Melatonin ameliorates necrotizing enterocolitis by preventing Th17/Treg imbalance through activation of the AMPK/SIRT1 pathway

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. NEC was induced in 10-day-old C57BL/6 pups via hypoxia and gavage feeding of for...

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Bibliographic Details
Published in:Theranostics 2020-01, Vol.10 (17), p.7730-7746
Main Authors: Ma, Fei, Hao, Hu, Gao, Xiaoyan, Cai, Yao, Zhou, Jialiang, Liang, Puping, Lv, Junjian, He, Qiuming, Shi, Congcong, Hu, Dandan, Chen, Bowei, Zhu, Lixin, Xiao, Xin, Li, Sitao
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - metabolism
Animals
Animals, Newborn
Disease Models, Animal
Enterocolitis, Necrotizing - drug therapy
Enterocolitis, Necrotizing - immunology
Enterocolitis, Necrotizing - microbiology
Enterocolitis, Necrotizing - pathology
Experiments
Gastrointestinal diseases
Humans
Infant, Newborn
Intestinal Mucosa - drug effects
Intestinal Mucosa - immunology
Intestinal Mucosa - microbiology
Intestinal Mucosa - pathology
Intestine, Small - drug effects
Intestine, Small - immunology
Intestine, Small - microbiology
Intestine, Small - pathology
Lymphocytes
Melatonin
Melatonin - pharmacology
Melatonin - therapeutic use
Mice
Necrosis
Permeability
Research Paper
Signal Transduction - drug effects
Signal Transduction - immunology
Sirtuin 1 - metabolism
Small intestine
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Th17 Cells - drug effects
Th17 Cells - immunology
Umbilical cord
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Summary: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. 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. 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. 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.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.45862