New Therapeutic Approach for Intestinal Fibrosis Through Inhibition of pH-Sensing Receptor GPR4

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Inflammatory bowel diseases (IBDs) are linked to increased pH-sensing receptor levels.
• Acidification promotes angiogenesis and extracellular matrix remodeling in IBD.
• G protein-coupled receptor 4 (GPR4) is a key pH-sensing receptor implicated in these processes.

Purpose of the Study:

• To investigate GPR4 expression in fibrotic lesions of Crohn's disease (CD) patients.
• To evaluate the therapeutic potential of GPR4 deficiency or inhibition in IBD-associated fibrosis.

Main Methods:

• Human tissue samples from CD patients were analyzed for GPR4 and fibrosis markers.
• Gpr4-deficient mice and GPR4 antagonist were used in preclinical colitis and intestinal transplantation models.
• Fibrosis markers, angiogenesis, and collagen deposition were assessed.

Main Results:

• GPR4 expression positively correlated with fibrosis markers and procollagens in human CD ileum.
• Gpr4 deficiency reduced angiogenesis and fibrogenesis in murine colitis models.
• GPR4 inhibition decreased collagen deposition and fibroblast activation in transplantation models.

Conclusions:

• GPR4 expression is elevated in fibrotic CD lesions and correlates with profibrotic markers.
• Gpr4 deficiency and pharmacological inhibition attenuate IBD-associated fibrosis.
• Targeting GPR4 presents a potential therapeutic strategy for IBD fibrosis.