Necrotizing enterocolitis: Pathophysiology from a historical context

Abstract

Necrotizing enterocolitis (NEC) continues to afflict approximately 7% of preterm infants born weighing less than 1500g, though recent investigations have provided novel insights into the pathogenesis of this complex disease. The disease has been a major cause of morbidity and mortality in neonatal intensive care units worldwide for many years, and our current understanding reflects exceptional observations made decades ago. In this review, we will describe NEC from a historical context and summarize seminal findings that underscore the importance of enteral feeding, the gut microbiota, and intestinal inflammation in this complex pathophysiology.

Keywords: Breast milk; Endotoxin; Necrotizing enterocolitis; Neonatal sepsis; Surgery; Toll like receptor.

Figure 1.. The development of necrotizing enterocolitis requires TLR4 activation on the intestinal epithelium.

i-iv: epresentative H&E micrographs from sections of the terminal ileum in mice without (i) or with (ii-iv) NEC that are either wild-type (i-ii), globally deficient in TLR4 (iii), or lacking TLR4 on the intestinal epithelium (iv). Shown also is the expression by RT-PCR of iNOS and IL-6, and NEC severity in the indicated groups. Reproduced with permission from Gastroenterology 2012 Sep;143(3).

Figure 2. The development of necrotizing enterocolitis is associated with induction of Th17 cells and reduction in Tregs in the newborn intestine of mice and humans.

A-H: Representative confocal micrographs from sections of the terminal ileum in mice (A-D) and human infant (B-H) with or without NEC, immunostained for CD3 or CD4 as indicated. Characterization of the immune cell infiltrate in the lamina propria in mouse (I) and human (J) is shown. Scale bar = 10mm. K-M: qRT-PCR expression of the lamina propria CD4+ T cells in mice with and without NEC for the indicated lymphocyte transcription factors in murine CD4+ T cells. N-R: Flow cytometric analysis of Foxp3+ (N-O) or RORgt+ (P-Q) cells in the lamina propria of mice with and without NEC; quantification is shown in R. Reproduced from Journal of Clinical Investigation, 2016 Feb;126(2):495–508.

Figure 3.. Breast milk attenuates TLR4 signaling in vivo via EGFR.

A: Pseudocolor images demonstrating whole animal NF-κB luciferase activity treated with either saline (i), LPS (5 mg/kg, 6 hr, ii), gavage pretreatment with breast milk (50 μL/gram body weight, iii) and/or cetuximab (Cetux), an EGFR inhibitor (100 μg/day for 3 days, iv) 1 h prior to LPS administration, quantification of images in Total Flux (photons/sec × 10⁴, v). B: IL-6 (i) and TLR4 mRNA expression (ii) for above groups. *p<0.05 versus saline (white bar), **p<0.05 versus LPS, ***p<0.05 versus LPS + breast milk (BM). Data are mean ±SD. Representative of at least three separate experiments with at least three mice per group. Reproduced with permission from Mucosal Immunol. 2015 Sep;8(5):1166–79.