Mucosal immunity as regulator of epithelial cell functions in inflammatory bowel diseases
Project Summary
Polarized immune responses in the gut are key effector mechanisms in chronic inflammatory bowel diseases, while simultaneously providing protection against bacterial and parasitic infections through the intestinal epithelium. In our project, we investigate the temporal and spatial dynamics of immune-epithelial interactions with a focus on the regulation and function of the ALPK1-TIFA-NFκB signaling pathway. This pathway, recently identified as essential for the recognition of microbial ADP-heptose, is active in both epithelial and immune cells. Our data show that mucosal immune cells control the intestinal barrier’s response to ADP-heptose, inducing transcriptional changes in epithelial cells that weaken barrier function and promote intestinal inflammation. Our long-term goal is to elucidate the role of this signaling pathway in the pathogenesis of inflammatory bowel diseases and to identify therapeutic targets within immune-epithelial communication.
Selected project-relevant publications
Trajanoski Z, Plattner C, Sturm G, Kühl A, Atreya R, Carollo S, Gronauer R, Rieder D, Günther M, Ormanns S, Manzl C, Wirtz S, Meneghetti A, Hegazy A, Patankar J, Carrero Z, Neurath M, Kather J, Becker C, Siegmund B.
IBDome: An integrated molecular, histopathological, and clinical atlas of inflammatory bowel diseases.
Res Sq [Preprint]. 2025 May 6:rs.3.rs-6443303. doi: 10.21203/rs.3.rs-6443303/v1. PMID: 40386420; PMCID: PMC12083645.
Bao LL, Yu YQ, González-Acera M, Patankar JV, Giessl A, Sturm G, Kühl AA, Atreya R, Erkert L, Gámez-Belmonte R, Krug SM, Schmid B, Tripal P, Chiriac MT, Hildner K, Siegmund B, Wirtz S, Stürzl M, Mohamed Abdou M, Trajanoski Z; TRR241 IBDome Consortium; Neurath MF, Zorzano A, Becker C.
Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
Sci Transl Med. 2025 Jan 15;17(781):eadn8699. doi: 10.1126/scitranslmed.adn8699.
Gonzalez-Acera M, Patankar JV, Erkert L, Cineus R, Gamez-Belmonte R, Leupold T, Bubeck M, Bao LL, Dinkel M, Wang R, Schickedanz L, Limberger H, Stolzer I, Gerlach K, Diemand L, Mascia F, Gupta P, Naschberger E, Koop K, Plattner C, Sturm G, Weigmann B, Günther C, Wirtz S, Stürzl M, Hildner K, Kühl AA, Siegmund B, Gießl A, Atreya R; TRR241 IBDome Consortium; Hegazy AN, Trajanoski Z, Neurath MF, Becker C.
Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD.
Gut. 2025 Apr 29:gutjnl-2024-333729. doi: 10.1136/gutjnl-2024-333729.
Plattner C, Sturm G, Kühl AA, Atreya R, Carollo S, Gronauer R, Rieder D, Günther M, Ormanns S, Manzl C, Wirtz S, Meneghetti AR, Hegazy AN, Patankar JV, Carrero ZI; TRR241 IBDome Consortium; Neurath MF, Kather JN, Becker C, Siegmund B, Trajanoski Z.
IBDome: An integrated molecular, histopathological, and clinical atlas of inflammatory bowel diseases.
bioRxiv [Preprint]. 2025 Apr 10:2025.03.26.645544. doi: 10.1101/2025.03.26.645544.
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.
Hecker J, Plattner C, Cancino CA, Löscher BS, Saurenbach J, Letizia M, Rieder D; TRR241 IBDome Consortium; Freise I, Koop K, Neufert C, Kunkel D, Al Khatim Z, Schaafs LA, Schütz A, Becker C, Atreya R, Trajanoski Z, Franke A, Sonnenberg E, Hegazy AN, Siegmund B, Weidinger C.
IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations.
EMBO Mol Med. 2025 May 30. doi: 10.1038/s44321-025-00245-z.
Cineus R, Luo Y, Saliutina M, Manna S, Cancino CA, Velasco Blázquez L, Wang L, Bösel D, Abdelrahman A, Klementowicz JE, Scherl A, Hainbuch S, Bréart B, Kwon G, Konopka A, Guerra GM, von Coburg E, Gerbeth L, Roels J, Heinrich F, Müller N, Durek P, Deigendesch N, Ziai J, Hung J, Conrad T; TRR241 IBDome Consortium; Kühl AA, Wirtz S, Löhning M, Keir M, Diefenbach A, Mashreghi MF, Siegmund B, Schumann M, Romagnani C, West NR, Hegazy AN.
The IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis.
Nat Immunol. 2025 Jun;26(6):837-853. doi: 10.1038/s41590-025-02149-z.
Erkert L, Kabisch M, Gamez-Belmonte R, Gonzalez-Acera M, Patankar JV, Schödel L, Hofmann K, Wagner Y, Plattner C, Spath EM, Distler U, Tenzer S; TRR241 IBDome Consortium; Neufert C, Neurath MF, Becker C.
Pharmacological inhibitors of the gamma-secretase enzyme complex disrupt epithelial cell function triggering colitis in mice.
J Crohns Colitis. 2025 Jun 12:jjaf096. doi: 10.1093/ecco-jcc/jjaf096.
Dorner H, Stolzer I, Mattner J, Kaminski S, Leistl S, Edrich LM, Schwendner R, Hobauer J, Sebald A, Leikam S, Gonzalez Acera M, Düll M, Lang R, Seidel G, Seitz T, Hellerbrand C, Fuhrmann G, Distler U, Tenzer S, Eichhorn P, Vieth M, Schramm C, Arnold P, Becker C, Weidinger C, Siegmund B, Atreya R, Leppkes M, Naschberger E, Sampaziotis F, Dietrich P, Rauh M, Wirtz S, Kremer AE, Neurath MF, Günther C.
Gut Pathobiont-Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease.
Gastroenterology. 2024 Nov;167(6):1183-1197.e16. doi: 10.1053/j.gastro.2024.06.032. Epub 2024 Jul 9. PMID: 38992449.
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.
Wiese JJ, Manna S, Kühl AA, Fascì A, Elezkurtaj S, Sonnenberg E, Bubeck M, Atreya R, Becker C, Weixler B, Siegmund B, Patankar JV, Prüß MS, Schumann M.
Myenteric Plexus Immune Cell Infiltrations and Neurotransmitter Expression in Crohn’s Disease and Ulcerative Colitis.
J Crohns Colitis. 2024 Jan 27;18(1):121-133. doi: 10.1093/ecco-jcc/jjad122. PMID: 37565754; PMCID: PMC10821712.
Gámez-Belmonte R, Wagner Y, Mahapatro M, Wang R, Erkert L, González-Acera M, Cineus R, Hainbuch S, Patankar JV, Voehringer D, Hegazy AN, Neurath MF, Wirtz S, Becker C.
Intestinal epithelial Gasdermin C is induced by IL-4R/STAT6 signaling but is dispensable for gut immune homeostasis.
Sci Rep. 2024 Nov 3;14(1):26522. doi: 10.1038/s41598-024-78336-z. PMID: 39489845; PMCID: PMC11532336.
Erkert L, Gamez-Belmonte R, Kabisch M, Schödel L, Patankar JV, Gonzalez-Acera M, Mahapatro M, Bao LL, Plattner C, Kühl AA, Shen J, Serneels L, De Strooper B; TRR241 IBDome Consortium; Neurath MF, Wirtz S, Becker C.
Alzheimer’s disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis.
Gut. 2024 Sep 9;73(10):1618-1631. doi: 10.1136/gutjnl-2023-331622. PMID: 38684238.
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.
Vitali F, Rath T, Klenske E, Vögele AL, Ganzleben I, Zundler S, Strobel D, Geppert C, Hartmann A, Neurath MF, Atreya R.
Long-term outcomes of cyclosporin induction and ustekinumab maintenance combination therapy in patients with steroid-refractory acute severe ulcerative colitis.
Therap Adv Gastroenterol. 2023 Dec 30;17:17562848231218555. doi: 10.1177/17562848231218555. PMID: 38164363; PMCID: PMC10757791.
Plattner C, Lamberti G, Blattmann P, Kirchmair A, Rieder D, Loncova Z, Sturm G, Scheidl S, Ijsselsteijn M, Fotakis G, Noureen A, Lisandrelli R, Böck N, Nemati N, Krogsdam A, Daum S, Finotello F, Somarakis A, Schäfer A, Wilflingseder D, Gonzalez Acera M, Öfner D, Huber LA, Clevers H, Becker C, Farin HF, Greten FR, Aebersold R, de Miranda NFCC, Trajanoski Z.
Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.
iScience. 2023 Nov 4;26(12):108399. doi: 10.1016/j.isci.2023.108399. PMID: 38047086; PMCID: PMC10692669.
Ullrich KA, Derdau J, Baltes C, Battistella A, Rosso G, Uderhardt S, Schulze LL, Liu LJ, Dedden M, Spocinska M, Kainka L, Kubánková M, Müller TM, Schmidt NM, Becker E, Ben Brahim O, Atreya I, Finotto S, Prots I, Wirtz S, Weigmann B, López-Posadas R, Atreya R, Ekici AB, Lautenschläger F, Guck J, Neurath MF, Zundler S.
IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells.
Gut. 2023 Nov;72(11):2081-2094. doi: 10.1136/gutjnl-2023-329818. Epub 2023 Aug 4. PMID: 37541770; PMCID: PMC10579496.
Gamez-Belmonte R, Mahapatro M, Erkert L, Gonzalez-Acera M, Naschberger E, Yu Y, Tena-Garitaonaindia M, Patankar JV, Wagner Y, Podstawa E, Schödel L, Bubeck M, Neurath MF, Stürzl M, Becker C.
Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling.
Gut. 2023 Jun;72(6):1155-1166. doi: 10.1136/gutjnl-2022-327323. Epub 2022 Oct 19. PMID: 36261293.
Wittner L, Wagener L, Wiese JJ, Stolzer I, Krug SM, Naschberger E, Jackstadt R, Beyaert R, Atreya R, Kühl AA, Sturm G, Gonzalez-Acera M, Patankar JV, Becker C, Siegmund B, Trajanoski Z, Winner B, Neurath MF, Schumann M, Günther C.
Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing.
Int J Mol Sci. 2023 Apr 17;24(8):7402. doi: 10.3390/ijms24087402. PMID: 37108564; PMCID: PMC10138456.
Krug J, Rodrian G, Petter K, Yang H, Khoziainova S, Guo W, Bénard A, Merkel S, Gellert S, Maschauer S, Spermann M, Waldner M, Bailey P, Pilarsky C, Liebl A, Tripal P, Christoph J, Naschberger E, Croner R, Schellerer VS, Becker C, Hartmann A, Tüting T, Prante O, Grützmann R, Grivennikov SI, Stürzl M, Britzen-Laurent N.
N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy.
Gastroenterology. 2023 Mar;164(3):392-406.e5. doi: 10.1053/j.gastro.2022.11.018. Epub 2022 Nov 17. PMID: 36402190; PMCID: PMC10009756.
Schneider I, Allner C, Mühl L, Melde M, Lissner D, Mantzivi E, Glauben R, Vitali F, Becker E, Atreya I, Müller TM, Atreya R, Siegmund B, Neurath MF, Zundler S.
Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease.
Transl Res. 2023 Mar;253:8-15. doi: 10.1016/j.trsl.2022.10.003. Epub 2022 Oct 20. PMID: 36272713.
Martínez-Sánchez LDC, Ngo PA, Pradhan R, Becker LS, Boehringer D, Soteriou D, Kubankova M, Schweitzer C, Koch T, Thonn V, Erkert L, Stolzer I, Günther C, Becker C, Weigmann B, Klewer M, Daniel C, Amann K, Tenzer S, Atreya R, Bergo M, Brakebusch C, Watson AJM, Guck J, Fabry B, Atreya I, Neurath MF, López-Posadas R.
Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation.
Gut. 2023 Feb;72(2):275-294. doi: 10.1136/gutjnl-2021-325520. Epub 2022 Mar 3. PMID: 35241625; PMCID: PMC9872254.
Schmalzl A, Leupold T, Kreiss L, Waldner M, Schürmann S, Neurath MF, Becker C, Wirtz S.
Interferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection.
Nat Commun. 2022 Sep 29;13(1):5730. doi: 10.1038/s41467-022-33326-5. PMID: 36175404; PMCID: PMC9522774.
Kreiss L, Ganzleben I, Mühlberg A, Ritter P, Schneidereit D, Becker C, Neurath MF, Friedrich O, Schürmann S, Waldner M.
Label-free analysis of inflammatory tissue remodeling in murine lung tissue based on multiphoton microscopy, Raman spectroscopy and machine learning.
J Biophotonics. 2022 Sep;15(9):e202200073. doi: 10.1002/jbio.202200073. Epub 2022 Jun 26. PMID: 35611635.
Yu YQ, Thonn V, Patankar JV, Thoma OM, Waldner M, Zielinska M, Bao LL, Gonzalez-Acera M, Wallmüller S, Engel FB, Stürzl M, Neurath MF, Liebing E, Becker C.
SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth.
Cell Death Dis. 2022 Jan 12;13(1):52. doi: 10.1038/s41419-021-04483-0. PMID: 35022391; PMCID: PMC8755774.