Necrotizing enterocolitis: The intestinal microbiome, metabolome and inflammatory mediators

https://doi.org/10.1016/j.siny.2018.08.001Get rights and content

Abstract

Necrotizing enterocolitis (NEC) is a disease of preterm infants and associated with significant mortality and morbidity. Although the pathogenesis of NEC is not clear, microbial dysbiosis, with a bloom of the phylum Proteobacteria, has been reported. Antibiotics and the use of H2 blockers, which affect the gut microbiome, are associated with increased incidence of NEC. In association with dysbiosis, inflammatory processes are upregulated with increased Toll-like receptor signaling, leading to translocation of nuclear factor kappa-β, a transcription factor that induces transcription of various pro-inflammatory cytokines and chemokines. Microbial metabolites, short chain fatty acids including acetate and butyrate, may modulate immunity, inflammation, intestinal integrity and regulate transcription by epigenetic mechanisms. Evaluation of microbiome and metabolome may provide biomarkers for early diagnosis of NEC and microbial therapeutic approaches to correct microbial dysbiosis.

Section snippets

Necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a major cause of mortality in preterm infants who survive the first few days after birth [1,2]. NEC is seen in 7% of very low birth weight infants (birth weight <1500 g) and up to 5% of admissions to the neonatal intensive care unit (NICU) [2,3]. NEC is associated with a mortality of 15–30% and a significant long-term neurodevelopmental morbidity but we have made little progress for 60 years [[3], [4], [5]]. The pathogenesis of NEC is not clear but microbial

Microbiome and human health

The microbial communities on the surface of the human body outnumber human cells and genes. Host–microbe interactions on intestinal and respiratory mucosal surfaces play a major role in the prevention of infections and development of immunity. Intestinal microbiota, the best studied, has a bacterial load in the magnitude of 1014 bacteria/mm3, which makes it the most densely colonized surface of the human body. Bacteroidetes represent the most abundant phylum, followed by Firmicutes [11,12]. In

Microbial–host interactions and innate immunity, inflammation

The relationship between microbes and the innate immune system in the gastrointestinal tract has been reviewed [56,57]. Intestinal cells including the intestinal epithelium harbor receptors to microbial components, TLRs, which play a major role in innate immunity [26,58]. Activation of these Toll-like receptors results in signaling cascades that induce nuclear translocation of nuclear factor kappa-β (NFKβ), a transcription factor that induced transcription of various pro- and anti-inflammatory

Metabolome in necrotizing enterocolitis

Microbiota-derived metabolites, short chain fatty acids (SCFAs), butyrate, propionate and acetate induce IL-18 production from the intestinal epithelial cells (IECs) through activation of NOD-like family, receptors (NLRs) [65]. Acetate produced by Bifidobacteria promotes epithelial cell barrier function by inducing an anti-apoptotic response in the IECs. Microbiota-derived sphingolipids presented on CD1d by dendritic cells inhibit colonic invariant natural killer T-cell development. Thus

Future directions

For the prediction and diagnosis of NEC, diagnostic biomarkers include those that may not be specific for NEC such as the C-reactive protein, white blood cell count, and platelet count. However, more specific biomarkers are being developed which include tight junction proteins such as claudin-3, intestinal epithelial cell proteins such as intestinal fatty acid binding protein (IFAB), both of which can be analyzed non-invasively in the urine. More predictive biomarkers using the proteomic,

Conflicts of interest

None declared.

Funding sources

None.

References (86)

  • A. Romaine et al.

    Safety of histamine-2 receptor blockers in hospitalized VLBW infants

    Early Hum Dev

    (2016)
  • M.S. Caplan et al.

    The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis

    Semin Pediatr Surg

    (2005)
  • P. Lu et al.

    Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis

    Pathophysiology

    (2014)
  • C.P. Sodhi et al.

    Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis

    Gastroenterology

    (2010)
  • A.M. Kabat et al.

    Modulation of immune development and function by intestinal microbiota

    Trends Immunol

    (2014)
  • T. Hoverstad et al.

    Short-chain fatty acids in germfree mice and rats

    J Nutr

    (1986)
  • L. Peng et al.

    Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers

    J Nutr

    (2009)
  • S.G. Oliver et al.

    Systematic functional analysis of the yeast genome

    Trends Biotechnol

    (1998)
  • J. Neu et al.

    Necrotizing enterocolitis

    N Engl J Med

    (2011)
  • A.A. Fanaroff et al.

    Trends in neonatal morbidity and mortality for very low birthweight infants

    Am J Obstet Gynecol

    (2007)
  • B.J. Stoll et al.

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

    J Am Med Assoc

    (2004)
  • M.J. Bell et al.

    Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging

    Ann Surg

    (1978)
  • W.H. Yee et al.

    Incidence and timing of presentation of necrotizing enterocolitis in preterm infants

    Pediatrics

    (2012)
  • R. Gonzalez-Rivera et al.

    The age of necrotizing enterocolitis onset: an application of Sartwell's incubation period model

    J Perinatol

    (2011)
  • P.V. Gordon et al.

    Can a national dataset generate a nomogram for necrotizing enterocolitis onset?

    J Perinatol

    (2014)
  • M. Pammi et al.

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

    Microbiome

    (2017)
  • P.B. Eckburg et al.

    Diversity of the human intestinal microbial flora

    Science

    (2005)
  • V. Robles Alonso et al.

    Linking the gut microbiota to human health

    Br J Nutr

    (2013)
  • M.A. Sze et al.

    The lung tissue microbiome in chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2012)
  • J.R. Erb-Downward et al.

    Analysis of the lung microbiome in the “healthy” smoker and in COPD

    PLoS One

    (2011)
  • E.S. Charlson et al.

    Topographical continuity of bacterial populations in the healthy human respiratory tract

    Am J Respir Crit Care Med

    (2011)
  • E.S. Charlson et al.

    Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant

    Am J Respir Crit Care Med

    (2012)
  • K. Aagaard et al.

    The placenta harbors a unique microbiome

    Sci Transl Med

    (2014)
  • F.H. Heida et al.

    A necrotizing enterocolitis-associated gut microbiota is present in the meconium: results of a prospective study

    Clin Infect Dis

    (2016)
  • M.J. Gosalbes et al.

    Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants

    Clin Exp Allergy

    (2013)
  • P.S. La Rosa et al.

    Patterned progression of bacterial populations in the premature infant gut

    Proc Natl Acad Sci USA

    (2014)
  • E.C. Claud et al.

    Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis

    Faseb J

    (2001)
  • E.C. Claud et al.

    Bacterial colonization, probiotics, and necrotizing enterocolitis

    J Clin Gastroenterol

    (2008)
  • N.N. Nanthakumar et al.

    Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis

    Proc Natl Acad Sci USA

    (2000)
  • N. Nanthakumar et al.

    The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response

    PLoS One

    (2011)
  • A. Afrazi et al.

    New insights into the pathogenesis and treatment of necrotizing enterocolitis: Toll-like receptors and beyond

    Pediatr Res

    (2011)
  • M.J. Morowitz et al.

    Redefining the role of intestinal microbes in the pathogenesis of necrotizing enterocolitis

    Pediatrics

    (2010)
  • I. Brook

    Microbiology and management of neonatal necrotizing enterocolitis

    Am J Perinatol

    (2008)
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      Citation Excerpt :

      Neonatal necrotizing enterocolitis (NEC) is a common and devastating disease in neonates.1 The precise pathogenesis of NEC remains unknown, but premature birth, an imbalance in microvascular tone, and gut dysbiosis have been implicated.2,3 Accumulating data suggest that gut dysbiosis plays a vital role in developing NEC; hence, maintaining gut microbiota homeostasis is necessary to prevent NEC.

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