Impact of Toll-Like Receptor 4 Signaling in Necrotizing Enterocolitis: The State of the Science

Abstract

Necrotizing enterocolitis (NEC) remains a leading cause of preterm infant mortality. NEC is multifactorial and believed a consequence of intestinal immaturity, microbial dysbiosis, and an exuberant inflammatory response. Over the past decade, exaggerated Toll-like receptor 4 (TLR4) activity in the immature intestine of preterm neonates emerged as an inciting event preceding NEC. Increased TLR4 signaling in epithelial cells results in the initiation of an uncontrolled immune response and destruction of the mucosal barrier. This article discusses the state of the science of the molecular mechanisms involved in TLR4-mediated inflammation during NEC and the development of new therapeutic strategies to prevent NEC.

Keywords: Epithelial cells; Inflammation; Necrotizing enterocolitis; TLR4.

Figure 1.. Inhibition of TLR4 signaling as a potential strategy to cure/prevent the development of necrotizing enterocolitis.

During the first days of life, several factors such as formula feeding, high expression of TLR4, microbial colonization and hypoxic stress can trigger an inflammatory process leading to the development of NEC. Exaggerated TLR4 activity in the premature intestine plays a critical role in the pathogenesis of NEC by inducing epithelial cell apoptosis as well as reducing cell proliferation and cell migration throughout the crypt villi-axis. All together, these events lead to the impairment of the epithelial barrier integrity and the translocation of the luminal microorganisms which in turn initiate an exaggerated intestinal inflammatory response. Factors found in the breast milk and/or in amniotic fluid including EGF/HB-EGF and vitamin D have the ability to counteract the TLR4-mediated inflammation. In addition, probiotics can prevent the development of NEC by activating TLR9 and NOD2 and dampen TLR4 signaling.