Cellular and molecular gastroenterology and hepatology · 2026
Single Immunoglobulin Interleukin1-Related Receptor-TWIST1 Axis Regulates Barrier Function in Neonatal Intestine.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Venkatraman Aparna, Yu Wei, Menden Heather L, Mabry Sherry M, Wheatley Joshua L, Umar Shahid, Chavez-Bueno Susana, Sampath Venkatesh
Аннотация
BACKGROUND & AIMS: The genetic basis of impaired intestinal barrier function in preterm infants is poorly understood. Variants in single immunoglobulin interleukin1-related receptor, a negative regulator of Toll-like receptor signaling, have been identified in preterm infants with necrotizing enterocolitis. We hypothesized that single immunoglobulin interleukin1-related receptor variants associated with necrotizing enterocolitis impair gut barrier function to pathobionts. The aim of this study was to determine how single immunoglobulin interleukin1-related receptor genetic variants disrupt neonatal intestinal barrier integrity and promote susceptibility to Gram-negative bacteria implicated in sepsis and necrotizing enterocolitis pathogenesis.
METHODS: Transgenic mice and preterm infant-derived enteroids expressing SIGIRR variants identified in necrotizing enterocolitis were used to define how single immunoglobulin interleukin1-related receptor regulates epithelial junctional protein assembly. An Escherichia coli strain identified in neonatal sepsis was used for functional evaluation of gut barrier function.
RESULTS: Neonatal mice harboring the SIGIRR p.Y168X mutation (Sigirrmu/mu), exhibited loss of epithelial junctional proteins, impaired barrier function, and activation of Twist family BHLH transcription factor 1 with exaggerated Toll-like receptor signaling. Sigirrmu/mu mice were highly susceptible to bacteremia when enterally challenged with pathogenic E coli. Pharmacologic inhibition of Twist family BHLH transcription factor 1 or genetic deletion of Toll-like receptor 4 restored barrier integrity. Preterm human enteroids expressing the SIGIRR p.Y168X and p.P115R variants recapitulated barrier defects and Twist family BHLH transcription factor 1 activation in a bacteria-free environment. Twist family BHLH transcription factor 1 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 necrotizing enterocolitis and neonatal sepsis.
METHODS: Transgenic mice and preterm infant-derived enteroids expressing SIGIRR variants identified in necrotizing enterocolitis were used to define how single immunoglobulin interleukin1-related receptor regulates epithelial junctional protein assembly. An Escherichia coli strain identified in neonatal sepsis was used for functional evaluation of gut barrier function.
RESULTS: Neonatal mice harboring the SIGIRR p.Y168X mutation (Sigirrmu/mu), exhibited loss of epithelial junctional proteins, impaired barrier function, and activation of Twist family BHLH transcription factor 1 with exaggerated Toll-like receptor signaling. Sigirrmu/mu mice were highly susceptible to bacteremia when enterally challenged with pathogenic E coli. Pharmacologic inhibition of Twist family BHLH transcription factor 1 or genetic deletion of Toll-like receptor 4 restored barrier integrity. Preterm human enteroids expressing the SIGIRR p.Y168X and p.P115R variants recapitulated barrier defects and Twist family BHLH transcription factor 1 activation in a bacteria-free environment. Twist family BHLH transcription factor 1 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 necrotizing enterocolitis and neonatal sepsis.