Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella , and fimbriae-encoding bacteria
Abstract
Necrotizing enterocolitis (NEC) is a devastating intestinal disease that occurs primarily in premature infants. We performed genome-resolved metagenomic analysis of 1163 fecal samples from premature infants to identify microbial features predictive of NEC. Features considered include genes, bacterial strain types, eukaryotes, bacteriophages, plasmids, and growth rates. A machine learning classifier found that samples collected before NEC diagnosis harbored significantly more Klebsiella, bacteria encoding fimbriae, and bacteria encoding secondary metabolite gene clusters related to quorum sensing and bacteriocin production. Notably, replication rates of all bacteria, especially Enterobacteriaceae, were significantly higher 2 days before NEC diagnosis. The findings uncover biomarkers that could lead to early detection of NEC and targets for microbiome-based therapeutics.
- Authors:
-
- Univ. of California, Berkeley, CA (United States)
- Univ. of Pittsburgh School of Medicine, PA (United States)
- Univ. of Pittsburgh Medical Center Magee Womens Hospital, PA (United States)
- Univ. of California, Berkeley, CA (United States); Chan Zuckerberg Biohub, San Francisco, CA (United States)
- Chan Zuckerberg Biohub, San Francisco, CA (United States); Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH); Alfred P. Sloan Foundation; National Science Foundation (NSF)
- OSTI Identifier:
- 1591850
- Grant/Contract Number:
- AC02-05CH11231; RAI092531A; R01-GM109454; APSF-2012-10-05; DGE 1106400
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science Advances
- Additional Journal Information:
- Journal Volume: 5; Journal Issue: 12; Journal ID: ISSN 2375-2548
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Olm, Matthew R., Bhattacharya, Nicholas, Crits-Christoph, Alexander, Firek, Brian A., Baker, Robyn, Song, Yun S., Morowitz, Michael J., and Banfield, Jillian F. Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella , and fimbriae-encoding bacteria. United States: N. p., 2019.
Web. doi:10.1126/sciadv.aax5727.
Olm, Matthew R., Bhattacharya, Nicholas, Crits-Christoph, Alexander, Firek, Brian A., Baker, Robyn, Song, Yun S., Morowitz, Michael J., & Banfield, Jillian F. Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella , and fimbriae-encoding bacteria. United States. doi:https://doi.org/10.1126/sciadv.aax5727
Olm, Matthew R., Bhattacharya, Nicholas, Crits-Christoph, Alexander, Firek, Brian A., Baker, Robyn, Song, Yun S., Morowitz, Michael J., and Banfield, Jillian F. Wed .
"Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella , and fimbriae-encoding bacteria". United States. doi:https://doi.org/10.1126/sciadv.aax5727. https://www.osti.gov/servlets/purl/1591850.
@article{osti_1591850,
title = {Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella , and fimbriae-encoding bacteria},
author = {Olm, Matthew R. and Bhattacharya, Nicholas and Crits-Christoph, Alexander and Firek, Brian A. and Baker, Robyn and Song, Yun S. and Morowitz, Michael J. and Banfield, Jillian F.},
abstractNote = {Necrotizing enterocolitis (NEC) is a devastating intestinal disease that occurs primarily in premature infants. We performed genome-resolved metagenomic analysis of 1163 fecal samples from premature infants to identify microbial features predictive of NEC. Features considered include genes, bacterial strain types, eukaryotes, bacteriophages, plasmids, and growth rates. A machine learning classifier found that samples collected before NEC diagnosis harbored significantly more Klebsiella, bacteria encoding fimbriae, and bacteria encoding secondary metabolite gene clusters related to quorum sensing and bacteriocin production. Notably, replication rates of all bacteria, especially Enterobacteriaceae, were significantly higher 2 days before NEC diagnosis. The findings uncover biomarkers that could lead to early detection of NEC and targets for microbiome-based therapeutics.},
doi = {10.1126/sciadv.aax5727},
journal = {Science Advances},
number = 12,
volume = 5,
place = {United States},
year = {2019},
month = {12}
}
Web of Science
Works referenced in this record:
Genome-resolved metagenomics of eukaryotic populations during early colonization of premature infants and in hospital rooms
journal, February 2019
- Olm, Matthew R.; West, Patrick T.; Brooks, Brandon
- Microbiome, Vol. 7, Issue 1
The role of quorum sensing in Escherichia coli (ETEC) virulence factors
journal, November 2015
- Sturbelle, Régis Tuchtenhagen; Avila, Luciana Farias da Costa de; Roos, Talita Bandeira
- Veterinary Microbiology, Vol. 180, Issue 3-4
Origins and virulence mechanisms of uropathogenic Escherichia coli
journal, August 2008
- Wiles, Travis J.; Kulesus, Richard R.; Mulvey, Matthew A.
- Experimental and Molecular Pathology, Vol. 85, Issue 1
A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair
journal, September 2007
- Leaphart, Cynthia L.; Cavallo, Jaime; Gribar, Steven C.
- The Journal of Immunology, Vol. 179, Issue 7
The Roles of Bacteria and TLR4 in Rat and Murine Models of Necrotizing Enterocolitis
journal, August 2006
- Jilling, Tamas; Simon, Dyan; Lu, Jing
- The Journal of Immunology, Vol. 177, Issue 5
Necrotizing Enterocolitis
journal, January 2011
- Neu, Josef; Walker, W. Allan
- New England Journal of Medicine, Vol. 364, Issue 3
Complete Sequencing and Diversity Analysis of the Enterotoxin-Encoding Plasmids in Clostridium perfringens Type A Non-Food-Borne Human Gastrointestinal Disease Isolates
journal, February 2006
- Miyamoto, K.; Fisher, D. J.; Li, J.
- Journal of Bacteriology, Vol. 188, Issue 4
Factors Influencing the Composition of the Intestinal Microbiota in Early Infancy
journal, August 2006
- Penders, J.; Thijs, C.; Vink, C.
- PEDIATRICS, Vol. 118, Issue 2
Metagenomic engineering of the mammalian gut microbiome in situ
journal, January 2019
- Ronda, Carlotta; Chen, Sway P.; Cabral, Vitor
- Nature Methods, Vol. 16, Issue 2
Machine Learning Leveraging Genomes from Metagenomes Identifies Influential Antibiotic Resistance Genes in the Infant Gut Microbiome
journal, January 2018
- Rahman, Sumayah F.; Olm, Matthew R.; Morowitz, Michael J.
- mSystems, Vol. 3, Issue 1
Mechanism of pathogen-specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection
journal, February 2006
- Fischer, Hans; Yamamoto, Masahiro; Akira, Shizuo
- European Journal of Immunology, Vol. 36, Issue 2
Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis
journal, March 2017
- Pammi, Mohan; Cope, Julia; Tarr, Phillip I.
- Microbiome, Vol. 5, Issue 1
Gamma-Butyrolactone Regulatory System of Streptomyces chattanoogensis Links Nutrient Utilization, Metabolism, and Development
journal, September 2011
- Du, Yi-Ling; Shen, Xue-Ling; Yu, Pin
- Applied and Environmental Microbiology, Vol. 77, Issue 23
BIGSdb: Scalable analysis of bacterial genome variation at the population level
journal, December 2010
- Jolley, Keith A.; Maiden, Martin CJ
- BMC Bioinformatics, Vol. 11, Issue 1
Interactive Tree Of Life (iTOL): an online tool for phylogenetic tree display and annotation
journal, October 2006
- Letunic, I.; Bork, P.
- Bioinformatics, Vol. 23, Issue 1
Necrotizing Enterocolitis – 150 Years of Fruitless Search for the Cause
journal, January 2009
- Obladen, Michael
- Neonatology, Vol. 96, Issue 4
Early Intestinal Bacterial Colonization and Necrotizing Enterocolitis in Premature Infants: The Putative Role of Clostridium
journal, September 2004
- de la Cochetière, Marie-France; Piloquet, Hugues; des Robert, Clotilde
- Pediatric Research, Vol. 56, Issue 3
Antibiotics, birth mode, and diet shape microbiome maturation during early life
journal, June 2016
- Bokulich, Nicholas A.; Chung, Jennifer; Battaglia, Thomas
- Science Translational Medicine, Vol. 8, Issue 343
Prodigal: prokaryotic gene recognition and translation initiation site identification
journal, March 2010
- Hyatt, Doug; Chen, Gwo-Liang; LoCascio, Philip F.
- BMC Bioinformatics, Vol. 11, Issue 1
The histone deacetylase inhibitor trichostatin A alters the pattern of DNA replication origin activity in human cells
journal, January 2005
- Kemp, M. G.
- Nucleic Acids Research, Vol. 33, Issue 1
VirSorter: mining viral signal from microbial genomic data
journal, January 2015
- Roux, Simon; Enault, Francois; Hurwitz, Bonnie L.
- PeerJ, Vol. 3
Pathogenesis of Neonatal Necrotising Enterocolitis
journal, January 1982
- Lawrence, Gregor; Bates, John; Gaul, Anne
- The Lancet, Vol. 319, Issue 8264
Isolation of a Variant of Subtilosin A with Hemolytic Activity
journal, July 2009
- Huang, T.; Geng, H.; Miyyapuram, V. R.
- Journal of Bacteriology, Vol. 191, Issue 18
MaxBin 2.0: an automated binning algorithm to recover genomes from multiple metagenomic datasets
journal, October 2015
- Wu, Yu-Wei; Simmons, Blake A.; Singer, Steven W.
- Bioinformatics, Vol. 32, Issue 4
Fast and sensitive protein alignment using DIAMOND
journal, November 2014
- Buchfink, Benjamin; Xie, Chao; Huson, Daniel H.
- Nature Methods, Vol. 12, Issue 1
Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants
journal, April 2013
- Morrow, Ardythe L.; Lagomarcino, Anne J.; Schibler, Kurt R.
- Microbiome, Vol. 1, Issue 1
MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability
journal, January 2013
- Katoh, K.; Standley, D. M.
- Molecular Biology and Evolution, Vol. 30, Issue 4
Search and clustering orders of magnitude faster than BLAST
journal, August 2010
- Edgar, Robert C.
- Bioinformatics, Vol. 26, Issue 19, p. 2460-2461
IQ-TREE: A Fast and Effective Stochastic Algorithm for Estimating Maximum-Likelihood Phylogenies
journal, November 2014
- Nguyen, Lam-Tung; Schmidt, Heiko A.; von Haeseler, Arndt
- Molecular Biology and Evolution, Vol. 32, Issue 1
Functional interactions of archaea, bacteria and viruses in a hypersaline endolithic community: Halite metagenome
journal, March 2016
- Crits-Christoph, Alexander; Gelsinger, Diego R.; Ma, Bing
- Environmental Microbiology, Vol. 18, Issue 6
Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples
journal, July 2015
- Korem, T.; Zeevi, D.; Suez, J.
- Science, Vol. 349, Issue 6252
Recovery of genomes from metagenomes via a dereplication, aggregation and scoring strategy
journal, May 2018
- Sieber, Christian M. K.; Probst, Alexander J.; Sharrar, Allison
- Nature Microbiology, Vol. 3, Issue 7
IDBA-UD: a de novo assembler for single-cell and metagenomic sequencing data with highly uneven depth
journal, April 2012
- Peng, Y.; Leung, H. C. M.; Yiu, S. M.
- Bioinformatics, Vol. 28, Issue 11
Strain-resolved analysis of hospital rooms and infants reveals overlap between the human and room microbiome
journal, November 2017
- Brooks, Brandon; Olm, Matthew R.; Firek, Brian A.
- Nature Communications, Vol. 8, Issue 1
The Pfam protein families database in 2019
journal, October 2018
- El-Gebali, Sara; Mistry, Jaina; Bateman, Alex
- Nucleic Acids Research, Vol. 47, Issue D1
ViromeScan: a new tool for metagenomic viral community profiling
journal, March 2016
- Rampelli, Simone; Soverini, Matteo; Turroni, Silvia
- BMC Genomics, Vol. 17, Issue 1
Profile Hidden Markov Models for the Detection of Viruses within Metagenomic Sequence Data
journal, August 2014
- Skewes-Cox, Peter; Sharpton, Thomas J.; Pollard, Katherine S.
- PLoS ONE, Vol. 9, Issue 8
Binning metagenomic contigs by coverage and composition
journal, September 2014
- Alneberg, Johannes; Bjarnason, Brynjar Smári; de Bruijn, Ino
- Nature Methods, Vol. 11, Issue 11
MMseqs2 enables sensitive protein sequence searching for the analysis of massive data sets
journal, October 2017
- Steinegger, Martin; Söding, Johannes
- Nature Biotechnology, Vol. 35, Issue 11
VirFinder: a novel k-mer based tool for identifying viral sequences from assembled metagenomic data
journal, July 2017
- Ren, Jie; Ahlgren, Nathan A.; Lu, Yang Young
- Microbiome, Vol. 5, Issue 1
Measurement of bacterial replication rates in microbial communities
journal, November 2016
- Brown, Christopher T.; Olm, Matthew R.; Thomas, Brian C.
- Nature Biotechnology, Vol. 34, Issue 12
Evidence for persistent and shared bacterial strains against a background of largely unique gut colonization in hospitalized premature infants
journal, June 2016
- Raveh-Sadka, Tali; Firek, Brian; Sharon, Itai
- The ISME Journal, Vol. 10, Issue 12
Gut bacteria are rarely shared by co-hospitalized premature infants, regardless of necrotizing enterocolitis development
journal, March 2015
- Raveh-Sadka, Tali; Thomas, Brian C.; Singh, Andrea
- eLife, Vol. 4
Pathology of neonatal necrotizing enterocolitis: A ten-year experience
journal, July 1990
- Ballance, William A.; Dahms, Beverly B.; Shenker, Nancy
- The Journal of Pediatrics, Vol. 117, Issue 1
Metagenomic Sequencing with Strain-Level Resolution Implicates Uropathogenic E. coli in Necrotizing Enterocolitis and Mortality in Preterm Infants
journal, March 2016
- Ward, Doyle V.; Scholz, Matthias; Zolfo, Moreno
- Cell Reports, Vol. 14, Issue 12
Fast gapped-read alignment with Bowtie 2
journal, March 2012
- Langmead, Ben; Salzberg, Steven L.
- Nature Methods, Vol. 9, Issue 4
Strain-resolved community genomic analysis of gut microbial colonization in a premature infant
journal, December 2010
- Morowitz, M. J.; Denef, V. J.; Costello, E. K.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 3
New Insights Into the Pathogenesis and Treatment of Necrotizing Enterocolitis: Toll-Like Receptors and Beyond
journal, March 2011
- Afrazi, Amin; Sodhi, Chhinder P.; Richardson, Ward
- Pediatric Research, Vol. 69, Issue 3
dRep: a tool for fast and accurate genomic comparisons that enables improved genome recovery from metagenomes through de-replication
journal, July 2017
- Olm, Matthew R.; Brown, Christopher T.; Brooks, Brandon
- The ISME Journal, Vol. 11, Issue 12
Redefining the Role of Intestinal Microbes in the Pathogenesis of Necrotizing Enterocolitis
journal, March 2010
- Morowitz, M. J.; Poroyko, V.; Caplan, M.
- PEDIATRICS, Vol. 125, Issue 4
Evolution of the Chaperone/Usher Assembly Pathway: Fimbrial Classification Goes Greek
journal, December 2007
- Nuccio, S. -P.; Baumler, A. J.
- Microbiology and Molecular Biology Reviews, Vol. 71, Issue 4
Developmentally regulated I B expression in intestinal epithelium and susceptibility to flagellin-induced inflammation
journal, April 2004
- Claud, E. C.; Lu, L.; Anton, P. M.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 19
antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters
journal, May 2015
- Weber, Tilmann; Blin, Kai; Duddela, Srikanth
- Nucleic Acids Research, Vol. 43, Issue W1
FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix
journal, April 2009
- Price, M. N.; Dehal, P. S.; Arkin, A. P.
- Molecular Biology and Evolution, Vol. 26, Issue 7
Necrotizing enterocolitis of the neonate with Clostridium perfringens: diagnosis, clinical course, and role of alpha toxin
journal, October 2007
- Dittmar, Elke; Beyer, Peter; Fischer, Doris
- European Journal of Pediatrics, Vol. 167, Issue 8
Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature
journal, January 2013
- Arnison, Paul G.; Bibb, Mervyn J.; Bierbaum, Gabriele
- Nat. Prod. Rep., Vol. 30, Issue 1
Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control
journal, November 2012
- Rutherford, S. T.; Bassler, B. L.
- Cold Spring Harbor Perspectives in Medicine, Vol. 2, Issue 11
Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium
journal, February 2018
- Zhang, Sicai; Lebreton, Francois; Mansfield, Michael J.
- Cell Host & Microbe, Vol. 23, Issue 2
Necrotizing Enterocolitis
journal, February 2009
- Henry, Marion C. W.; Moss, R. Lawrence
- Annual Review of Medicine, Vol. 60, Issue 1
Works referencing / citing this record:
Consistent Metagenome-Derived Metrics Verify and Delineate Bacterial Species Boundaries
journal, January 2020
- Olm, Matthew R.; Crits-Christoph, Alexander; Diamond, Spencer
- mSystems, Vol. 5, Issue 1