Necrotizing Enterocolitis: A Comprehensive Review on Toll-like Receptor 4-Mediated Pathophysiology, Clinical, and Therapeutic Insights
Asuka Ishiyama, Hee‐Seong Jang, Jay Dintaman, Johannes W. Duess, Cody Tragesser, Chhinder P. Sodhi
Abstract
This review integrates clinical, immunological, microbial, pathophysiological, and therapeutic perspectives on necrotizing enterocolitis (NEC)-a leading cause of morbidity and mortality in premature infants. We summarize the clinical burden and risk factors; elucidate key immune and cellular mechanisms, including TLR4 signaling, epithelial barrier dysfunction, and enteric nervous system involvement; and provide a concise overview of experimental models. We also highlight microbial dysbiosis, ischemia, multiorgan injury, and recent advances in pathogenesis, as well as current and emerging therapies such as probiotics, breast milk components, TLR4 inhibitors, and immunomodulators, emphasizing the need for a multidisciplinary approach to accelerate discovery and improve outcomes. Overall, this review bridges mechanistic insights to clinical applications and supports the pursuit of personalized NEC prevention.