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

doi:10.1016/j.cell.2025.05.010

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

School of Life Science and Health

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	4530-4548.e25
Journal	Cell
Volume	188
Issue number	17
DOIs	https://doi.org/10.1016/j.cell.2025.05.010
State	Published - 21 Aug 2025

Keywords

GPCR
bile acids
microbiota
type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2025.05.010

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Lin, J., Nie, Q., Cheng, J., Zhong, Y. N., Zhang, T., Zhang, X., Ge, X., Ding, Y., Niu, C., Gao, Y., Wang, K., Gao, M., Wang, X., Chen, W., Yun, C., Ye, C., Xu, J., Shaoyong, W., Zhang, L., ... Jiang, C. (2025). A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE. Cell, 188(17), 4530-4548.e25. https://doi.org/10.1016/j.cell.2025.05.010

@article{ec9d9b6b0f5e484bacd3e121a898e689,

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

abstract = "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.",

keywords = "GPCR, bile acids, microbiota, type 2 diabetes",

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

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = aug,

day = "21",

doi = "10.1016/j.cell.2025.05.010",

language = "英语",

volume = "188",

pages = "4530--4548.e25",

journal = "Cell",

issn = "0092-8674",

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Lin, J, Nie, Q, Cheng, J, Zhong, YN, Zhang, T, Zhang, X, Ge, X, Ding, Y, Niu, C, Gao, Y, Wang, K, Gao, M, Wang, X, Chen, W, Yun, C, Ye, C, Xu, J, Shaoyong, W, Zhang, L, Shang, P, Luo, X, Zhang, Z, Zheng, X, Sha, X, Zhang, J, Nie, S, Zhang, X, Ren, F, Liu, H, Dong, E, Yu, X, Ji, L, Pang, Y, Sun, JP & Jiang, C 2025, 'A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE', Cell, vol. 188, no. 17, pp. 4530-4548.e25. https://doi.org/10.1016/j.cell.2025.05.010

TY - JOUR

T1 - A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE

AU - Lin, Jun

AU - Nie, Qixing

AU - Cheng, Jie

AU - Zhong, Ya Ni

AU - Zhang, Tianyao

AU - Zhang, Xiuying

AU - Ge, Xiaoyan

AU - Ding, Yong

AU - Niu, Canyang

AU - Gao, Yuhua

AU - Wang, Kai

AU - Gao, Mingxin

AU - Wang, Xuemei

AU - Chen, Weixuan

AU - Yun, Chuyu

AU - Ye, Chuan

AU - Xu, Jinkun

AU - Shaoyong, Weike

AU - Zhang, Lijun

AU - Shang, Pan

AU - Luo, Xi

AU - Zhang, Zhiwei

AU - Zheng, Xin

AU - Sha, Xueying

AU - Zhang, Jinxin

AU - Nie, Shaoping

AU - Zhang, Xuguang

AU - Ren, Fazheng

AU - Liu, Huiying

AU - Dong, Erdan

AU - Yu, Xiao

AU - Ji, Linong

AU - Pang, Yanli

AU - Sun, Jin Peng

AU - Jiang, Changtao

PY - 2025/8/21

Y1 - 2025/8/21

N2 - 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.

AB - 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.

KW - GPCR

KW - bile acids

KW - microbiota

KW - type 2 diabetes

UR - https://www.scopus.com/pages/publications/105006939504

U2 - 10.1016/j.cell.2025.05.010

DO - 10.1016/j.cell.2025.05.010

M3 - 文章

C2 - 40446798

AN - SCOPUS:105006939504

SN - 0092-8674

VL - 188

SP - 4530-4548.e25

JO - Cell

JF - Cell

IS - 17

ER -

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

Abstract

Keywords

UN SDGs

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