Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants. Mounting evidence supports the therapeutic effect of melatonin on NEC, although the underlying mechanisms remain unclear./nMethods: NEC was induced in 10-day-old C57BL/6 pups via hypoxia and gavage feeding of formula containing enteric bacteria, and then, mice received melatonin, melatonin + recombinant IL-17, melatonin + anti-CD25 monoclonal antibody, melatonin + Ex-527, or melatonin + Compound C treatment. Control mice were left with their dams to breastfeed and vehicle-treated NEC pups were used as controls for treatment. Ileal tissues were collected from mice and analyzed by histopathology, immunoblotting, and flow cytometry. FITC-labeled dextran was administered to all surviving pups to evaluate gut barrier function by fluorometry. We used molecular biology and cell culture approaches to study the related mechanisms in CD4⁺ T cells from umbilical cord blood./nResults: We demonstrated that melatonin treatment ameliorates disease in an NEC mouse model in a manner dependent on improved intestinal Th17/Treg balance. We also showed that melatonin blocks the differentiation of pathogenic Th17 cells and augments the generation of protective Treg cells in vitro. We further demonstrated that the Th17/Treg balance is influenced by melatonin through activation of AMPK in the intestine, in turn promoting SIRT1 activation and stabilization./nConclusions: These results demonstrate that melatonin-induced activation of AMPK/SIRT1 signaling regulates the balance between Th17 and Treg cells and that therapeutic strategies targeting the Th17/Treg balance via the AMPK/SIRT1 pathway might be beneficial for the treatment of NEC.

中文翻译：

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褪黑素通过激活AMPK / SIRT1途径来防止Th17 / Treg失衡，从而改善坏死性小肠结肠炎。

坏死性小肠结肠炎（NEC）是一种严重的胃肠道疾病，会影响早产儿。越来越多的证据支持褪黑激素对NEC的治疗作用，尽管其潜在机制尚不清楚。通过缺氧和强饲喂食含有肠细菌的配方奶，在10日龄的C57BL / 6幼崽中诱导NEC，然后，小鼠接受褪黑素，褪黑素+重组IL-17，褪黑素+抗CD25单克隆抗体，褪黑素+ Ex- 527，或褪黑素+化合物C处理。将对照小鼠的母坝留给母乳喂养，并用媒介物处理的NEC幼仔作为对照。从小鼠收集回肠组织，并通过组织病理学，免疫印迹和流式细胞术进行分析。将FITC标记的葡聚糖施用于所有存活的幼崽，以通过荧光测定法评估肠屏障功能。我们用分子生物学和细胞培养方法来研究CD4的相关机制⁺脐带blood./n T细胞的结果：我们证明褪黑激素治疗可以改善肠道Th17 / Treg平衡，从而改善NEC小鼠模型的疾病。我们还显示，褪黑素可阻断致病性Th17细胞的分化并增加体外保护性Treg细胞的生成。我们进一步证明Th17 / Treg平衡受褪黑素通过激活肠内AMPK的影响，进而促进SIRT1激活和稳定。/n结论：这些结果表明褪黑素诱导的AMPK / SIRT1信号传导调节了两者之间的平衡。 Th17和Treg细胞以及通过AMPK / SIRT1途径靶向Th17 / Treg平衡的治疗策略可能对NEC的治疗有益。