Gut microbiota-derived metabolites mediates the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation

Background: Sleep loss is a serious global health concern, displaying not only well-known memory deficits but also gastrointestinal dysfunctions. Our previous research proved that melatonin can effectively improve cognitive impairment and intestinal microbiota disturbance caused by sleep deprivation (SD). Present study further explored the mechanism whereby exogenous melatonin prevented SD-induced cognitive impairment. Here, we established fecal microbiota transplantation, Aeromonas colonization and LPS or butyrate supplementation tests to evaluate the role of intestinal microbiota and its metabolites in melatonin alleviating SD-induced memory impairment.Results: We found that transplantation of the SD-gut microbiota into normal mice induced microglia overactivation and neuronal apoptosis in hippocampus, cognitive decline and colonic microbiota disorder, manifesting as an increase in Aeromonas and LPS levels and decrease in Lachnospiraceae_NK4A136 and butyrate levels. However, the above events were reversed as the transplanting the SD+melatonin-gut microbiota. Colonization of Aeromonas and addition of LPS caused inflammatory response in hippocampus and spatial memory impairment in the mice, whereas supplementation of melatonin reversed these changes accompanied by decreased in Aeromonas and LPS levels. Additionally, administration of butyrate was given to sleep-deprived mice, and the inflammatory responses and memory impairment was restored. In vitro, the supplementation of LPS caused inflammatory response in BV2 cells, but was improved by butyrate supplementation. In contrast, this ameliorative effect of butyrate was blocked with pretreatments of MCT1 inhibitor and HDAC3 agonist but was mimicked by TLR4 and p-P65 antagonists.Conclusions: Our studies demonstrated that gut microbial and their metabolites mediate the ameliorative effect of melatonin on SD-induced cognitive impairment. A feasible mechanism is that melatonin down-regulated the levels of Aeromonas and its LPS and up-regulated the levels of Lachnospiraceae_NK4A136 and its butyrate in colon, thereby improving inflammatory response and neuronal apoptosis in hippocampus by role of crosstalk between TLR4/NF-kB and MCT1/ HDAC3 signaling pathways.