title: Dysbiosis anticipating necrotizing enterocolitis in very premature infants.
abstract: BACKGROUND
  Necrotizing enterocolitis (NEC) is a devastating inflammatory bowel disease of premature infants speculatively associated with infection. Suspected NEC can be indistinguishable from sepsis, and in established cases an infant may die within hours of diagnosis. Present treatment is supportive. A means of presymptomatic diagnosis is urgently needed. We aimed to identify microbial signatures in the gastrointestinal microbiota preceding NEC diagnosis in premature infants.
  
  
  METHODS
  Fecal samples and clinical data were collected from a 2-year cohort of 369 premature neonates. Next-generation sequencing of 16S ribosomal RNA gene regions was used to characterize the microbiota of prediagnosis fecal samples from 12 neonates with NEC, 8 with suspected NEC, and 44 controls. Logistic regression was used to determine clinical characteristics and operational taxonomic units (OTUs) discriminating cases from controls. Samples were cultured and isolates identified using matrix-assisted laser desorption/ionization-time of flight. Clostridial isolates were typed and toxin genes detected.
  
  
  RESULTS
  A clostridial OTU was overabundant in prediagnosis samples from infants with established NEC (P = .006). Culture confirmed the presence of Clostridium perfringens type A. Fluorescent amplified fragment-length polymorphism typing established that no isolates were identical. Prediagnosis samples from NEC infants not carrying profuse C. perfringens revealed an overabundance of a Klebsiella OTU (P = .049). Prolonged continuous positive airway pressure (CPAP) therapy with supplemental oxygen was also associated with increased NEC risk.
  
  
  CONCLUSIONS
  Two fecal microbiota signatures (Clostridium and Klebsiella OTUs) and need for prolonged CPAP oxygen signal increased risk of NEC in presymptomatic infants. These biomarkers will assist development of a screening tool to allow very early diagnosis of NEC. Clinical Trials Registration. NCT01102738.
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sim
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: Paul
authors.initials: P
authors.lastname: Randell
authors.affiliation: Department of Molecular Genetics and Genomics, National Heart and Lung Institute.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cox
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: Zoë E
authors.initials: ZE
authors.lastname: McClure
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: Ming-Shi
authors.initials: MS
authors.lastname: Li
authors.affiliation: Department of Paediatric Surgery, Imperial College London, United Kingdom.
authors.forename: Munther
authors.initials: M
authors.lastname: Haddad
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Langford
authors.affiliation: Department of Molecular Genetics and Genomics, National Heart and Lung Institute.
authors.forename: William O C M
authors.initials: WO
authors.lastname: Cookson
authors.affiliation: Department of Molecular Genetics and Genomics, National Heart and Lung Institute.
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Moffatt
authors.affiliation: Department of Medicine, Section of Paediatrics.
authors.forename: J Simon
authors.initials: JS
authors.lastname: Kroll
mesh_terms: D003016:Clostridium perfringens / Q000235:genetics / Q000302:isolation & purification; D045422:Continuous Positive Airway Pressure; D064806:Dysbiosis; D020345:Enterocolitis, Necrotizing / Q000382:microbiology* / Q000628:therapy; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000382:microbiology* / Q000628:therapy; D007709:Klebsiella / Q000235:genetics / Q000302:isolation & purification; D008297:Male; D011247:Pregnancy; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D012336:RNA, Ribosomal, 16S
keywords: NEC; fecal microbiota; necrotizing enterocolitis; premature infant