SIGIRR-TWIST1 axis regulates barrier function in neonatal intestine

BACKGROUND: The genetic basis of impaired intestinal barrier function in preterm infants is poorly understood. Variants in single immunoglobulin interleukin-1-related receptor (SIGIRR), a negative regulator of Toll-Like Receptor (TLR) signaling, have been identified in preterm infants with necrotizing enterocolitis (NEC). We hypothesized that SIGIRR variants associated with NEC impair gut barrier function to pathobionts. To determine how SIGIRR genetic variants disrupt neonatal intestinal barrier integrity and promote susceptibility to Gram-negative bacteria implicated in sepsis and NEC pathogenesis. METHODS: Transgenic mice and preterm infant-derived enteroids expressing SIGIRR variants identified in NEC were used to define how SIGIRR regulates epithelial junctional protein assembly. An E. coli strain identified in neonatal sepsis was used for functional evaluation of gut barrier function. RESULTS: mice were highly susceptible to bacteremia when enterally challenged with pathogenic E. coli. Pharmacological inhibition of TWIST1 or genetic deletion of TLR4 restored barrier integrity. Preterm human enteroids expressing the SIGIRR p.Y168X and p.P115R variants recapitulated barrier defects and TWIST1 activation in a bacteria-free environment. TWIST1 inhibition reversed these defects in both human and murine enteroids CONCLUSIONS: SIGIRR preserves neonatal intestinal epithelial barrier integrity by repressing TWIST1-mediated disruption of junctional proteins. Loss of SIGIRR function compromises epithelial barrier and promotes bacterial translocation, revealing a genetic mechanism underlying gut barrier dysfunction in NEC and neonatal sepsis.