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A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE

Jun Lin,Qixing Nie,Jie Cheng,Ya-Ni Zhong,Tianyao Zhang,Xiuying Zhang,Xiaoyan Ge,Yong Ding,Canyang Niu,Yuhua Gao,Kai Wang,Mingxin Gao,Xuemei Wang,Weixuan Chen,Chuyu Yun,Chuan Ye,Jinkun Xu,Weike Shaoyong,Lijun Zhang,Pan Shang,Xi Luo,Zhiwei Zhang,Xin Zheng,Xueying Sha,Jinxin Zhang,Shaoping Nie,Xuguang Zhang,Fazheng Ren,Huiying Liu,Erdan Dong,Xiao Yu,Linong Ji,Yanli Pang,Jin-Peng Sun,Changtao Jiang

Recently, microbial amino-acid-conjugated bile acids (MABAs) have been found to be prevalent in human samples. However, their physiological significance is still unclear. Here, we identify tryptophan-conjugated cholic acid (Trp-CA) as the most significantly decreased MABA in patients with type 2 diabetes (T2D), and its abundance is negatively correlated with clinical glycemic markers. We further demonstrate that Trp-CA improves glucose tolerance in diabetic mice. Mechanistically, we find that Trp-CA is a ligand of the orphan G protein-coupled receptor (GPCR) Mas-related G protein-coupled receptor family member E (MRGPRE) and determine the binding mode between the two. Both MRGPRE-Gs-cyclic AMP (cAMP) and MRGPRE-β-arrestin-1-aldolase A (ALDOA) signaling pathways contribute to the metabolic benefits of Trp-CA. Additionally, we find that the bacterial bile salt hydrolase/transferase of Bifidobacterium is responsible for the production of Trp-CA. Together, our findings pave the way for further research on MABAs and offer additional therapeutic targets for the treatment of T2D.