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Biol Blood Marrow Transplant. 2017 May;23(5):820-829. doi: 10.1016/j.bbmt.2017.02.004. Epub 2017 Feb 9.

Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients.

Author information

1
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
2
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas.
3
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
4
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas.
5
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas.
6
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
7
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio.
8
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: andrew.koh@utsouthwestern.edu.

Abstract

Adult stem cell transplantation (SCT) patients with graft-versus-host-disease (GVHD) exhibit significant disruptions in gut microbial communities. These changes are associated with higher overall mortality and appear to be driven by specific antibiotic therapies. It is unclear whether pediatric SCT patients who develop GVHD exhibit similar antibiotic-induced gut microbiota community changes. Here, we show that pediatric SCT patients (from Children's Medical Center Dallas, n = 8, and Cincinnati Children's Hospital, n = 7) who developed GVHD showed a significant decline, up to 10-log fold, in gut anti-inflammatory Clostridia (AIC) compared with those without GVHD. In fact, the development of GVHD is significantly associated with this AIC decline and with cumulative antibiotic exposure, particularly antibiotics effective against anaerobic bacteria (P = .003, Firth logistic regression analysis). Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, including AIC, that were significantly depleted in GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Clindamycin depleted AIC and exacerbated GVHD in mice, whereas oral AIC supplementation increased gut AIC levels and mitigated GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients.

KEYWORDS:

Anti-inflammatory Clostridia; Graft-versus-host disease; Microbiome; Microbiota; Pediatrics; Stem cell transplantation

PMID:
28192251
DOI:
10.1016/j.bbmt.2017.02.004
[Indexed for MEDLINE]
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