Trp-CA Activates MRGPRE to Regulate Glucose Metabolism
On May 29, 2025, Professor Jiang Changtao of Peking University and his team of collaborators published a research paper entitled "A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE" in Cell.
The study revealed the physiological and pathophysiological functions of the novel microbial amino-acid-conjugated bile acids (MABAs), tryptophan-conjugated cholic acid (Trp-CA), identified the membrane receptor MRGPRE of Trp-CA, and deeply analyzed the new mechanism by which Trp-CA activates MRGPRE to promote GLP-1 secretion through Gs-cAMP and β-arrestin-1-ALDOA Phosphorylation. This work provides a new paradigm for the analysis of the function and molecular mechanism of novel bacterial bile acids, and provides new targets and strategies for the development of drugs for metabolic diseases.
Fig. 1 Trp-CA improves glucose homeostasis via the orphan receptor MRGPRE. (Lin, et al., 2025)
This study used non-targeted metabolomics to analyze the content of MABAs in the stool of diabetic patients and healthy people, and found that Trp-CA was significantly decreased in diabetic patients, and its level was negatively correlated with fasting blood sugar, glycated hemoglobin A1c and body mass index. This suggests that Trp-CA may play a key role in the occurrence and development of diabetes.
This study found that oral administration of Trp-CA significantly improved the abnormal Glucose Tolerance of mice induced by a high-fat diet. Through acute perfusion and clamp experiments of Trp-CA in vein, duodenum and colon, only intestinal perfusion of Trp-CA can significantly promote the first and second phase secretion of insulin and inhibit hepatic gluconeogenesis, suggesting that Trp-CA acts on the receptors of intestinal tissue to regulate blood sugar.
Trp-CA does not activate traditional bile acid receptors (such as TGR5, FXR, etc.), but can cause an increase in the level of cAMP, a second messenger in the small intestine. Therefore, this study systematically screened GPCRs highly expressed in intestinal tissues and found that Trp-CA specifically activated the orphan receptor Mas-related G protein-coupled receptor family member E (MRGPRE). MRGPRE belongs to the itch receptor family, but existing studies have found that it does not activate itch, and its physiological function has not been elucidated for a long time.
Through systemic and intestinal tissue-specific MRGPRE knockout mouse models, this study confirmed that the glucose regulation effect of Trp-CA depends on the MRGPRE receptor. Further studies revealed that Trp-CA synergistically promotes GLP-1 secretion and improves glucose metabolism through dual pathways of Gαs-cAMP and β-arrestin-1/ALDOA phosphorylation.
This study revealed for the first time the mechanism of action of bacterial bile acid Trp-CA in improving glucose homeostasis by activating MRGPRE, providing new potential drug targets and therapeutic strategies for T2D treatment. The study also discovered the microbial source of Trp-CA, providing a new microbial therapy strategy for diabetes intervention.
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