Melatonin alleviates weanling stress in mice: Involvement of intestinal microbiota

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 0.2 mg/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 (ie, villus length, crypt depth, and villus to crypt ratio), 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 (eg, 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 (eg, 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 acid 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 in 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.

Melatonin reprogramming of gut microbiota improves lipid dysmetabolism in high‐fat diet‐fed mice

“…Our previous study found that melatonin treatment in healthy mice significantly decreased the relative abundance of Bacteroidales and increased the relative abundance of Lactobacillales , which is in contrast with the current study that melatonin enhanced Bacteroidales level but reduced Lactobacillales abundance in HF diet‐fed mice (Figure ). Indeed, microbiota transplantation from melatonin‐treated mice tended to increase the relative abundance of Firmicutes but decrease Bacteroidetes ( P > 0.05) and Actinobacteria ( P < 0.05) at the phylum level (Figure ).…”

“…At the genus level, Lactobacillus is decreased, but Bacteroides , Alistipes , and Parasutterella are increased in response to melatonin exposure. Our previous study found that microbiota deficiency by antibiotics treatment reverses melatonin‐mediated improvements of body weight gain, intestinal morphology, and intestinal enterotoxigenic Escherichia coli infection in weaning mice . However, antibiotics exposure in this study fails to block the anti‐obese effect of melatonin in HF diet‐fed mice.…”

“…We and others have previously shown that gut microbiota are sensitive to melatonin exposure and melatonin treatment markedly shapes or reverses gut microbiota in healthy or obese animal models . In these studies, however, no direct evidence was obtained to support that gut microbiota mediate the melatonin‐induced beneficial potentials.…”

“…Mice in MelHF group received the HF diet and drinking water supplemented with 0.4 mg/mL melatonin (Sangon Biotech, Shanghai, China, directly diluted in drinking water) at a double dosage of our previous as we found 0.2 mg/mL melatonin failed to affect gut development in older mice (data not show) and 1 mg/mL melatonin improved host lipid metabolism, gut health, and allergy status in pig and murine models (J. Yin, H. Han, Y. Li, W. Ren, G. Liu, X. Wu, T. Li & Y. Yin, unpublished data). According to our previous study, average 8.10 ± 0.71 mL/d melatonin water was drunk per mouse; thus, the approximate intake of melatonin might be about 108 mg/kg BW/d in this study. The melatonin water was prepared daily and kept in a normal bottle with an aluminum foil cover to prevent light‐induced degradation of melatonin.…”

Role of melatonin in sleep deprivation‐induced intestinal barrier dysfunction in mice

“…Improvements in intestinal barrier dysfunction were substantial at the high dose (40.0 mg/kg) of MT supplementation (SD + 2MT group). Previous studies have reported that MT treatment significantly changes the richness, diversity and composition of the gut microbiota in both murine models of obesity and weanling stress . These results indicate that MT suppression plays a crucial role in SD‐induced intestinal homoeostasis disorder.…”