On May 29, 2025, Professor Sun Jinpeng's team and Professor Yu Xiao's team at Shandong University, collaborating with Professor Jiang Changtao from Peking University, Professor Pang Yanli, and Professor Ji Linong, 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.

This study revealed the physiological and pathophysiological functions of a novel microbial-derived amino acid-conjugated bile acid, tryptophan-cholic acid (Trp-CA). It identified the membrane receptor for Trp-CA as MRGPRE. It elucidated the novel mechanism by which Trp-CA activates MRGPRE, promoting GLP-1 secretion through dual pathways: Gs-cAMP signaling and β-arrestin-1-mediated ALDOA phosphorylation, thereby improving glucose metabolism. This work provides a new paradigm for understanding the functions and molecular mechanisms of novel microbial bile acids. It offers new targets and strategies for the development of therapies against metabolic diseases.

Fig 1 Trp-CA Negatively Correlates with Clinical Glycemic Markers

Using untargeted metabolomics analysis, the study quantified microbial amino acid-bile acid conjugates (MABAs) in fecal samples from diabetic patients and healthy individuals. They found that Trp-CA was significantly decreased in diabetic patients, and its levels negatively correlated with fasting blood glucose (FBG), glycosylated hemoglobin A1c (HbA1c), and body mass index (BMI). This suggests that Trp-CA may play a critical role in the development and progression of diabetes. The study also showed that oral gavage of Trp-CA significantly improved glucose intolerance in mice fed a high-fat diet. Using acute perfusion and clamp tests in the portal vein, duodenum, and colon, only intestinal perfusion of Trp-CA significantly stimulated both the first and second phases of insulin secretion and suppressed hepatic gluconeogenesis. This indicates that Trp-CA exerts its glucose-regulating effects by acting on receptors within the intestinal tissue.

Fig 2 Trp-CA Improves Glucose Metabolism by Activating Gαs / β-arrestin-1 Pathways Downstream of MRGPRE.

Trp-CA does not activate traditional bile acid receptors (such as TGR5, FXR, etc.) but does increase cAMP levels, a key second messenger, in the small intestine. The study systematically screened GPCRs highly expressed in intestinal tissue and discovered that Trp-CA specifically activates the orphan receptor Mas-related G protein-coupled receptor E (MRGPRE). MRGPRE belongs to the Mas-related gene family, often associated with itch sensation. However, existing research found it does not induce itch, and its physiological function has long remained unknown. Using both whole-body and intestine-specific MRGPRE knockout mouse models, the study confirmed that Trp-CA's glucose-regulating effects depend on the MRGPRE receptor. Further investigation revealed that Trp-CA synergistically promotes GLP-1 secretion and improves glucose metabolism through dual signaling pathways: the Gαs-cAMP cascade and β-arrestin-1-mediated phosphorylation of ALDOA.

This study is the first to reveal that the microbial-derived bile acid Trp-CA improves glucose homeostasis by activating MRGPRE. It provides a new potential drug target and therapeutic strategy for Type 2 Diabetes (T2D) treatment. Furthermore, the identification of the microbial origin of Trp-CA offers a new microbial therapeutic strategy for diabetes intervention.