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Review
. 2018 Apr 6;6(2):229-238.e1.
doi: 10.1016/j.jcmgh.2018.04.001. eCollection 2018.

Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis

Affiliations
Review

Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis

David J Hackam et al. Cell Mol Gastroenterol Hepatol. .

Abstract

Necrotizing enterocolitis (NEC) remains the leading cause of death from gastrointestinal disease in premature infants and attacks the most fragile patients at a time when they appear to be the most stable. Despite significant advances in our overall care of the premature infant, NEC mortality remains stubbornly high. There is no specific treatment for NEC beyond broad-spectrum antibiotics and intestinal resection, and current efforts have focused on preventive strategies. Over the past decade, we have proposed a unifying hypothesis to explain the pathogenesis of NEC in premature infants that suggests that NEC develops in response to an imbalance between exaggerated proinflammatory signaling in the mucosa of the premature gut leading to mucosal injury, which is not countered effectively by endogenous repair processes, and in the setting of impaired mesenteric perfusion leads to intestinal ischemia and disease development. One of the most important pathways that mediates the balance between injury and repair in the premature intestine, and that plays a key role in NEC pathogenesis, is Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide on gram-negative bacteria. This review focuses on the role that the TLR4-mediated imbalance between proinflammatory and anti-inflammatory signaling in the premature intestinal epithelium leads to the development of NEC, and will explore how an understanding of the role of TLR4 in NEC pathogenesis has led to the identification of novel preventive or treatment approaches for this devastating disease.

Keywords: Enterocyte; LPS, lipopolysaccharide; Microbiome; NEC, necrotizing enterocolitis; Nutrition; Probiotic; Sepsis; TLR, Toll-like receptor; TLR4, Toll-like receptor 4; lneonate.

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Figures

Figure 1
Figure 1
The role of TLR4 in the pathogenesis of NEC. The premature infant gut is characterized by elevated expression of TLR4 on the intestinal epithelium, which is a function of the role of TLR4 in regulation of normal intestinal epithelial development. Activation of TLR4 by microbes within the intestinal lumen leads to barrier injury and impaired repair, resulting in translocation of luminal bacteria, which then interact with TLR4 on the lining of the mesenteric blood vessels, resulting in vasoconstriction and intestinal ischemia and NEC. Importantly, intestinal TLR4 is inhibited by factors including probiotic bacteria whose DNA can activate TLR9, as well as human milk oligosaccharides and other components of breast milk, while the provision of nitrates can induce mesenteric vasodilation and counter the negative effects of endothelial TLR4 activation on gut perfusion.
Supplemental Graphical Summary
Supplemental Graphical Summary

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