Document Type
Article
Publication Date
9-2026
Identifier
DOI: 10.1016/j.jcmgh.2026.101823; PMCID: PMC13380487
Abstract
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.
Journal Title
Cell Mol Gastroenterol Hepatol
Volume
20
Issue
9
First Page
101823
Last Page
101823
MeSH Keywords
Animals; Intestinal Barrier Function; Humans; Mice; Animals, Newborn; Mice, Transgenic; Receptors, Interleukin-1; Infant, Newborn; Intestinal Mucosa; Twist-Related Protein 1; Enterocolitis, Necrotizing; Infant, Premature; Signal Transduction; Escherichia coli; Neonatal Sepsis; Disease Models, Animal; Mutation; Toll-Like Receptor 4
PubMed ID
42248551
Keywords
Gut barrier; Neonatal intestine; Preterm human enteroids; SIGIRR; Sepsis; TLR signaling
Recommended Citation
Venkatraman A, Yu W, Menden HL, et al. Single Immunoglobulin Interleukin1-Related Receptor-TWIST1 Axis Regulates Barrier Function in Neonatal Intestine. Cell Mol Gastroenterol Hepatol. 2026;20(9):101823. doi:10.1016/j.jcmgh.2026.101823
Comments
Grants and funding
This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
Publisher's Link: https://www.cmghjournal.org/article/S2352-345X(26)00101-3/fulltext