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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: We studied how genetic deletion or overexpression of Gpr15l 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.