Abstract
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. Melatonin improved dextran sulfate 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. Herein, 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.
Highlights
Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD)
To explore the involvement of TLR4 signalling in the anti-colitic effects of melatonin in vivo, colitis was induced in 8-week-old wild type (WT) and TLR4 KO mice by administration of 2.5% dextran sulfate sodium (DSS) in drinking water and intraperitoneal (i.p.) treatment with melatonin (Mel) or vehicle (Veh)
There were no significant differences in body weights between DSS + Veh and DSS + Mel groups (Fig. S1a,b), melatonin improved the disease activity index (DAI) (Fig. 1a,b) and attenuated shortening of the colon (Fig. 1c,d) only in wild type mice but not in TLR4 KO mice
Summary
Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). 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. Recent studies reported that melatonin increases the ratio of Firmicutes to Bacteroidetes and Akkermania[10] and suppresses pathogenic bacteria[17] in the intestine. Despite this knowledge, the pivotal signal pathway for the anti-colitic effect of melatonin and the exact mechanism for control of the intestinal microbiota remains unknown. We explored the effects on microbiota dysbiosis and antimicrobial peptide (AMP) regulation of melatonin in colitis
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