α-Linolenic acid from Mori Folltfm found as Choloylglycine hydrolase inhibitor by the developed fluorescent probe to alleviate type 2 diabetes

Choloylglycine hydrolase (CH), also known as bile salt hydrolase, is expressed by intestinal microbiota and plays a key role in the hydrolysis of conjugated bile acids, influencing the composition and levels of various bile acids. In this study, a conjugate (CA-ACDI) of cholic acid and a semi-cyanine derivative was developed as an enzyme-activated fluorescent probe for detecting CH activity, showing potential applications in this area. By the high-throughput screening of CH activity using CA-ACDI, Mori Folium was identified as a significant CH inhibitor from a collection of 95 traditional herbal medicines. Further analysis using various chromatographic techniques and spectroscopic data identified α-linolenic acid as the key bioactive component in Mori Folium responsible for inhibiting CH activity. Importantly, α-Linolenic acid, as a natural CH inhibitor, was shown to significantly regulate glucose metabolism in a type 2 diabetes mellitus (T2DM) mouse model via the FXR signaling pathway. This work not only developed a novel fluorescent probe for CH detection but also discovered potential CH inhibitors that may help alleviate type 2 diabetes.