Preterm infant gut microbial patterns related to the development of necrotizing enterocolitis

Lindberg, Tristan P.; Caimano, Melissa J.; Hagadorn, James I.; Bennett, Erin; Maas, Kendra; Brownell, Elizabeth A.; Matson, Adam

doi:10.1080/14767058.2018.1490719

Cited by 36 publications

(31 citation statements)

References 60 publications

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“…We previously reported that NEC_unk_OTU was considerably more abundant in fecal samples of infants with NEC compared to matched controls [8]. BLASTN (blastn suite/NCBI) searches identified K. oxytoca, K. michiganensis and Enterobacter cloacae as potential matches for this 16S sequence.…”

Section: Resultsmentioning

confidence: 92%

“…Fecal samples were processed and analyzed as previously described [8]. Briefly, total DNA was extracted using the MoBio Power Soil kit (MoBio Laboratories, Inc., Carlsbad, CA).…”

Section: S Rrna Gene Analysismentioning

confidence: 99%

“…With the development of Next Generation 16S rRNA sequencing, we [8] and others [9][10][11] demonstrated that the gut microbiome of preterm infants with NEC is dominated by lipopolysaccharide (LPS)producing Proteobacteria. There is evidence that stimulation of Toll-like receptor 4 (TLR4), the ligand for LPS, compromises intestinal barrier function, allowing bacterial proinflammatory products to penetrate into the submucosa [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxin-producing Klebsiella oxytoca in the preterm gut and its association with necrotizing enterocolitis

Paveglio

Ledala

Rezaul

et al. 2020

Emerging Microbes & Infections

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Necrotizing enterocolitis (NEC) is a devastating intestinal inflammatory disease of premature infants associated with gut bacterial dysbiosis. Using 16S rRNA-based methods, our laboratory identified an unclassified Enterobacteriaceae sequence (NEC_unk_OTU) with high abundance in NEC fecal samples. We aimed to identify this bacterium and determine its potential role in the disease. NCBI database searches for the 16S sequence, selective culture systems, biotyping and polymerase chain reaction were employed to refine classification of NEC_unk_OTU and identify toxinencoding genes from the index NEC case. Bacterial cytotoxin production was confirmed by mass spectrometry and apoptosis assays. Additional fecal samples from 9 NEC and 5 non-NEC controls were analyzed using similar methods and multi-locus sequence typing (MLST) was performed to investigate clonal relationships and define sequence types of the isolates. NEC_unk_OTU was identified as Klebsiella oxytoca, a pathobiont known to cause antibiotic-associated hemorrhagic colitis, but not previously linked to NEC. Including the index case, cytotoxin-producing strains of K. oxytoca were isolated from 6 of 10 subjects with NEC; in these, the K. oxytoca 16S sequence predominated the fecal microbiota. Cytotoxin-producing strains of K. oxytoca also were isolated from 4 of 5 controls; in these, however, the abundance of the corresponding 16S sequence was very low. MLST analysis of the toxin-positive isolates demonstrated no clonal relationships and similar genetic clustering between cases and controls. These results suggest cytotoxin-producing strains of K. oxytoca colonize a substantial proportion of premature infants. Some, perhaps many, cases of NEC may be precipitated by outgrowth of this opportunistic pathogen.

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Section: Resultsmentioning

confidence: 92%

“…Fecal samples were processed and analyzed as previously described [8]. Briefly, total DNA was extracted using the MoBio Power Soil kit (MoBio Laboratories, Inc., Carlsbad, CA).…”

Section: S Rrna Gene Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxin-producing Klebsiella oxytoca in the preterm gut and its association with necrotizing enterocolitis

Paveglio

Ledala

Rezaul

et al. 2020

Emerging Microbes & Infections

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“…In the last decade, several studies of the gut microbiome in preterm infants have associated Gammaproteobacteria and its constituent families Enterobacteriaceae, Vibrionaceae, and Pseudomonadaceae, with increased risk of NEC (1)(2)(3)(5)(6)(7)(8)(9). Wang et al (2009) analyzed fecal samples from a small sample of preterm infants (10 infants with a diagnosis of NEC and 10 gestational age-matched controls), and showed that the stool microbiome from NEC patients clustered separately from controls and showed low bacterial diversity with a marked increase in the relative abundance of Gammaproteobacteria (2).…”

Section: Strength Of the Associationmentioning

confidence: 99%

Intestinal dysbiosis and necrotizing enterocolitis: assessment for causality using Bradford Hill criteria

et al. 2019

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In recent years, several studies have shown that premature infants who develop NEC frequently display enteric dysbiosis with increased Gram-negative bacteria for several days to weeks prior to NEC onset. The importance of these findings, for the possibility of a causal role of these bacteria in NEC pathogenesis, and for potential value of gut dysbiosis as a biomarker of NEC, is wellrecognized. In this review, we present current evidence supporting the association between NEC in premature infants and enteric dysbiosis, and its evaluation using the Bradford Hill criteria for causality. To provide an objective appraisal, we developed a novel scoring system for causal inference. Despite important methodological and statistical limitations, there is support for the association from several large studies and a meta-analysis. The association draws strength from strong biological plausibility of a role of Gram-negative bacteria in NEC and from evidence for temporality, that dysbiosis may antedate NEC onset. The weakness of the association is in the low level of consistency across studies, and the lack of specificity of effect. There is a need for an improved definition of dysbiosis, either based on a critical threshold of relative abundances or at higher levels of taxonomic resolution.

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“…Specifically, an increased abundance of Clostridium spp. and associated toxins has also been observed in the stool of neonates with NEC [ 37 , 38 , 39 ]. Acquisition of Group B Streptococcus (GBS) and E. coli during the birth process has been identified as the primary cause of EONS within 3 days postpartum among preterm infants [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Role of Gut Bacteria in Health and Disease in Preterm Neonates

Lee

Tan

Ramadas

et al. 2020

IJERPH

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The mortality rate of very preterm infants with birth weight <1500 g is as high as 15%. The survivors till discharge have a high incidence of significant morbidity, which includes necrotising enterocolitis (NEC), early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). More than 25% of preterm births are associated with microbial invasion of amniotic cavity. The preterm gut microbiome subsequently undergoes an early disruption before achieving bacterial maturation. It is postulated that bacterial gut colonisation at birth and postnatal intestinal dysbacteriosis precede the development of NEC and LONS in very preterm infants. In fact, bacterial colonization patterns in preterm infants greatly differ from term infants due to maternal chorioamnionitis, gestational age, delivery method, feeding type, antibiotic exposure and the environment factor in neonatal intensive care unit (NICU). In this regard, this review provides an overview on the gut bacteria in preterm neonates’ meconium and stool. More than 50% of preterm meconium contains bacteria and the proportion increases with lower gestational age. Researchers revealed that the gut bacterial diversity is reduced in preterm infants at risk for LONS and NEC. Nevertheless, the association between gut dysbacteriosis and NEC is inconclusive with regards to relative bacteria abundance and between-sample beta diversity indices. With most studies show a disruption of the Proteobacteria and Firmicutes preceding the NEC. Hence, this review sheds light on whether gut bacteria at birth either alone or in combination with postnatal gut dysbacteriosis are associated with mortality and the morbidity of LONS and NEC in very preterm infants.

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Preterm infant gut microbial patterns related to the development of necrotizing enterocolitis

Cited by 36 publications

References 60 publications

Cytotoxin-producing Klebsiella oxytoca in the preterm gut and its association with necrotizing enterocolitis

Cytotoxin-producing Klebsiella oxytoca in the preterm gut and its association with necrotizing enterocolitis

Intestinal dysbiosis and necrotizing enterocolitis: assessment for causality using Bradford Hill criteria

Exploring the Role of Gut Bacteria in Health and Disease in Preterm Neonates

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