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

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.

Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis

“…We also reported an increase in pro-inflammatory Gram-negative Enterobacteriaceae in the distal small bowel of rat pups exposed to both PNGR and hyperoxia (15). Recognition of lipopolysaccharide (LPS) in the cell wall of Enterobacteriaceae by the host Toll-like receptor (TLR)4 is important in the pathogenesis of NEC, and both inhibition of TLR4 and manipulation of the intestinal microbiota with probiotic organisms prevents this disease (16,17). TLR4 signaling is also important in lung injury and inflammation (18).…”

Necrotizing Enterocolitis, Gut Microbiota, and Brain Development: Role of the Brain-Gut Axis

“…First, in TLR mutant or knockout animals, NEC is not inducible. Second, probiotic bacteria that activate TLR9, which in turn limits the degree of TLR4 signaling, are associated with reduced NEC in clinical studies [38, 41, 42]. …”

Berberine reduces the occurrence of neonatal necrotizing enterocolitis by reducing the inflammatory response

“…Necrotizing enterocolitis (NEC) is a serious, life-threatening disease in premature infants. The incidence of NEC has increased in spite of clinical developments (1)(2)(3). Additionally, the mortality rate of infants with NEC remains high (~20-30%), although the clinical outcome for many premature infants has improved (4).…”

“…Studies have hypothesized that NEC is caused by an uncontrolled inflammatory response induced by a characteristic intestinal bacterial colonization in premature infants (12,13). Various inflammatory mediators, receptors and signal transduction pathways are involved in the pathophysiological processes of the disease; however, it remains unclear which factors are most crucial (1,2). These factors are potential targets for regulating the prevention and treatment of NEC (14).…”