Core Viewpoint - The research identifies a novel bile acid receptor, MRGPRE, activated by a microbial amino-acid-conjugated bile acid, tryptophan-cholic acid (Trp-CA), which plays a significant role in glucose homeostasis and offers new targets for drug development in metabolic diseases like type 2 diabetes [3][4][5]. Group 1: Discovery of Trp-CA and MRGPRE - The study reveals that Trp-CA is significantly reduced in type 2 diabetes (T2D) patients, with its abundance negatively correlated with clinical blood glucose indicators [5]. - Trp-CA improves glucose tolerance in diabetic mice, indicating its potential therapeutic effects [5]. - Unlike traditional bile acids that activate FXR and TGR5 receptors, Trp-CA specifically activates the orphan G protein-coupled receptor (GPCR) MRGPRE [5][6]. Group 2: Mechanism of Action - The research elucidates the mechanism by which Trp-CA regulates GLP-1 secretion through two pathways: MRGPRE-Gs-cAMP and MRGPRE-β-arrestin-1-ALDOA, with the latter being a previously unknown mechanism [6][8]. - GLP-1 is known to promote insulin secretion, thereby contributing to blood glucose regulation [6]. Group 3: Implications for Drug Development - The findings provide a new paradigm for understanding the physiological significance of microbial-derived bile acids and pave the way for further research on amino-acid-conjugated bile acids (MABA) [4][8]. - The study suggests that Trp-CA could lead to the development of new glucose-lowering drugs without the side effect of itchiness associated with traditional bile acids [8].