The central function and specific molecular mechanisms of the TLR4 pathway underlying impaired intestinal barrier in...

Neonatal necrotizing enterocolitisis a fatal gastrointestinal emergency affecting preterm infants, which is linked to destruction of intestinal barrier. The structural overexpression and negative regulation of Toll like receptor 4, a key receptor of lipopolysaccharidefrom Gram-negative bacteria in preterm intestinal epithelial cells, constitute a core hub connecting flora dysbiosis and barrier breakdown. When TLR4 neutrally binds with LPS, it signals the activation of the NF-κB-mediated inflammatory cascade through the MyD88/TRIF pathway which in turn induces apoptosis, necroptosis, and tight junction protein degradation in intestinal epithelial cells. degradation of tight junction protein of intestinal epithelial cells. The body naturally possesses protective mechanisms such as competitive receptors, intracellular negative regulatory networks, and microbial metabolites, which can be the target of drugs. Methods for the protection of the intestinal barrier by fine-tuning TLR4 signaling activity include small-molecule drugs, nano-delivery systems and nutritional interventions. Nonetheless, clinical translation remains hindered by the issues of TLR4 gene polymorphism, gestational age-dependent regulation, and immune balance maintenance. In the future, efforts should concentrate on the regulatory mechanisms of small molecule drugs and naturally occurring foodborne peptides. The goal is to combine the precision offered by genetic screening with a specific delivery system. This will allow for the targeted prevention and control of TLR4 signal systems. Ultimately, this will lead to a breakthrough in tackling the challenges associated with NEC treatment.