Melatonin-induced restoration of the intestinal mucosal barrier in inflammatory bowel disease via activation of the SIRT1-LKB1-pAMPK axis.

BACKGROUND

Numerous studies indicated inflammatory bowel disease (IBD) patients suffered from sleep disturbances. Although melatonin (MT) exerts positive effects on maintaining circadian rhythms and anti-inflammation, its impact on the gut microbiome and its function in mediating gut health remain largely unexplored. To evaluate the efficacy and investigate the mechanisms of MT in repairing the intestinal mucosal barrier in IBD.

METHODS

Fecal MT and its metabolites in IBD patients were detected. A DSS-induced colitis mice model and a LPS-stimulated NCM460 cell inflammation model were used to explore the mechanism of melatonin in IBD.

RESULTS

IBD patients had lower levels of serum MT and fecal 2-oxomelatonin. Furthermore, MT enhances intestinal antimicrobial peptides and effectively alleviates colitis. Mechanistically, MT restored the abundance of the probiotic Akkermansia and decreased the conditional pathogen Desulfovibrio. MT upregulates the SIRT1 (Sirtuin 1) and pAMPK (phosphorylated AMP-Activated Protein Kinase) in mouse colonic tissues. Whereas Ex-527 (the SIRT1 inhibitor) and Compound C (the pAMPK inhibitor) abolished the protective effects of MT in DSS mice. In LPS-stimulated cells, the inhibitor blocked the regulation of MT on proinflammatory factors, antimicrobial peptides and tight junctions. Mechanistically, MT was associated with activation of the SIRT1-LKB1-pAMPK pathway, suggesting its potential involvement in regulating the above changes.

CONCLUSION

Our findings suggest that MT may ameliorate colitis by regulating gut microbiota, modulating antimicrobial peptide secretion, and reinforcing intestinal epithelial barrier integrity potentially via activation of the SIRT1-LKB1-pAMPK axis.