Necrotizing enterocolitis in premature infants-A defect in the brakes? Evidence from clinical and animal studies

Abstract

A key aspect of postnatal intestinal adaptation is the establishment of symbiotic relationships with co-evolved gut microbiota. Necrotizing enterocolitis (NEC) is the most severe disease arising from failure in postnatal gut adaptation in premature infants. Although pathological activation of intestinal Toll-like receptors (TLRs) is believed to underpin NEC pathogenesis, the mechanisms are incompletely understood. We postulate that unregulated aberrant TLR activation in NEC arises from a failure in intestinal-specific mechanisms that tamponade TLR signaling (the brakes). In this review, we discussed the human and animal studies that elucidate the developmental mechanisms inhibiting TLR signaling in the postnatal intestine (establishing the brakes). We then evaluate evidence from preclinical models and human studies that point to a defect in the inhibition of TLR signaling underlying NEC. Finally, we provided a framework for the assessment of NEC risk by screening for signatures of TLR signaling and for NEC prevention by TLR-targeted therapy in premature infants.

Fig. 1

Overview of mechanisms from mouse and human studies that reveal how “the brakes on TLRs” are established in the neonatal gut. (1) Human milk components such as lactoferrin and secretory IgA inhibit growth of pathogenic microbes that can activate TLR signaling. (2) Epidermal growth factor and glutamine in breastmilk enhance intestinal epithelial barrier by inducing mucin production and tight junction protein activity. (3) HMOs present in human milk promote growth of commensal microbes such as Bifidobacteria and Lactobacillus. (4) The intestinal epithelial barrier—which includes mucin, antimicrobial peptides, and tight junction proteins—acts as a physical barrier that separates pathogenic microbes from the developing gut. (5) SCFAs, produced in part from the fermentation of HMOs by commensal bacteria, induce mucosal mechanisms such as increased mucin production to help repress intestinal TLR sensitivity. (6) Commensals such as Bifidobacterium and Lactobacillus, whose growth was promoted in part by HMOs, induce negative regulators of TLR4 (SIGIRR, A20, TOLLIP) to suppress TLR4 activity in the gut. (7) Development of postnatal tolerance to LPS through reduced surface TLR4 expression and repression of IRAK1. (8) Postnatal induction of genes that inhibit intestinal TLR signaling (SIGIRR, A20, TOLLIP) helps prevent aberrant intestinal TLR activation to colonizing microbes. (9) Postnatal repression of IRAK1 through SIGIRR-STAT3-miR-146a pathway dampens TLR4 signaling and contributes to LPS tolerance. (10) Developmental increase in IκB sequesters NFκB in the cytoplasm preventing its transcriptional activation. (11) Compartmentalization of TLRs in the basolateral membrane of IECs decreases TLR activation from bacteria in the apical lumen. HMOs = human milk oligosaccharides; IEC = intestinal epithelial cell; Ig = immunoglobulin; LPS = lipopolysaccharide; NEC = necrotizing enterocolitis; SCFAs = Short-chain fatty acids; Th = T helper; TLR = toll-like receptor.

Fig. 2

Conceptual framework. Clinical applications for improving outcomes of NEC based on the concept that NEC as a defect in the brakes on TLR signaling. HMOs = human milk oligosaccharides; Ig = immunoglobulin; IL = interleukin; LPS = lipopolysaccharide; NEC = necrotizing enterocolitis; SCFAs = short-chain fatty acids; TLR = Toll-like receptor.