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

Ernst Holler; Peter Butzhammer; Karin Schmid; Christian Hundsrucker; Josef Koestler; Katrin Peter; Wentao Zhu; Daniela Sporrer; Thomas Hehlgans; Marina Kreutz; Barbara Holler; Daniel Wolff; Matthias Edinger; Reinhard Andreesen; John E. Levine; James L. Ferrara; Andre Gessner; Rainer Spang; Peter J. Oefner

doi:10.1016/j.bbmt.2014.01.030

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

Ernst Holler, Peter Butzhammer, Karin Schmid, Christian Hundsrucker, Josef Koestler, Katrin Peter, Wentao Zhu, Daniela Sporrer, Thomas Hehlgans, Marina Kreutz, Barbara Holler, Daniel Wolff, Matthias Edinger, Reinhard Andreesen, John E. Levine, James L. Ferrara, Andre Gessner, Rainer Spang, Peter J. Oefner

Research output: Contribution to journal › Article › peer-review

427 Scopus citations

Abstract

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 toelucidate 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 sulfatelevels dropped from 42.5±11μmol/L to 11.8±2.8μmol/L in all post-transplant samples and to 3.5±3μmol/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.

Original language	English
Pages (from-to)	640-645
Number of pages	6
Journal	Biology of Blood and Marrow Transplantation
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.bbmt.2014.01.030
State	Published - May 2014
Externally published	Yes

Keywords

Clinical allogeneic transplantation
GVHD
Metagenomics
Microbiome

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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. https://doi.org/10.1016/j.bbmt.2014.01.030

Holler, Ernst ; Butzhammer, Peter ; Schmid, Karin 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. In: Biology of Blood and Marrow Transplantation. 2014 ; Vol. 20, No. 5. pp. 640-645.

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title = "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",

abstract = "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 toelucidate 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 sulfatelevels dropped from 42.5±11μmol/L to 11.8±2.8μmol/L in all post-transplant samples and to 3.5±3μmol/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.",

keywords = "Clinical allogeneic transplantation, GVHD, Metagenomics, Microbiome",

author = "Ernst Holler and Peter Butzhammer and Karin Schmid and Christian Hundsrucker and Josef Koestler and Katrin Peter and Wentao Zhu and Daniela Sporrer and Thomas Hehlgans and Marina Kreutz and Barbara Holler and Daniel Wolff and Matthias Edinger and Reinhard Andreesen and Levine, {John E.} and Ferrara, {James L.} and Andre Gessner and Rainer Spang and Oefner, {Peter J.}",

year = "2014",

month = may,

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language = "English",

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journal = "Biology of Blood and Marrow Transplantation",

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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, JE , Ferrara, JL, Gessner, A, Spang, R & Oefner, PJ 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, vol. 20, no. 5, pp. 640-645. https://doi.org/10.1016/j.bbmt.2014.01.030

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. / Holler, Ernst; Butzhammer, Peter; Schmid, Karin et al.
In: Biology of Blood and Marrow Transplantation, Vol. 20, No. 5, 05.2014, p. 640-645.

Research output: Contribution to journal › Article › peer-review

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T1 - Metagenomic Analysis of the Stool Microbiome in Patients Receiving Allogeneic Stem Cell Transplantation

T2 - Loss of Diversity Is Associated with Use of Systemic Antibiotics and More Pronounced in Gastrointestinal Graft-versus-Host Disease

AU - Holler, Ernst

AU - Butzhammer, Peter

AU - Schmid, Karin

AU - Hundsrucker, Christian

AU - Koestler, Josef

AU - Peter, Katrin

AU - Zhu, Wentao

AU - Sporrer, Daniela

AU - Hehlgans, Thomas

AU - Kreutz, Marina

AU - Holler, Barbara

AU - Wolff, Daniel

AU - Edinger, Matthias

AU - Andreesen, Reinhard

AU - Levine, John E.

AU - Ferrara, James L.

AU - Gessner, Andre

AU - Spang, Rainer

AU - Oefner, Peter J.

PY - 2014/5

Y1 - 2014/5

N2 - 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 toelucidate 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 sulfatelevels dropped from 42.5±11μmol/L to 11.8±2.8μmol/L in all post-transplant samples and to 3.5±3μmol/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.

AB - 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 toelucidate 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 sulfatelevels dropped from 42.5±11μmol/L to 11.8±2.8μmol/L in all post-transplant samples and to 3.5±3μmol/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.

KW - Clinical allogeneic transplantation

KW - GVHD

KW - Metagenomics

KW - Microbiome

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Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter 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. Biology of Blood and Marrow Transplantation. 2014 May;20(5):640-645. doi: 10.1016/j.bbmt.2014.01.030