The endogenous peptide GPR15L shapes the intestinal microbiota to counteract colitis
Abstract
BACKGROUND: The peptide GPR15L is produced by colonic epithelial cells and has been implicated in T cell recruitment to the large intestine. However, its role in chronic colitis has been unclear so far. OBJECTIVE: To explore the role of GPR15L in the pathogenesis of experimental colitis and IBD. DESIGN: as well as rectal application of recombinant GPR15L alters the course of acute dextran sodium sulfate colitis and T cell transfer colitis. The impact of GPR15L on microbiota was explored with co-housing, littermate and faecal microbiota transfer studies, by 16S rRNA sequencing as well as anti-microbial assays and shotgun metagenomics. The expression of GPR15L was evaluated across three independent cohorts of patients with IBD and correlated to microbial diversity and flare-free survival. RESULTS: GPR15L clearly mitigated experimental colitis, but this was independent of T cell recruitment and GPR15. Instead, we observed that the effects of GPR15L were mediated by altered microbiomes in the large intestine and, consistently, showed that GPR15L acts as an antimicrobial peptide under anaerobic conditions and shapes microbial communities towards a homeostatic phenotype. Rectal supplementation of GPR15L counteracted experimental colitis. In patients with IBD, GPR15L expression was decreased in active inflammation, correlated with microbial diversity and was associated with flare-free survival. CONCLUSIONS: GPR15L is a host-defence peptide that plays a beneficial role in the pathogenesis of intestinal inflammation. It seems promising to further evaluate its potential as a future therapeutic approach in IBD.
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BibTeX
@article{leggio2026endogenous,
title = {{The endogenous peptide GPR15L shapes the intestinal microbiota to counteract colitis}},
author = {Miriana Leggio and Sebastian Schramm and Lisa Dietz and Borja Ocón and Stefan Wirtz and Fabiola Puertolas Balint and Bahtiyar Yilmaz and Jana Petzold and Li-Juan Liu and Mark Dedden and Arif Ekici and Xi Meng and David Bingham and Karen Anne-Marie Ullrich and Stefanie Heltmann-Meyer and Claudia Günther and Kai Hildner and Raja Atreya and Imke Atreya and Tanja Müller and Roman Gerlach and Bjoern Schroeder and Andrew Macpherson and Eugene Butcher and Markus Neurath and Sebastian Zundler},
journal = {Gut},
year = {2026},
month = may,
doi = {10.1136/gutjnl-2025-337619},
url = {https://hal.science/hal-05771865v1},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - The endogenous peptide GPR15L shapes the intestinal microbiota to counteract colitis
AU - Miriana Leggio
AU - Sebastian Schramm
AU - Lisa Dietz
AU - Borja Ocón
AU - Stefan Wirtz
AU - Fabiola Puertolas Balint
AU - Bahtiyar Yilmaz
AU - Jana Petzold
AU - Li-Juan Liu
AU - Mark Dedden
AU - Arif Ekici
AU - Xi Meng
AU - David Bingham
AU - Karen Anne-Marie Ullrich
AU - Stefanie Heltmann-Meyer
AU - Claudia Günther
AU - Kai Hildner
AU - Raja Atreya
AU - Imke Atreya
AU - Tanja Müller
AU - Roman Gerlach
AU - Bjoern Schroeder
AU - Andrew Macpherson
AU - Eugene Butcher
AU - Markus Neurath
AU - Sebastian Zundler
PY - 2026
DA - 2026/05/28
JO - Gut
DO - 10.1136/gutjnl-2025-337619
UR - https://hal.science/hal-05771865v1
AB - BACKGROUND: The peptide GPR15L is produced by colonic epithelial cells and has been implicated in T cell recruitment to the large intestine. However, its role in chronic colitis has been unclear so far. OBJECTIVE: To explore the role of GPR15L in the pathogenesis of experimental colitis and IBD. DESIGN: as well as rectal application of recombinant GPR15L alters the course of acute dextran sodium sulfate colitis and T cell transfer colitis. The impact of GPR15L on microbiota was explored with co-housing, littermate and faecal microbiota transfer studies, by 16S rRNA sequencing as well as anti-microbial assays and shotgun metagenomics. The expression of GPR15L was evaluated across three independent cohorts of patients with IBD and correlated to microbial diversity and flare-free survival. RESULTS: GPR15L clearly mitigated experimental colitis, but this was independent of T cell recruitment and GPR15. Instead, we observed that the effects of GPR15L were mediated by altered microbiomes in the large intestine and, consistently, showed that GPR15L acts as an antimicrobial peptide under anaerobic conditions and shapes microbial communities towards a homeostatic phenotype. Rectal supplementation of GPR15L counteracted experimental colitis. In patients with IBD, GPR15L expression was decreased in active inflammation, correlated with microbial diversity and was associated with flare-free survival. CONCLUSIONS: GPR15L is a host-defence peptide that plays a beneficial role in the pathogenesis of intestinal inflammation. It seems promising to further evaluate its potential as a future therapeutic approach in IBD.
SN - 0017-5749
SN - 1468-3288
ER -