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

Abstract

Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep‐deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down‐regulation of anti‐inflammatory cytokines and up‐regulation of pro‐inflammatory cytokines in sleep‐deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen‐positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p‐P65 and p‐IκB. High‐throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep‐deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD‐induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD‐induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF‐κB pathway by oxidative stress.

Impact of Melatonin on Skeletal Muscle and Exercise

“…Finally, sleep deprived mice showed reduced gut microbiota and limited probiotic species such as Bacteroides, Akkermasia, and Faecalibacterium [235]. Interestingly, in this animal model, melatonin reversed abnormal microbiota composition, indicating that sleep deprivation might reduce local melatonin secretion and melatonin type-1 receptor activity in the gut.…”

Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling

“…Recent experiments have shown that melatonin also acts as an immune system modulator 7 and ameliorates DSS colitis in mice 8,9 . Numerous studies have indicated that melatonin affects the permeability, motility, and barrier function of the intestine 10,11 . Melatonin treatment can improve GI tract diseases, such as irritable bowel syndrome 12 , IBD 13 , and necrotizing enterocolitis 14 , suggesting it has a critical role in the physiologic function of the GI tract.…”

“…The GI tract is also the largest source of enzymes for melatonin production 16 , and melatonin receptors are highly expressed in the GI tract, suggesting that melatonin affects the immune response and the microbiota. Recent studies reported that melatonin increases the ratio of Firmicutes to Bacteroidetes and Akkermania 10 and suppresses pathogenic bacteria 17 in the intestine. Despite this knowledge, the pivotal signal pathway for the anti-colitic effect of melatonin and the exact mechanism for control of the intestinal microbiota remains unknown.…”

Melatonin regulates the neurotransmitter secretion disorder induced by caffeine through the gut-brain axis in zebrafish (Danio rerio)

“…There is growing evidence suggesting that the gut microbiota produce and release many similar neurotransmitters to help regulate mood and promote sleep, while possibly affecting the CNS through the gutbrain axis [9,17] . In addition to the variation in the levels of neurotransmitters, the structure of the zebrafish intestinal microbiota is disordered after caffeine induction, potentially indicating that the imbalance of the intestinal microbiota may be related to the disorder of neurotransmitters.…”