Radical cure
colitis is a severe public health threat worldwide. Our previous studies have confirmed that
melatonin can effectively improve gut microbiota disorder and mucosal injury caused by
sleep deprivation (SD). The present study further explored the mechanism whereby exogenous
melatonin prevented SD-induced
colitis.
16S rRNA high-throughput sequencing and metabolomics analysis were used to explore the correlation between SD-induced
colitis and intestinal microbiota and metabolite composition in mice.
Fecal microbiota transplantation (FMT) and
melatonin or
butyrate supplementation tests verified the core role of gut microbiota in
melatonin-alleviating SD-induced
colitis. Further, in vitro tests studied the modulatory mechanism of metabolite
butyrate. The results demonstrated that SD leads to reductions in plasma
melatonin levels and colonic Card9 expression and consequent occurrence of
colitis and gut microbiota disorder, especially the downregulation of Faecalibacterium and
butyrate levels. The FMT from SD-mice to normal mice could restore SD-like
colitis, while
butyrate supplementation to SD-mice inhibited the occurrence of
colitis, but with no change in the plasma
melatonin level in both treatments. However,
melatonin supplementation reversed all inductions in SD-mice. In intestinal epithelial cells, the inflammatory ameliorative effect of
butyrate was blocked with pretreatments of HDAC3 agonist and HIF-1α antagonist but was mimicked by GSK-3β and p-P65 antagonists. Therefore, the administration of MLT may be a better
therapy for SD-induced
colitis relative to
butyrate. A feasible mechanism would involve that
melatonin up-regulated the Faecalibacterium population and production of its metabolite
butyrate and MCT1 expression and inhibited HDAC3 in the colon, which would allow p-GSK-3β/β-
catenin/HIF-1α activation and NF-κB/NLRP3 suppression to up-regulate Card9 expression and suppress
inflammation response.