P041 Melatonin controls microbiota in colitis through Toll-like receptor 4 signalling

Abstract

Abstract Background Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Methods Colitis was induced in 8-week-old wild-type (WT) and TLR4 KO mice by administration of 2.5% dextran sulphate sodium (DSS) in drinking water and intraperitoneal (i.p.) treatment with melatonin (Mel) or vehicle (Veh). Body weight changes were monitored daily. Results DSS-treatment for 10 days significantly increased body weight loss in the vehicle-treated group of both wild-type and TLR4 KO mice. Melatonin improved dextran sulphate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3β, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Conclusion we showed that melatonin significantly increases goblet cells, Reg3β and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for IBD.