title: Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.
abstract: Necrotizing enterocolitis (NEC) is a catastrophic disease of preterm infants, and microbial dysbiosis has been implicated in its pathogenesis. Studies evaluating the microbiome in NEC and preterm infants lack power and have reported inconsistent results.
  
  
  
  Our objectives were to perform a systematic review and meta-analyses of stool microbiome profiles in preterm infants to discern and describe microbial dysbiosis prior to the onset of NEC and to explore heterogeneity among studies. We searched MEDLINE, PubMed, CINAHL, and conference abstracts from the proceedings of Pediatric Academic Societies and reference lists of relevant identified articles in April 2016. Studies comparing the intestinal microbiome in preterm infants who developed NEC to those of controls, using culture-independent molecular techniques and reported α and β-diversity metrics, and microbial profiles were included. In addition, 16S ribosomal ribonucleic acid (rRNA) sequence data with clinical meta-data were requested from the authors of included studies or searched in public data repositories. We reprocessed the 16S rRNA sequence data through a uniform analysis pipeline, which were then synthesized by meta-analysis. We included 14 studies in this review, and data from eight studies were available for quantitative synthesis (106 NEC cases, 278 controls, 2944 samples). The age of NEC onset was at a mean ± SD of 30.1 ± 2.4 weeks post-conception (n = 61). Fecal microbiome from preterm infants with NEC had increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes prior to NEC onset. Alpha- or beta-diversity indices in preterm infants with NEC were not consistently different from controls, but we found differences in taxonomic profiles related to antibiotic exposure, formula feeding, and mode of delivery. Exploring heterogeneity revealed differences in microbial profiles by study and the target region of the 16S rRNA gene (V1-V3 or V3-V5).
  
  
  
  Microbial dysbiosis preceding NEC in preterm infants is characterized by increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes. Microbiome optimization may provide a novel strategy for preventing NEC.
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, 77030, Houston, TX, USA. mohanv@bcm.edu.
authors.forename: Mohan
authors.identifier: 0000-0002-5571-6239
authors.initials: M
authors.lastname: Pammi
authors.affiliation: Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Cope
authors.affiliation: Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Tarr
authors.affiliation: Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Warner
authors.affiliation: Department of Pediatrics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Ohio, USA.
authors.forename: Ardythe L
authors.initials: AL
authors.lastname: Morrow
authors.affiliation: Department of Epidemiology, College of Public Health and Health Professions and College of Medicine and Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Mai
authors.affiliation: Department of Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Gregory
authors.affiliation: Department of Medicine, Section of Paediatrics, Imperial College London, London, UK.
authors.forename: J Simon
authors.initials: JS
authors.lastname: Kroll
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Children's Hospital, New Orleans, LA, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: McMurtry
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Children's Hospital, New Orleans, LA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ferris
authors.affiliation: Director of Clinical Genomics and Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Engstrand
authors.affiliation: Department of Women's and Children's Health, Uppsala University, 751 85, Uppsala, Sweden.
authors.forename: Helene Engstrand
authors.initials: HE
authors.lastname: Lilja
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Hollister
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
authors.forename: James
authors.initials: J
authors.lastname: Versalovic
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, 77030, Houston, TX, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Neu
mesh_terms: D001419:Bacteria / Q000302:isolation & purification; D001439:Bacteroides / Q000235:genetics / Q000302:isolation & purification; D064806:Dysbiosis; D020345:Enterocolitis, Necrotizing / Q000382:microbiology*; D005243:Feces / Q000382:microbiology*; D000068536:Bacillota / Q000235:genetics / Q000302:isolation & purification; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D007422:Intestines / Q000382:microbiology / Q000503:physiopathology*; D020560:Proteobacteria / Q000235:genetics / Q000302:isolation & purification; D012336:RNA, Ribosomal, 16S
chemical_list: D012336:RNA, Ribosomal, 16S
keywords: 16S rRNA sequencing; Intestinal; Microbiome; NEC; Neonate; Preterm