褪黑素通过调节肠道菌群来缓解小鼠的断奶压力

Title：
Melatonin alleviates weanling stress in mice: involvement of intestinal microbiota

DOI：
10.1111/jpi.12448

Abstract：
Melatonin influences intestinal microbiota, and the pathogenesis of various diseases. This study was conducted to explore whether melatonin alleviates weanling stress through intestinal microbiota in a weanling mouse model. Melatonin supplementation in weanling mice (provided in the drinking water at a dosage of 0.2mg/ml for 2 weeks) significantly improved body weight gain (1.4±0.03 g/day in melatonin group vs. 1.2±0.06 g/day in control group) and intestinal morphology [i.e., villus length (258.1±12.2 um in melatonin group vs. 219.5±5.5 um in control group), crypt depth (105.9±0.2 um in melatonin group vs. 119.3±3.6 um in control group) and villus to crypt ratio (2.5±0.03 in melatonin group vs. 1.8±0.06 in control group)], but had little effect on the proliferation or apoptosis of intestinal cells, the numbers of Paneth cells and goblet cells, as well as the expression of makers related to enterocytes (sucrase) and endocrine cells (chromogranin A and peptide YY) in the ileum. Melatonin supplementation had little effect on serum levels of amino acids or stress-related parameters (e.g., SOD, TNF-α, and angiotensin I). 16S rRNA sequencing suggested that melatonin supplementation increased the richness indices of intestinal microbiota (observed species, Chao 1 and ACE), and shaped the composition of intestinal microbiota [e.g., increase in the abundance of Lactobacillus (19±3% in melatonin group vs. 6±2% in control group)], which was demonstrated using an ex vivo proliferation assay and colonic loop proliferation assay. Melatonin supplementation also significantly influenced the metabolism of intestinal microbiota, such as amino acids metabolism and drug metabolism. More importantly, in antibiotic-treated weanling mice and germ-free weanling mice, melatonin failed to affect body weight gain or intestinal morphology. Melatonin significantly reduced (by about 60%) the bacterial load of enterotoxigenic Escherichia coli (ETEC)-infected weanling mice, but had little effect on ETEC load in antibiotic-pretreated animals. In conclusion, melatonin affects body weight gain, intestinal morphology, and intestinal ETEC infection through intestinal microbiota in weanling mice. The findings highlight the importance of intestinal microbiota in mediating the various physiological functions of melatonin in the host.

All Authors：
Wenkai Ren, Peng Wang, Jiameng Yan, Gang Liu, Benhua Zeng, Tarique Hussain, Can Peng, Jie Yin, Bie Tan, Tiejun Li, Hong Wei, Guoqiang Zhu, Russel J Reiter, Yulong Yin

First Authors：
Wenkai Ren

Correspondence：
Gang Liu, Bie Tan, Yulong Yin

摘要：

       给断奶小鼠补充褪黑素后，发现小鼠体重显著增加，且肠道形态、隐窝深度、绒毛/隐窝比得到显著改善；褪黑素对肠道细胞的增殖或凋亡、Paneth细胞及杯状细胞的数量、回肠中肠上皮细胞相关标记物（蔗糖酶）及内分泌细胞相关标记物（嗜铬粒蛋白A、YY肽）表达影响较小；对血清氨基酸及压力相关参数的影响较小；增加肠道菌群的丰度，并增加乳杆菌属的丰度，显著改变肠道菌群的氨基酸及药物代谢都表明了肠道菌群可能介导了褪黑素的上述作用。