GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism

Gut. 2025 Jul 7;74(8):1279-1292. doi: 10.1136/gutjnl-2024-334010.

Abstract

Background: GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear.

Objective: We aimed to investigate the role of GPR171 in modulating CD4+ T cell effector functions in IBD and evaluate its therapeutic potential.

Design: We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4+ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RBhighCD4+ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis.

Results: GPR171 was markedly increased in inflamed mucosa and CD4+ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RBhighCD4+ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 -/- mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice.

Conclusions: GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.

Keywords: INFLAMMATORY BOWEL DISEASE; INTESTINAL GENE REGULATION; INTESTINAL T CELLS; MUCOSAL IMMUNITY.

MeSH terms

  • Animals
  • Cell Differentiation
  • Colitis* / immunology
  • Colitis* / metabolism
  • Disease Models, Animal
  • Fatty Acid-Binding Proteins* / metabolism
  • Female
  • Humans
  • Inflammatory Bowel Diseases* / immunology
  • Inflammatory Bowel Diseases* / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Th17 Cells* / immunology
  • Th17 Cells* / metabolism

Substances

  • Receptors, G-Protein-Coupled
  • Fatty Acid-Binding Proteins
  • FABP5 protein, human
  • Fabp5 protein, mouse
  • Neoplasm Proteins