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
Open accessAbstract
Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Allogeneic HCT patients show microbiota disruption, including overgrowth of potential pathogens and reduced alpha diversity.
“We and others have reported that patients undergoing allogeneic hematopoietic-cell transplantation have microbiota disruption that is characterized by expansions of potentially pathogenic bacteria and loss of alpha diversity — a variable that reflects the number of unique bacterial taxa present and their relative frequencies.2–5”
From Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation (2020) · cites this paper as [2]
Single-center studies have linked post-HCT intestinal microbiota features to relapse, GVHD, infection, organ toxicity, and overall survival.
“Each of these outcomes, as well as overall survival, has been associated in single-center studies with features of the intestinal microbiota in the period after hematopoietic-cell transplantation.2–4,8–15”
From Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation (2020) · cites this paper as [2]
After allogeneic stem cell transplant, the gut microbiota loses diversity and stability and becomes dominated by Enterococcus, Streptococcus and Proteobacteria.
“a disruption of the existing state of equilibrium of the gut microbiota post-HSCT with a relative dysbiosis and a loss of bacterial diversity and stability and dominance of Enterococcus, Streptococcus and various Proteobacteria”
From The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy (2018) · cites this paper as Holler et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., et al. (2013) · Nature · doi:10.1038/nature12721 · Cited by 5,549 · see citing works
The gut microbiota shapes intestinal immune responses during health and disease
Round, J. L., & Mazmanian, S. K. (2009) · Nature Reviews Immunology · doi:10.1038/nri2515 · Cited by 5,029 · see citing works
The human microbiome: at the interface of health and disease
Cho, I., & Blaser, M. J. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3182 · Cited by 3,449 · see citing works
Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota
Atarashi, K., Tanoue, T., Oshima, K., Suda, W., Nagano, Y., Nishikawa, H., Fukuda, S., Saito, T., Narushima, S., Hase, K., et al. (2013) · Nature · doi:10.1038/nature12331 · Cited by 2,872 · see citing works
Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites
Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C., & Siuzdak, G. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812874106 · Cited by 2,677 · see citing works
Dethlefsen, L., Huse, S., Sogin, M. L., & Relman, D. A. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060280 · Cited by 2,361 · see citing works
The rise of the Enterococcus: beyond vancomycin resistance
Arias, C. A., & Murray, B. E. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2761 · Cited by 1,776 · see citing works
Hill, G. R., & Ferrara, J. L. M. (2000) · Blood · doi:10.1182/blood.v95.9.2754.009k25_2754_2759 · Cited by 717 · see citing works
Self-citationRegulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation
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., et al. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112408 · Cited by 626 · see citing works
Bekkum, D. W. V., Roodenburg, J., Heidt, P. J., & Waaij, D. V. D. (1974) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/52.2.401 · Cited by 330 · see citing works
Eriguchi, Y., Takashima, S., Oka, H., Shimoji, S., Nakamura, K., Uryu, H., Shimoda, S., Iwasaki, H., Shimono, N., Ayabe, T., et al. (2012) · Blood · doi:10.1182/blood-2011-12-401166 · Cited by 317 · see citing works
Beelen, D. W., Elmaagacli, A. H., Müller, K., Hirche, H., & Schaefer, U. W. (1999) · Blood · doi:10.1182/blood.v93.10.3267.410k22_3267_3275 · Cited by 270 · see citing works
Pathogenesis and immunity in enterococcal infections
Sava, I. G., Heikens, E., & Hüebner, J. (2010) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2010.03213.x · Cited by 266 · see citing works
Kinnebrew, M. A., Ubeda, C., Zenewicz, L. A., Smith, N., Flavell, R. A., & Pamer, E. G. (2010) · The Journal of Infectious Diseases · doi:10.1086/650203 · Cited by 236 · see citing works
Probiotic effects on experimental graft-versus-host disease: let them eat yogurt
Gerbitz, A., Schultz, M., Wilke, A., Linde, H.-J., Schölmerich, J., Andreesen, R., & Holler, E. (2004) · Blood · doi:10.1182/blood-2003-11-3769 · Cited by 186 · see citing works
Self-citationChakraverty, R. K., Côté, D. C., Buchli, J., Cotter, P., Hsu, R., Zhao, G., Sachs, T. E., Pitsillides, C. M., Bronson, R. T., Means, T. K., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060376 · Cited by 178 · see citing works
Cox, C. R., Coburn, P. S., & Gilmore, M. S. (2005) · Current Protein and Peptide Science · doi:10.2174/1389203053027557 · Cited by 159 · see citing works
Levine, J. E., Huber, E., Hammer, S. T. G., Harris, A. C., Greenson, J. K., Braun, T., Ferrara, J. L. M., & Holler, E. (2013) · Blood · doi:10.1182/blood-2013-02-485813 · Cited by 154 · see citing works
Self-citationZhu, W., Stevens, A. P., Dettmer, K., Gottfried, E., Hoves, S., Kreutz, M. P., Holler, E., Canelas, A. B., Kema, I. P., & Oefner, P. J. (2011) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-011-5436-y · Cited by 153 · see citing works
Self-citationCooke, K. R., Olkiewicz, K. M., Erickson, N. T., & Ferrara, J. L. M. (2002) · Journal of Endotoxin Research · doi:10.1177/09680519020080061301 · Cited by 101 · see citing works
Self-citationSpecies identification of enterococci via intergenic ribosomal PCR
Tyrrell, G. J., Bethune, R. N., Willey, B. M., & Low, D. E. (1997) · Journal of Clinical Microbiology · doi:10.1128/jcm.35.5.1054-1060.1997 · Cited by 92 · see citing works
Cooke, K. R., Olkiewicz, K. M., Erickson, N. T., & Ferrara, J. L. M. (2002) · Journal of Endotoxin Research · doi:10.1179/096805102125001046 · Cited by 46 · see citing works
Self-citationMori, H., Maruyama, F., & Kurokawa, K. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-332 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy
Gopalakrishnan, V., Helmink, B. A., Spencer, C. N., Reuben, A., & Wargo, J. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.015 · Cited by 1,392 · see citing works
Microbiota: a key orchestrator of cancer therapy
Roy, S., & Trinchieri, G. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.13 · Cited by 883 · see citing works
Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation
Peled, J. U., Gomes, A. L. C., Devlin, S. M., Littmann, E. R., Taur, Y., Sung, A. D., Weber, D., Hashimoto, D., Slingerland, A. E., Slingerland, J. B., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1900623 · Cited by 765 · see citing works
Self-citationIntestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease
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., et al. (2015) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2015.04.016 · Cited by 748 · see citing works
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., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf2311 · Cited by 592 · see citing works
Lactose drives <i>Enterococcus</i> expansion to promote graft-versus-host disease
Stein-Thoeringer, C. K., Nichols, K. B., Lazrak, A., Docampo, M. D., Slingerland, A. E., Slingerland, J. B., Clurman, A. G., Armijo, G., Gomes, A. L. C., Shono, Y., et al. (2019) · Science · doi:10.1126/science.aax3760 · Cited by 384 · see citing works
Self-citationKakihana, K., Fujioka, Y., Suda, W., Najima, Y., Kuwata, G., Sasajima, S., Mimura, I., Morita, H., Sugiyama, D., Nishikawa, H., et al. (2016) · Blood · doi:10.1182/blood-2016-05-717652 · Cited by 367 · see citing works
Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation
Peled, J. U., Devlin, S. M., Staffas, A., Lumish, M., Khanin, R., Littmann, E. R., Ling, L., Kosuri, S., Maloy, M., Slingerland, J. B., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.70.3348 · Cited by 325 · see citing works
Weber, D., Jenq, R. R., Peled, J. U., Taur, Y., Hiergeist, A., Koestler, J., Dettmer, K., Weber, M., Wolff, D., Hahn, J., et al. (2017) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2017.02.006 · Cited by 245 · see citing works
Self-citationGolob, J. L., Pergam, S. A., Srinivasan, S., Fiedler, T. L., Liu, C., Garcia, K., Mielcarek, M., Ko, D., Aker, S., Marquis, S., et al. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/cix699 · Cited by 201 · see citing works
Weber, D., Oefner, P. J., Hiergeist, A., Koestler, J., Gessner, A., Weber, M., Hahn, J., Wolff, D., Stämmler, F., Spang, R., et al. (2015) · Blood · doi:10.1182/blood-2015-04-638858 · Cited by 195 · see citing works
Candida albicans induces mucosal bacterial dysbiosis that promotes invasive infection
Bertolini, M., Ranjan, A., Thompson, A., Diaz, P. I., Sobue, T., Maas, K., & Dongari-Bagtzoglou, A. (2019) · PLOS Pathogens · doi:10.1371/journal.ppat.1007717 · Cited by 176 · see citing works
Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT
Biagi, E., Zama, D., Nastasi, C., Consolandi, C., Fiori, J., Rampelli, S., Turroni, S., Centanni, M., Severgnini, M., Peano, C., et al. (2015) · Bone Marrow Transplantation · doi:10.1038/bmt.2015.16 · Cited by 158 · see citing works
Roles of the intestinal microbiota and microbial metabolites in acute GVHD
Lin, D., Hu, B., Li, P., Zhao, Y., Xu, Y., & Wu, D. (2021) · Experimental Hematology & Oncology · doi:10.1186/s40164-021-00240-3 · Cited by 71 · see citing works
Peric, Z., Botti, S., Stringer, J., Krawczyk, J., van der Werf, S., van Biezen, A., Aljurf, M., Murray, J., Liptrott, S., Greenfield, D. M., et al. (2018) · Bone Marrow Transplantation · doi:10.1038/s41409-018-0137-1 · Cited by 54 · see citing works
Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy
Davar, D., & Zarour, H. M. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1129 · Cited by 40 · see citing works
Hidaka, D., Hayase, E., Shiratori, S., Hasegawa, Y., Ishio, T., Tateno, T., Okada, K., Goto, H., Sugita, J., Onozawa, M., et al. (2018) · Clinical Transplantation · doi:10.1111/ctr.13361 · Cited by 39 · see citing works
Applications of gut microbiota in patients with hematopoietic stem-cell transplantation
Yu, J., Sun, H., Cao, W., Han, L., Song, Y., Wan, D., & Jiang, Z. (2020) · Experimental Hematology & Oncology · doi:10.1186/s40164-020-00194-y · Cited by 25 · see citing works
The role of microbiota in allogeneic hematopoietic stem cell transplantation
Chang, C.-C., Hayase, E., & Jenq, R. R. (2021) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2021.1872541 · Cited by 20 · see citing works
- Authors
- 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.
- Affiliations
- University Hospital Regensburg (DE)
- University of Regensburg (DE)
- University of Michigan (US)
- Corresponding author
- Holler, Ernst
- ORCID
- Venue
- Biology of Blood and Marrow Transplantation
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 20
- Issue
- 5
- Pages
- 640-645
- ISSN
- 1083-8791 (ISSN-L)
- PMC
- PMC4973578
- OpenAlex
- W1974092500
- Cited by
- 544
- References
- 23
- Citations by year
- 2026: 25 · 2025: 24 · 2024: 31 · 2023: 41 · 2022: 61 · 2021: 74 · 2020: 67 · 2019: 51 · 2018: 32 · 2017: 53 · 2016: 51 · 2015: 26 · 2014: 6 · 2012: 1
- FWCI
- 18.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Transplantation and Cellular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA039542)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
- Keywords
- gut microbiota, allogeneic stem cell transplantation, gastrointestinal graft-versus-host disease, Enterococcus faecium, Enterococcus faecalis, antibiotic prophylaxis, bacterial load, intestinal inflammation, stool microbiome
- MeSH terms
- Adult, Anti-Bacterial Agents, Feces, Female, Graft vs Host Disease, Humans, Indican, Male, Middle Aged, RNA, Ribosomal, 16S, Enterococcus faecalis, Transplantation, Homologous, Enterococcus faecium, Hematopoietic Stem Cell Transplantation, Gastrointestinal Tract, Biodiversity, Metagenome, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
