title: Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients.
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.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Tiffany R
authors.initials: TR
authors.lastname: Simms-Waldrip
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Gauri
authors.initials: G
authors.lastname: Sunkersett
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Coughlin
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Milan R
authors.initials: MR
authors.lastname: Savani
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Carlos
authors.initials: C
authors.lastname: Arana
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jiwoong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: David E
authors.initials: DE
authors.lastname: Greenberg
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, Ohio.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.affiliation: 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.
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Koh
mesh_terms: D000293:Adolescent; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D002981:Clindamycin / Q000009:adverse effects / Q000494:pharmacology; D003013:Clostridium / Q000472:pathogenicity; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D006086:Graft vs Host Disease / Q000139:chemically induced* / Q000209:etiology / Q000382:microbiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007223:Infant; D051379:Mice; D010865:Pilot Projects
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D002981:Clindamycin
keywords: Anti-inflammatory Clostridia; Graft-versus-host disease; Microbiome; Microbiota; Pediatrics; Stem cell transplantation