DOP44 Melatonin Ameliorates Colitis In DSS-fed Mice Via The SIRT1 Pathway

Abstract Background Melatonin is an amine hormone with high content in gastrointestinal tract, which plays a positive role in anti-inflammatory. Intestinal microbiota imbalance and intestinal immune damage caused by colitis are often accompanied by a decrease in endogenous melatonin. However, whether melatonin supplementation improves colitis, and the mechanism is unclear. Methods The study focused on melatonin treatment of colitis in dextran sodium sulfate(DSS)-fed mice and analyzed the mechanism multidimensionally by quantitative real-time PCR, western blotting, immunofluorescence, 16s-rDNA, and mRNA-seq. Results The weight, colon length, and microscopic structure of the colonic crypts were improved in DSS-fed mice after melatonin supplementation. Tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and IL-6 were significantly elevated in colon tissues of the DSS group, and this result was down-regulated in the melatonin group. Tight junction proteins(ZO-1 and occludin) in the colonic mucosa were significantly decreased in the DSS group, and improved in the melatonin group. In terms of antimicrobial peptides, melatonin supplementation significantly increased levels of defa-3, defa-4, and CRAMP. Surprisingly, our study found increased expression of SIRT1 protein in the intestinal tissues of the melatonin group. After the addition of Ex-527, a SIRT1 inhibitor, the protective effect of melatonin on DDS-fed mice disappeared, and tight junction proteins did not differ from those of the DSS group. In addition, fecal 16s-rRNA results in the control, DSS, and melatonin groups suggested some differences. The DSS group had an increase in α-diversity (Shannon's Diversity Index) and a decrease in β-diversity (PCoA) in comparison to the control group, and all of these changes were reversed in the melatonin group, but there was no significance between the three groups. At the phylum level, Firmicutes were significantly increased in the DSS-fed group, and the melatonin group reversed this change. At the genus level, the abundance of Akkermansia was decreased in the DSS group and increased with melatonin supplementation. While the abundance of Desulfovibrio, a pathogenic genus was increased in the DSS group and decreased with melatonin supplementation. Colon tissue mRNA-seq identified a number of possible pathogenic and therapeutic pathways, such as Slc7a2, a cationic amino acid transporter. Conclusion The study suggests that melatonin modulates the intestinal mucosal barrier through the SIRT1 pathway to alleviate colitis.