Gut microbiota mediate melatonin signalling in association with type 2 diabetes

Aims/hypothesis It has been shown that melatonin plays a general beneficial role in type 2 diabetes in rodents but its role in humans is controversial. In the present study, we investigated the association between serum melatonin and type 2 diabetes risk in a southern Chinese population in a case–control study. We also examined the role of gut microbiota in this relationship. Methods Individuals with type 2 diabetes (cases) and healthy individuals (controls) ( n =2034) were recruited from a cross-sectional study and were matched for age and sex in a case–control study. The levels of serum melatonin were measured and the association between serum melatonin and type 2 diabetes risk was examined using a multivariable logistic regression model. We further conducted a rigorously matched case–control study ( n =120) in which gut microbial 16S rRNA was sequenced and metabolites were profiled using an untargeted LC-MS/MS approach. Results Higher levels of serum melatonin were significantly associated with a lower risk of type 2 diabetes (OR 0.82 [95% CI 0.74, 0.92]) and with lower levels of fasting glucose after adjustment for covariates (β −0.25 [95% CI −0.38, −0.12]). Gut microbiota exhibited alteration in the individuals with type 2 diabetes, in whom lower levels of serum melatonin, lower α- and β-diversity of gut microbiota (p <0.05), greater abundance of Bifidobacterium and lower abundance of Coprococcus (linear discriminant analysis [LDA] >2.0) were found. Seven genera were correlated with melatonin and type 2 diabetes-related traits; among them Bifidobacterium was positively correlated with serum lipopolysaccharide (LPS) and IL-10, whereas Coprococcus was negatively correlated with serum IL-1β, IL-6, IL-10, IL-17, TNF-α and LPS (Benjamini–Hochberg-adjusted p value [false discovery rate (FDR)] <0.05). Moreover, altered metabolites were detected in the participants with type 2 diabetes and there was a significant correlation between tryptophan (Trp) metabolites and the melatonin-correlated genera including Bifidobacterium and Coprococcus (FDR<0.05). Similarly, a significant correlation was found between Trp metabolites and inflammation factors, such as IL-1β, IL-6, IL-10, IL-17, TNF-α and LPS (FDR<0.05). Further, we showed that Trp metabolites may serve as a biomarker to predict type 2 diabetes status (AUC=0.804). Conclusions/interpretation A higher level of serum melatonin was associated with a lower risk of type 2 diabetes. Gut microbiota-mediated melatonin signalling was involved in this association; especially, Bifidobacterium - and Coprococcus -mediated Trp metabolites may be involved in the process. These findings uncover the importance of melatonin and melatonin-related bacteria and metabolites as potential therapeutic targets for type 2 diabetes. Graphical abstract