Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis

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Abstract

Background

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.

Methods and 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).

Conclusions

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.

Electronic supplementary material

The online version of this article (doi:10.1186/s40168-017-0248-8) contains supplementary material, which is available to authorized users.

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Most cited references 37

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Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.

Barbara Stoll, Nellie I Hansen, Ira Adams-Chapman … (2004)

Neonatal infections are frequent complications of extremely low-birth-weight (ELBW) infants receiving intensive care. To determine if neonatal infections in ELBW infants are associated with increased risks of adverse neurodevelopmental and growth sequelae in early childhood. Infants weighing 401 to 1000 g at birth (born in 1993-2001) were enrolled in a prospectively collected very low-birth-weight registry at academic medical centers participating in the National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth outcomes were assessed at a comprehensive follow-up visit at 18 to 22 months of corrected gestational age and compared by infection group. Eighty percent of survivors completed the follow-up visit and 6093 infants were studied. Registry data were used to classify infants by type of infection: uninfected (n = 2161), clinical infection alone (n = 1538), sepsis (n = 1922), sepsis and necrotizing enterocolitis (n = 279), or meningitis with or without sepsis (n = 193). Cognitive and neuromotor development, neurologic status, vision and hearing, and growth (weight, length, and head circumference) were assessed at follow-up. The majority of ELBW survivors (65%) had at least 1 infection during their hospitalization after birth. Compared with uninfected infants, those in each of the 4 infection groups were significantly more likely to have adverse neurodevelopmental outcomes at follow-up, including cerebral palsy (range of significant odds ratios [ORs], 1.4-1.7), low Bayley Scales of Infant Development II scores on the mental development index (ORs, 1.3-1.6) and psychomotor development index (ORs, 1.5-2.4), and vision impairment (ORs, 1.3-2.2). Infection in the neonatal period was also associated with impaired head growth, a known predictor of poor neurodevelopmental outcome. This large cohort study suggests that neonatal infections among ELBW infants are associated with poor neurodevelopmental and growth outcomes in early childhood. Additional studies are needed to elucidate the pathogenesis of brain injury in infants with infection so that novel interventions to improve these outcomes can be explored.

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Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization

Itai Sharon, Michael Morowitz, Brian C Thomas … (2013)

The gastrointestinal microbiome undergoes shifts in species and strain abundances, yet dynamics involving closely related microorganisms remain largely unknown because most methods cannot resolve them. We developed new metagenomic methods and utilized them to track species and strain level variations in microbial communities in 11 fecal samples collected from a premature infant during the first month of life. Ninety six percent of the sequencing reads were assembled into scaffolds of >500 bp in length that could be assigned to organisms at the strain level. Six essentially complete (∼99%) and two near-complete genomes were assembled for bacteria that comprised as little as 1% of the community, as well as nine partial genomes of bacteria representing as little as 0.05%. In addition, three viral genomes were assembled and assigned to their hosts. The relative abundance of three Staphylococcus epidermidis strains, as well as three phages that infect them, changed dramatically over time. Genes possibly related to these shifts include those for resistance to antibiotics, heavy metals, and phage. At the species level, we observed the decline of an early-colonizing Propionibacterium acnes strain similar to SK137 and the proliferation of novel Propionibacterium and Peptoniphilus species late in colonization. The Propionibacterium species differed in their ability to metabolize carbon compounds such as inositol and sialic acid, indicating that shifts in species composition likely impact the metabolic potential of the community. These results highlight the benefit of reconstructing complete genomes from metagenomic data and demonstrate methods for achieving this goal.

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Necrotising enterocolitis.

Patricia Lin, Barbara Stoll (2006)

Necrotising enterocolitis is one of the most common gastrointestinal emergencies in newborn infants. Here we review the epidemiology, clinical presentation, and pathophysiology of the disease, as well as strategies for diagnosis, management, and prevention. Necrotising enterocolitis is one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, its pathogenesis remains unclear; diagnosis can be difficult; and treatment is challenging. We will need to improve our understanding of intestinal defences in premature infants, dietary and bacterial factors, and genetic effects that could predispose infants to necrotising enterocolitis before we can develop new strategies for prevention and treatment.

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Author and article information

Contributors

Mohan Pammi:

ORCID: http://orcid.org/0000-0002-5571-6239

832-824-3206 , mohanv@bcm.edu

Julia Cope: Julia.cope@bcm.edu

Phillip I. Tarr: Tarr@wustl.edu

Barbara B. Warner: Warner_B@kids.wustl.edu

Ardythe L. Morrow: Ardythe.morrow@cchmc.org

Volker Mai: vmai@epi.ufl.edu

Katherine E. Gregory: kgregory1@partners.org

J. Simon Kroll: s.kroll@imperial.ac.uk

Valerie McMurtry: valariemcmurtry@gmail.com

Michael J Ferris: mferri1@lsuhc.edu

Helene Engstrand Lilja: Helene.lilja@kbh.uu.se

Emily B. Hollister: holliste@bcm.edu

James Versalovic: jamesv@bcm.edu

Josef Neu: neuj@peds.ufl.edu

Journal

Journal ID (nlm-ta): Microbiome

Journal ID (iso-abbrev): Microbiome

Title: Microbiome

Publisher: BioMed Central (London )

ISSN (Electronic): 2049-2618

Publication date (Electronic): 9 March 2017

Publication date PMC-release: 9 March 2017

Publication date Collection: 2017

Volume: 5

Electronic Location Identifier: 31

Affiliations

[1 ]ISNI 0000 0001 2200 2638, GRID grid.416975.8, Section of Neonatology, Department of Pediatrics, , Baylor College of Medicine and Texas Children’s Hospital, ; 77030 Houston, TX USA

[2 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Alkek Center for Metagenomics and Microbiome Research, , Baylor College of Medicine, ; Houston, TX USA

[3 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Pediatrics, , Washington University in St. Louis School of Medicine, ; St. Louis, MO USA

[4 ]ISNI 0000 0001 2179 9593, GRID grid.24827.3b, Department of Pediatrics, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, , University of Cincinnati College of Medicine, ; Ohio, USA

[5 ]ISNI 0000 0004 1936 8091, GRID grid.15276.37, Department of Epidemiology, College of Public Health and Health Professions and College of Medicine and Emerging Pathogens Institute, , University of Florida, ; Gainesville, FL USA

[6 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Department of Newborn Medicine, , Brigham and Women’s Hospital, ; Boston, MA USA

[7 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Medicine, Section of Paediatrics, , Imperial College London, ; London, UK

[8 ]GRID grid.413979.1, Department of Microbiology, Immunology and Parasitology, , Children’s Hospital, ; New Orleans, LA USA

[9 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Director of Clinical Genomics and Department of Microbiology, Tumor and Cell Biology, , Karolinska Institute, ; Stockholm, Sweden

[10 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Women’s and Children’s Health, , Uppsala University, ; 751 85 Uppsala, Sweden

[11 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Texas Children’s Microbiome Center, Department of Pathology, , Texas Children’s Hospital and Baylor College of Medicine, ; Houston, TX USA

Author information

Mohan Pammi http://orcid.org/0000-0002-5571-6239

Article

Publisher ID: 248

DOI: 10.1186/s40168-017-0248-8

PMC ID: 5343300

PubMed ID: 28274256

SO-VID: 7abfbfe2-6621-4619-84b9-cda1c92f36ea

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 September 2016

Date accepted : 27 February 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: P30DK052574

Award Recipient : Phillip I. Tarr

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: UH3 AI083265

Award Recipient : Phillip I. Tarr

Funded by: Washington University Institute of Clinical and Translational Sciences(US)

Award ID: UL1RR024992

Award Recipient : Phillip I. Tarr

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: K23 NR011320-01

Award Recipient : Katherine E. Gregory

Funded by: Harvard Catalyst CTSA Grant

Award ID: UL1 RR 025758-01

Award Recipient : Katherine E. Gregory

Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;

Award ID: R01 HD059140

Funded by: National Institute for Health Research (NIHR) Biomedical Research Centre

Funded by: Winnicott Foundation

Custom metadata

Keywords: microbiome,intestinal,preterm,neonate,nec,16s rrna sequencing

Data availability:

Keywords: microbiome, intestinal, preterm, neonate, nec, 16s rrna sequencing

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Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis

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Abstract

Background

Methods and results

Conclusions

Electronic supplementary material

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Tick microbiome

Most cited references 37

Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.

Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization

Necrotising enterocolitis.

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Cited by 246

Most referenced authors 2,198