A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE.
Summary
This study identifies tryptophan-conjugated cholic acid (Trp-CA) as a microbiome-derived bile acid reduced in type 2 diabetes, inversely associated with glycemic markers, and capable of improving glucose tolerance in diabetic mice. Trp-CA directly activates the orphan GPCR MRGPRE, engaging Gs–cAMP and β-arrestin-1–ALDOA signaling. Bifidobacterium enzymes generate Trp-CA, highlighting a tractable host–microbe metabolic axis.
Key Findings
- Trp-CA is significantly decreased in patients with type 2 diabetes and negatively correlates with glycemic markers.
- Trp-CA improves glucose tolerance in diabetic mouse models.
- MRGPRE is identified as a receptor for Trp-CA, with defined binding mode.
- Both MRGPRE–Gs–cAMP and MRGPRE–β-arrestin-1–ALDOA pathways mediate metabolic benefits.
- Bifidobacterium bile salt hydrolase/transferase activity produces Trp-CA.
Clinical Implications
While preclinical, the work nominates MRGPRE as a drug target and supports strategies such as MRGPRE agonists or microbiome-based augmentation of Trp-CA production to improve glycemic control.
Why It Matters
Deorphanizing MRGPRE with a human-relevant microbial bile acid and demonstrating glucose benefits establishes a novel metabolic signaling pathway with therapeutic potential for type 2 diabetes.
Limitations
- Human data are correlative; causality and effect size in humans remain unproven.
- Safety, pharmacokinetics, and tissue-specific MRGPRE signaling in humans are not characterized.
Future Directions
Develop selective MRGPRE agonists, test Trp-CA or analogs in early-phase clinical trials, and engineer microbiome strategies to elevate endogenous Trp-CA.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic evidence with in vivo validation in animal models and human association data.
- Study Design
- OTHER