Wiemers Thomas C, Riedel Jan, Dressler Niklas, Feng Xiaoyan, Peukert Nicole, Lacher Martin, Mayer Steffi
Department for Pediatric Surgery, University Hospital of Leipzig, Leipzig, Saxony, Germany.
Pediatr Res. 2025 Jul 21. doi: 10.1038/s41390-025-04262-z.
The gastrointestinal tract is particularly vulnerable to strong inflammatory responses during early development as seen in preterm infants with necrotizing enterocolitis (NEC). Intestinal maturation plays a crucial role in the pathogenesis of this condition.
Given the limited availability of human samples across different stages of gastrointestinal maturation, this study utilised a murine model that closely mirrors the fetal, preterm, term, and adult stages of human development. We investigated baseline and lipopolysaccharide (LPS)-induced inflammatory responses in isolated primary intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs).
IECs displayed greater sensitivity to LPS at early developmental stages, with reduced responsiveness as maturation progressed. In contrast, IELs exhibited inflammatory reactivity only at later stages. Regulation of phosphorylated p65 in both cell populations highlighted the role of the TLR-4/NFĸB pathway in these maturation-dependent responses.
A proinflammatory shift in key epithelial cell populations was observed, reflecting the development of the gastrointestinal system. These findings enhance the understanding of NEC pathogenesis and provide translational insights into intestinal inflammatory responses during maturation.
Intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) exhibit contrasting inflammatory responses during gastrointestinal maturation, with IECs being more reactive in early stages and IELs becoming reactive later. This study provides a detailed correlation between human and murine intestinal development, offering insights into maturation-dependent inflammatory mechanisms and the role of the TLR-4/NFĸB pathway. Our findings enhance understanding of gastrointestinal maturation and its role in inflammatory diseases like necrotizing enterocolitis (NEC).
胃肠道在早期发育过程中特别容易受到强烈炎症反应的影响，如坏死性小肠结肠炎（NEC）的早产儿所见。肠道成熟在这种疾病的发病机制中起着关键作用。
鉴于不同胃肠道成熟阶段的人类样本有限，本研究利用了一种小鼠模型，该模型密切反映了人类发育的胎儿、早产、足月和成人阶段。我们研究了分离的原代肠上皮细胞（IECs）和上皮内淋巴细胞（IELs）的基线和脂多糖（LPS）诱导的炎症反应。
IECs在早期发育阶段对LPS表现出更高的敏感性，随着成熟进程反应性降低。相比之下，IELs仅在后期表现出炎症反应性。两个细胞群体中磷酸化p65的调节突出了TLR-4/NFκB途径在这些成熟依赖性反应中的作用。
观察到关键上皮细胞群体的促炎转变，反映了胃肠道系统的发育。这些发现增强了对NEC发病机制的理解，并为成熟过程中的肠道炎症反应提供了转化见解。
肠上皮细胞（IECs）和上皮内淋巴细胞（IELs）在胃肠道成熟过程中表现出相反的炎症反应，IECs在早期更具反应性，IELs在后期变得有反应性。本研究提供了人与小鼠肠道发育之间的详细相关性，深入了解成熟依赖性炎症机制以及TLR-4/NFκB途径的作用。我们的发现增强了对胃肠道成熟及其在坏死性小肠结肠炎（NEC）等炎症性疾病中作用的理解。
