Tongviratskool Chalonerat, Pongsakul Nutkridta, Kanaprach Pasinee, Supapannachart Sarayut, Nuntnarumit Pracha, Chutipongtanate Somchai
Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
OMICS. 2022 Aug;26(8):440-450. doi: 10.1089/omi.2022.0075. Epub 2022 Jul 27.
Breastfeeding reduces the risk of necrotizing enterocolitis (NEC), one of the most common causes of morbidity and mortality in preterm infants. However, the molecular substrates by which human milk (HM) offers protection against NEC are not well known. Using fetal intestinal epithelial cells treated with known NEC aggravators, namely lipopolysaccharide (LPS) and platelet-activating factor (PAF), we mapped the time-course of changes in targeted expression analysis of 35 NEC-associated genes, so-called the NEC signature. We found, first, that HM treatment fully rescued LPS/PAF-induced fetal intestinal cell death at 12 and 24 h ( = 5). Differential gene expression and bioinformatics revealed that HM did not mitigate inflammatory and cell death signals, but instead promoted cell proliferation and stress response pathways to mitigate LPS/PAF-induced inflammatory cell death. From this, epidermal growth factor (EGF) synthesis emerged as the central player in rescue of the fetal intestinal cell death. Functional validation was supported by reversal of the cellular rescue by HM following EGF knockdown by small interfering RNA. In conclusion, this study suggests that HM might offer protection against NEC through enhancing intestinal EGF production to rescue the inflammatory cell death. Future studies are warranted to verify these HM molecular protective effects in NEC models . The findings reported herein also support future research avenues to discover new therapeutics to boost intrinsic EGF production in the injured intestinal tissues in neonates with NEC, for example, by bioactive components in human milk, natural compounds, or small molecules.
母乳喂养可降低坏死性小肠结肠炎（NEC）的风险，NEC是早产儿发病和死亡的最常见原因之一。然而，人乳（HM）预防NEC的分子机制尚不清楚。我们用已知的NEC加重剂，即脂多糖（LPS）和血小板活化因子（PAF）处理胎儿肠上皮细胞，绘制了35个NEC相关基因靶向表达分析的时间变化过程，即所谓的NEC特征。首先，我们发现HM处理在12小时和24小时时能完全挽救LPS/PAF诱导的胎儿肠细胞死亡（=5）。差异基因表达和生物信息学分析表明，HM并没有减轻炎症和细胞死亡信号，而是促进了细胞增殖和应激反应途径，以减轻LPS/PAF诱导的炎症性细胞死亡。由此可见，表皮生长因子（EGF）合成是挽救胎儿肠细胞死亡的关键因素。小干扰RNA敲低EGF后，HM对细胞的挽救作用被逆转，这支持了上述功能验证。总之，本研究表明，HM可能通过增强肠道EGF的产生来挽救炎症性细胞死亡，从而预防NEC。未来有必要开展研究，在NEC模型中验证这些HM的分子保护作用。本文报道的研究结果也为未来的研究提供了方向，即探索新的治疗方法，例如通过人乳中的生物活性成分、天然化合物或小分子，来促进患有NEC的新生儿受损肠道组织中内源性EGF的产生。
