MRGPRE is a G protein-coupled receptor expressed in enteroendocrine L cells that functions as a sensor for tryptophan-conjugated cholic acid (Trp-CA), a microbial amino-acid-conjugated bile acid 1. Ligand binding triggers conformational changes activating two parallel signaling cascades: a Gs-cAMP pathway via adenylate cyclase activation, and a β-arrestin-1-dependent pathway promoting ALDOA phosphorylation 1. Both pathways converge to enhance GLP-1 secretion, improving glucose tolerance and insulin secretion 1. Trp-CA levels are significantly decreased in type 2 diabetes patients and correlate inversely with glycemic markers, with Trp-CA administration improving glucose tolerance in diabetic mice 1. Bifidobacterium bile salt hydrolase/transferase enzymes produce Trp-CA, linking the microbiome-host axis to glucose homeostasis. Beyond metabolic function, epigenetic studies identify MRGPRE-associated DNA methylation patterns associated with lung function variation in Latino children with asthma 2 and BMI-related methylation in obesity 3, though mechanistic details remain unclear. MRGPRE has also emerged as a potential druggable target for migraine treatment 4.