In our previous study, we demonstrated that hypoglycemic agent DPP-4i changed the gut microbiota composition in diabetic patients and mice, and the DPP-4i-altered microbiome improved glucose tolerance in colonized mice. However, the mediators and their mechanisms remain to be elucidated. Comparing the intestinal metabolite profiles of HFD mice treated with or without sitagliptin (Sit) , we identified tryptophan derivative 5-methoxytryptomine (5-MT) was obviously increased after Sit treatment. In HFD and db/db mice, 5-MT treatment significantly reduced the body weight, improved glucose tolerance and insulin resistance, and ameliorated hepatic steatosis and inflammation. Drug affinity responsive target stability (DARTS) assay demonstrated the interaction between 5-MT and Aryl hydrocarbon receptor (AhR) . Specific inhibition of AhR attenuated the effects of 5-MT on improving insulin resistance. Furthermore, molecular mechanism exploration revealed that 5-MT promoted the expression and secretion of chemokine Cxcl14, which promoted macrophages maturation into alternative activation (M2-like) , subsequently inhibiting the production of inflammatory factors. These data demonstrate novel beneficial roles of 5-MT in improving obesity-related inflammation, insulin resistance and hepatic steatosis.
National Science Fund for Distinguished Young Scholars of China (No.81925007) , National Natural Science Foundation of China (No.81700757)