Anti-diabetic effect of di-caffeoylquinic acid is associated with the modulation of gut microbiota and bile acid metabolism

Abstract

Abstract Background The human gut microbiome plays a critical role in both health and disease. A classic example of host-gut microbial co-metabolism involves bile acids, which biosynthesis in liver are excreted into the intestine where they are deconjugated and transformed by the gut microbiota, this process, in turn, activates signaling pathways, influencing host glycolipid and energy metabolism. Ilex tea exhibits properties that alleviate disruptions in lipid metabolism and inflammation by modulating the gut microbiota, yet the underlying mechanism remains unelucidated. DiCQAs is one of the most active and abundant polyphenolic pigments in Ilex tea. Here, we investigated diCQAs regulate diabetes through the BA-related pathway, using HFD + STZ-induced diabetic mice model and long-term mice group to exclude direct stimulatory effects, and studied gut microbiota structure and functions in mice. Results Here, we show that diCQAs alleviating symptoms of diabetic mice by alters gut microbiota carrying the BSH gene which associated with obesity and diabetes mellitus. DiCQAs protecting the intestinal barrier while increased enterohepatic circulation conjugated BAs, inhibited the FXR-FGF15 signaling axis in the ileum decreased hepatic FGFR4 protein expression, increased bile acid synthesis in liver, increased BA efflux to reduces hepatic BA stasis, decreased hepatic and plasma cholesterol levels. Moreover, diCQAs induce an upregulation of glucolipid metabolism-related proteins in the liver and muscle (AKT/GSK3β, AMPK), ultimately alleviating hyperglycemia. Additionally, they reduce inflammation by down-regulating the MAPK signaling pathway in the diabetic group. Conclusions Our findings provide insights into the mechanisms underlying the anti-diabetic effects of ilex tea. They suggest that reducing gut microbiota (specifically Acetatifactor sp011959105 and Acetatifactor muris) carrying the BSH gene could potentially serve as an anti-diabetic therapy by decreasing FXR-FGF15 signaling.