagnon, K., Woerther, P. L., Ghez, D., & Lachance, S. (2016). The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation. Oncoimmunology, 6(1), e1258506. https://doi.org/10.1080/2162402X.2016.1258506. eCollection 2017.
Schmeiser, T., Kurrle, E., Arnold, R., Heit, W., Krieger, D., Kubanek, B., & Heimpel, H. (1985). The influence of the microbial flora on incidence of graft-versus-host disease in human allogeneic bone marrow transplantation. Progress in Clinical and Biological Research, 181, 433–435.
Schwab, L., Goroncy, L., Palaniyandi, S., Gautam, S., Triantafyllopoulou, A., Mocsai, A., Reichardt, W., Karlsson, F. J., Radhakrishnan, S. V., Hanke, K., Schmitt-Graeff, A., Freudenberg, M., von Loewenich, F. D., Wolf, P., Leonhardt, F., Baxan, N., Pfeifer, D., Schmah, O., Schönle, A., Martin, S. F., Mertelsmann, R., Duyster, J., Finke, J., Prinz, M., Henneke, P., Häcker, H., Hildebrandt, G. C., Häcker, G., & Zeiser, R. (2014). Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nature Medicine, 20(6), 648–654.
Shelburne, S. A., Ajami, N. J., Chibucos, M. C., Beird, H. C., Tarrand, J., Galloway-Peña, J., Albert, N., Chemaly, R. F., Ghantoji, S. S., Marsh, L., Pemmaraju, N., Andreeff, M., Shpall, E. J., Wargo, J. A., Rezvani, K., Alousi, A., Bruno, V. M., Futreal, P. A., Petrosino, J. F., & Kontoyiannis, D. P. (2015). Implementation of a pan-genomic approach to investigate holobiont-infecting microbe interaction: A case report of a leukemic patient with invasive mucormycosis. PLoS One, 10(11), e0139851.
Shono, Y., Docampo, M. D., Peled, J. U., Perobelli, S. M., Velardi, E., Tsai, J. J., Slingerland, A. E., Smith, O. M., Young, L. F., Gupta, J., Lieberman, S. R., Jay, H. V., Ahr, K. F., Porosnicu Rodriguez, K. A., Xu, K., Calarfiore, M., Poeck, H., Caballero, S., Devlin, S. M., Rapaport, F., Dudakov, J. A., Hanash, A. M., Gyurkocza, B., Murphy, G. F., Gomes, C., Liu, C., Moss, E. L., Falconer, S. B., Bhatt, A. S., Taur, Y., Pamer, E. G., van den Brink, M. R. M., & Jenq, R. R. (2016). Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Science Translational Medicine, 8(339), 339ra71.
Spindelboeck, W., Schulz, E., Uhl, B., Kashofer, K., Aigelsreiter, A., Zinke-Cerwenka, W., Mulabecirovic, A., Kump, P. K., Halwachs, B., Gorkiewicz, G., Sill, H., Greinix, H., Högenauer, C., & Neumeister, P. (2017). Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease. Haematologica, 102(5), e210-e213.
Storb, R., Prentice, R. L., Buckner, C. D., Clift, R. A., Appelbaum, F., Deeg, J., Doney, K., Hansen, J. A., Mason, M., Sanders, J. E., Singer, J., Sullivan, K. M., Witherspoon, R. P., & Thomas, E. D. (1983). Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. The New England Journal of Medicine, 308(6), 302–307.
Svahn, B. M., Remberger, M., Myrbäck, K. E., Holmberg, K., Eriksson, B., Hentschke, P., Aschan, J., Barkholt, L., & Ringdén, O. (2002). Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood, 100(13), 4317–4324.
Taur, Y., Jenq, R. R., Perales, M. A., Littmann, E. R., Morjaria, S., Ling, L., No, D., Gobourne, A., Viale, A., Dahi, P. B., Ponce, D. M., Barker, J. N., Giralt, S., van den Brink, M., & Pamer, E. G. (2014). The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood, 124(7), 1174–1182.
Taur, Y., Xavier, J. B., Lipuma, L., Ubeda, C., Goldberg, J., Gobourne, A., Lee, Y. J., Dubin, K. A., Socci, N. D., Viale, A., Perales, M. A., Jenq, R. R., van den Brink, M. R., & Pamer, E. G. (2012). Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clinical Infectious Diseases, 55(7), 905–914.
Tawara, I., Liu, C., Tamaki, H., Toubai, T., Sun, Y., Evers, R., Nieves, E., Mathewson, N., Nunez, G., & Reddy, P. (2013). Influence of donor microbiota on the severity of experimental graft-versus-host-disease. Biology of Blood and Marrow Transplantation, 19(1), 164–168.
van Bekkum, D. W., & Knaan, S. (1977). Role of bacterial microflora in development of intestinal lesions from graft-versus-host reaction. Journal of the National Cancer Institute, 58(3), 787–790.
van Bekkum, D. W., Roodenburg, J., Heidt, P. J., & van der Waaij, D. (1974). Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. Journal of the National Cancer Institute, 52(2), 401–404.
Varelias, A., Ormerod, K. L., Bunting, M. D., Koyama, M., Gartlan, K. H., Kuns, R. D., Lachner, N., Locke, K. R., Lim, C. Y., Henden, A. S., Zhang, P., Clouston, A. D., Hasnain, S. Z., McGuckin, M. A., Blazar, B. R., MacDonald, K. P., Hugenholtz, P., & Hill, G. R. (2017). Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. Blood, 129(15), 2172–2185.
Vossen, J. M., Guiot, H. F., Lankester, A. C., Vossen, A. C., Bredius, R. G., Wolterbeek, R., Bakker, H. D., & Heidt, P. J. (2014). Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation. PLoS One, 9(9), e105706. https://doi.org/10.1371/journal.pone.0105706. eCollection 2014. PubMed PMID: 25180821; PubMed Central PMCID: PMC4152127.
Vriesendorp, H. M., Klapwijk, W. M., Visser, T. P., Zurcher, C., & van Bekkum, D. W. (1982). Alternatives to donor matching for control of graft-versus-host disease. Immunogenetics, 15(1), 79–94.
Webb, B. J., Brunner, A., Ford, C. D., Gazdik, M. A., Petersen, F. B., & Hoda, D. (2016). Fecal microbiota transplantation for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. Transplant Infectious Disease, 18(4), 628–633.
Weber, D., Frauenschläger, K., Ghimire, S., Peter, K., Panzer, I., Hiergeist, A., Weber, M., Kutny, D., Wolff, D., Grube, M., Huber, E., Oefner, P., Gessner, A., Hehlgans, T., Herr, W., & Holler, E. (2017a). The association between acute graft-versus-host disease and antimicrobial peptide expression in the gastrointestinal tract after allogeneic stem cell transplantation. PLoS One, 12(9), e0185265. https://doi.org/10.1371/journal.pone.0185265. eCollection 2017.
Weber, D., Jenq, R. R., Peled, J. U., Taur, Y., Hiergeist, A., Koestler, J., Dettmer, K., Weber, M., Wolff, D., Hahn, J., Pamer, E. G., Herr, W., Gessner, A., Oefner, P. J., van den Brink, M. R., & Holler, E. (2017b). Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biology of Blood and Marrow Transplantation, 23(5), 845–852.
Weber, D., Oefner, P. J., Dettmer, K., Hiergeist, A., Koestler, J., Gessner, A., Weber, M., Stämmler, F., Hahn, J., Wolff, D., Herr, W., & Holler, E. (2016). Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplantation, 51(8), 1087–1092.
Weber, D., Oefner, P. J., Hiergeist, A., Koestler, J., Gessner, A., Weber, M., Hahn, J., Wolff, D., Stämmler, F., Spang, R., Herr, W., Dettmer, K., & Holler, E. (2015). Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood, 126(14), 1723–1728.
Whangbo, J., Ritz, J., & Bhatt, A. (2017). Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation, 52(2), 183–190. https://doi.org/10.1038/bmt.2016.206. Epub 2016 Aug 15. Review. PubMed PMID: 27526283.
Zeiser, R., Penack, O., Holler, E., & Idzko, M. (2011). Danger signals activating innate immunity in graft-versus-host disease. Journal of Molecular Medicine (Berlin), 89(9), 833–845.
Zitvogel, L., Daillère, R., Roberti, M. P., Routy, B., & Kroemer, G. (2017). Anticancer effects of the microbiome and its products. Nature Reviews. Microbiology, 15(8), 465–478. https://doi.org/10.1038/nrmicro.2017.44. Epub 2017 May 22. Review. PubMed PMID: 28529325.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Weber, D., Holler, E. (2018). Microbiome and Diseases: Graft-Versus-Host Disease. In: Haller, D. (eds) The Gut Microbiome in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-90545-7_13
Download citation
DOI: https://doi.org/10.1007/978-3-319-90545-7_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-90544-0
Online ISBN: 978-3-319-90545-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)