Direct and indirect crosstalk of epithelial GPR15L with immune cells via the intestinal microbiome in the pathogenesis of IBD
Project Summary
While the pathogenesis of chronic inflammatory bowel diseases (IBD) is multifactorial and the intestinal microbiome is believed to play a key role, current treatments primarily target downstream immune effector mechanisms.
Modulating the microbiome to prevent early inflammatory steps appears promising but remains unestablished. The peptide G-protein-coupled receptor 15 ligand (GPR15L), secreted by colonic epithelial cells, is a ligand for the G-protein-coupled receptor 15 (GPR15) expressed on T cells migrating into the colon. We hypothesize that GPR15L influences immune interactions both directly and indirectly via microbiome-mediated mechanisms, plays a key role in IBD pathogenesis, and represents a potential therapeutic target. Our aim is to elucidate the impact of GPR15L on colitis, its underlying mechanisms, and translational potential using Gpr15l-deficient and Gpr15l-overexpressing mice, 16S rRNA sequencing, trafficking assays, human samples, and experimental interventions.
Selected project-relevant publications
Müller TM, Liu LJ, Wiesinger M; TRR241 IBDome Consortium; Neurath MF, Voskens CJ, Zundler S.
Engineering Therapeutic Regulatory T Cells to Overexpress G Protein-Coupled Receptor 15 Improves Functional Fitness for In Vivo Gut Homing.
Gastroenterology. 2025 Feb;168(2):389-392.e4. doi: 10.1053/j.gastro.2024.10.003.
Roth D, Düll MM, Horst LJ, Lindemann A, Malzer X, Koop K, Zundler S, Vetter M, Jefremow A, Atreya R, Geppert C, Weidemann S, Waldner MJ, Dietrich P, Günther C, Munoz LE, Herrmann M, Scheffold A, Neurath MF, Siebler J, Schramm C, Kremer AE, Leppkes M.
Integrin αVβ6: Autoantigen and Driver of Epithelial Remodeling in Colon and Bile Ducts in Primary Sclerosing Cholangitis and Inflammatory Bowel Disease.
J Crohns Colitis. 2025 Feb 4;19(2):jjae131. doi: 10.1093/ecco-jcc/jjae131.
Horn V, Cancino CA, Steinheuer LM, Obermayer B, Fritz K, Nguyen AL, Juhran KS, Plattner C, Bösel D, Oldenburg L, Burns M, Schulz AR, Saliutina M, Mantzivi E, Lissner D, Conrad T, Mashreghi MF, Zundler S, Sonnenberg E, Schumann M, Haag LM, Beule D, Flatz L; TRR241 IBDome Consortium; Trajanoski Z, D’Haens G, Weidinger C, Mei HE, Siegmund B, Thurley K, Hegazy AN.
Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4+ T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease.
Gastroenterology. 2025 Feb;168(2):327-343. doi: 10.1053/j.gastro.2024.09.021.
Erkert L, Ruder B, Kabisch M, Gamez Belmonte R, Patankar JV, Gonzalez Acera M, Schödel L, Chiriac MT, Cineus R, Gnafakis S, Leupold T, Thoma OM, Stolzer I, Taut A, Thonn V, Zundler S, Günther C, Diefenbach A, Kühl AA, Hegazy AN, Waldner M, Basic M, Bleich A, Neurath MF, Wirtz S, Becker C; TRR241 IBDome Consortium.
TIFA renders intestinal epithelial cells responsive to microbial ADP-heptose and drives colonic inflammation in mice.
Mucosal Immunol. 2025 Apr;18(2):453-466. doi: 10.1016/j.mucimm.2025.01.003.
Wagner K, Müller TM, Vitali F, Fischer S, Haberkamp S, Rouse-Merkel R, Atreya R, Neurath MF, Zundler S.
Treatment trajectories and outcomes in inflammatory bowel disease: a tertiary single-centre experience.
Therap Adv Gastroenterol. 2024 Sep 28;17:17562848241284051. doi: 10.1177/17562848241284051. PMID: 39381754; PMCID: PMC11459667.
Weber S, Sitte S, Voegele AL, Sologub L, Wilfer A, Rath T, Nägel A, Zundler S, Franchi L, Opipari AW, Sonnewald S, Reid S, Hartmann A, Eichhorn P, Handtrack C, Weber K, Grützmann R, Neufert C, Schellerer VS, Naschberger E, Ekici AB, Büttner C, Neurath MF, Atreya R.
NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases.
J Crohns Colitis. 2024 Mar 1;18(3):446-461. doi: 10.1093/ecco-jcc/jjad164. PMID: 37748021.
Chiriac MT, Hracsko Z, Günther C, Gonzalez-Acera M, Atreya R, Stolzer I, Wittner L, Dressel A, Schickedanz L, Gamez-Belmonte R, Erkert L, Hundorfean G, Zundler S, Rath T, Vetrano S, Danese S, Sturm G, Trajanoski Z, Kühl AA, Siegmund B, Hartmann A, Wirtz S, Siebler J, Finotto S, Becker C, Neurath MF.
IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling.
Gut. 2024 Jan 5;73(2):282-297. doi: 10.1136/gutjnl-2023-329628. PMID: 37884352; PMCID: PMC10850655.
Müller TM, Liu LJ, Wiesinger M; TRR241 IBDome Consortium; Neurath MF, Voskens CJ, Zundler S.
Engineering Therapeutic Regulatory T Cells to Overexpress G Protein-Coupled Receptor 15 Improves Functional Fitness for In Vivo Gut Homing.
Gastroenterology. 2025 Feb;168(2):389-392.e4. doi: 10.1053/j.gastro.2024.10.003. Epub 2024 Oct 9. PMID: 39389186.
Wiendl M, Dedden M, Liu LJ, Schweda A, Paap EM, Ullrich KA, Hartmann L, Wieser L, Vitali F, Atreya I, Müller TM, Günther C, Atreya R, Neurath MF, Zundler S.
Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells.
Nat Commun. 2024 Feb 3;15(1):1043. doi: 10.1038/s41467-024-45352-6. PMID: 38310086; PMCID: PMC10838339.
Horn V, Cancino CA, Steinheuer LM, Obermayer B, Fritz K, Nguyen AL, Juhran KS, Plattner C, Bösel D, Oldenburg L, Burns M, Schulz AR, Saliutina M, Mantzivi E, Lissner D, Conrad T, Mashreghi MF, Zundler S, Sonnenberg E, Schumann M, Haag LM, Beule D, Flatz L; TRR241 IBDome Consortium; Trajanoski Z, D’Haens G, Weidinger C, Mei HE, Siegmund B, Thurley K, Hegazy AN.
Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4+ T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease.
Gastroenterology. 2025 Feb;168(2):327-343. doi: 10.1053/j.gastro.2024.09.021. Epub 2024 Sep 28. PMID: 39343250.
Schulz-Kuhnt A, Rühle K, Javidmehr A, Döbrönti M, Biwank J, Knittel S, Neidlinger P, Leupold J, Liu LJ, Dedden M, Taudte RV, Gessner A, Fromm MF, Mielenz D, Kreiss L, Waldner MJ, Schürmann S, Friedrich O, Dietel B, López-Posadas R, Plattner C; TRR241 IBDome Consortium; Zundler S, Becker C, Atreya R, Neurath MF, Atreya I.
ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo.
Gut. 2024 Mar 7;73(4):601-612. doi: 10.1136/gutjnl-2023-330543. PMID: 38176897.
Sommer K, Heidbreder K, Kreiss L, Dedden M, Paap EM, Wiendl M, Becker E, Atreya R, Müller TM, Atreya I, Waldner M, Schürmann S, Friedrich O, Neurath MF, Zundler S.
Anti-β7 integrin treatment impedes the recruitment on non-classical monocytes to the gut and delays macrophage-mediated intestinal wound healing.
Clin Transl Med. 2023 Apr;13(4):e1233. doi: 10.1002/ctm2.1233. PMID: 37029786; PMCID: PMC10082567.
Müller TM, Liu LJ, Czerwinski T, Wiesinger M, Dedden M, Paap EM, Ullrich KA, Atreya I, Siegmund B, Atreya R, Fabry B, Berking C, Neurath MF, Zundler S, Voskens CJ.
Increased Motility and Suppression of Ex Vivo-Expanded Regulatory T Cells Designed for Adoptive Transfer Therapy in Ulcerative Colitis.
Cell Mol Gastroenterol Hepatol. 2023;16(1):183-187.e2. doi: 10.1016/j.jcmgh.2023.04.002. Epub 2023 Apr 20. Erratum in: Cell Mol Gastroenterol Hepatol. 2025 Jun 6:101554. doi: 10.1016/j.jcmgh.2025.101554. PMID: 37085136; PMCID: PMC10285232.
Heidbreder K, Sommer K, Wiendl M, Müller TM, Atreya I, Hildner K, Neurath MF, Zundler S.
Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.
Front Immunol. 2023 Jan 18;13:1040775. doi: 10.3389/fimmu.2022.1040775. PMID: 36741412; PMCID: PMC9890957.
Voskens C, Stoica D, Rosenberg M, Vitali F, Zundler S, Ganslmayer M, Knott H, Wiesinger M, Wunder J, Kummer M, Siegmund B, Schnoy E, Rath T, Hartmann A, Hackstein H, Schuler-Thurner B, Berking C, Schuler G, Atreya R, Neurath MF.
Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis.
Gut. 2023 Jan;72(1):49-53. doi: 10.1136/gutjnl-2022-327075. Epub 2022 Apr 15. PMID: 35428657; PMCID: PMC9763232.
Schulze LL, Becker E, Dedden M, Liu LJ, van Passen C, Mohamed-Abdou M, Müller TM, Wiendl M, Ullrich KAM, Atreya I, Leppkes M, Ekici AB, Kirchner P, Stürzl M, Sexton D, Palliser D, Atreya R, Siegmund B; TRR241 IBDome consortium; Neurath MF, Zundler S.
Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease.
J Crohns Colitis. 2023 Nov 24;17(11):1817-1832. doi: 10.1093/ecco-jcc/jjad088. PMID: 37208197.
Besendorf L, Müller TM, Geppert CI, Schneider I, Mühl L, Atreya I, Vitali F, Atreya R, Neurath MF, Zundler S.
Vedolizumab blocks α4β7 integrin-mediated T cell adhesion to MAdCAM-1 in microscopic colitis.
Therap Adv Gastroenterol. 2022 Jun 28;15:17562848221098899. doi: 10.1177/17562848221098899. PMID: 35784193; PMCID: PMC9244938.