Gut Microbiota Mediate Melatonin Signaling in Association With Type 2 Diabetes

OBJECTIVES: To investigate the association between serum melatonin (MT) and type 2 diabetes (T2D) risk in southern Chinese population in a case-control study as well as the role of gut microbiota in the relationship between them. METHODS: T2D cases and healthy controls (n = 2034) were recruited from a cross-sectional study and matched age and sex for a case-control study, and the association between serum MT and T2D 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 RNA was sequenced and metabolites were profiled using an untargeted LC-MS/MS approach. RESULTS: Higher levels of serum MT were significantly associated with a lower risk of T2D (OR = 0.84; 95% CI 0.75–0.93) and with lower levels of fasting glucose after adjustment for covariates (β = −0.21; 95% CI −0.33, −0.09). T2D patients exhibited lower levels of serum MT, lower α- and β-diversity of gut microbiota (p < 0.05), greater abundance of Bifidobacterium and lower abundance of Coprococcus (LDA > 2.0). Seven genera were correlated with MT and T2D related traits, among them Bifidobacterium was positively correlated with serum LPS and IL-10, whereas Coprococcus was negatively correlated with serum IL-1β, IL-6, IL-10, IL-17, INF-α and LPS (FDR < 0.05). Moreover, altered metabolites were detected in the T2D patients, and there was a significant correlation between tryptophan (Trp) metabolites and the melatonin-correlated genera including Bifidobacterium and Coprococcus (FDR < 0.05). A significant correlation also was found between Trp metabolites and inflammation factors, such as IL-1β, IL-6, IL-10, IL-17, INF-α and LPS (FDR < 0.05). Further, we showed that Trp metabolites may serve as a biomarker to predict T2D status (AUC = 0.804). CONCLUSIONS: Higher level of serum MT was associated with lower risk of T2D, and that gut microbiota-mediated MT signaling was involved in this association, especially, Bifidobacterium and Coprococcus mediated Trp metabolites may be involved in the process. These findings uncover the importance of MT and MT-related bacteria and metabolites as potential therapeutic targets for T2D. FUNDING SOURCES: This work was supported by the National Natural Science Foundation of China (No.82060593), Natural Science Foundation of Guangxi Province (No. 2018GXNSFDA050019).