Tryptophan-conjugated cholic acid

Tryptophan-conjugated cholic acid (Trp-CA), a novel microbial amino-acid-conjugated bile acid, is an endogenous ligand for orphan GPCR MRGPRE (Mas-related G protein-coupled receptor family member E), revealing a non-itch glucose-regulatory function. CA-Trp activates MRGPRE (10 µM), initiating intestinal L-cell GLP-1 secretion via dual Gs-cAMP (EC50 = 9.6 µM) and β-arrestin-1-ALDOA pathways. The latter involves β-arrestin-1 recruitment and ALDOA phosphorylation. In vivo, oral Trp-CA improves glucose tolerance and ameliorates obesity in HFD-fed diabetic mice, highlighting its potential as a gut-localized T2D therapeutic.