{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T08:50:02Z","timestamp":1791881402759,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Italian Ministry of Health, Ricerca Corrente 2026"},{"name":"INNOVA-Hub Life Science\u2014Diagnostica Avanzata","award":["G23C22003360001"],"award-info":[{"award-number":["G23C22003360001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease with marked molecular heterogeneity, resulting in highly variable responses to biologic therapies. Despite the efficacy of Infliximab (IFX), many patients fail to achieve sustained remission. Identifying biomarkers predictive of treatment response is essential for advancing precision medicine in UC. Gene expression profiling of colonic mucosal biopsies from IFX responders, IFX non-responders, and healthy controls was performed using a multiplex array, followed by technical confirmation by RT-qPCR and immunohistochemical assessment to further characterize tissue expression and biological relevance. IFX non-responders displayed a stromal\u2013immune molecular signature marked by extracellular matrix remodeling, stromal remodeling, integrin-mediated signaling, and persistent inflammatory pathways. SPARC and SPP1 emerged as the most prominent biomarkers, with significantly increased gene and protein expression in non-responder patients, highlighting their association with chronic tissue remodeling and therapeutic resistance. Mucosal resistance to IFX is associated with a specific stromal\u2013immune profile characterized by SPARC and SPP1 upregulation. These findings suggest that both molecules may serve as promising candidate markers for patient stratification, highlighting the need for future prospective studies to explore their role in personalized management strategies for ulcerative colitis.<\/jats:p>","DOI":"10.3390\/ijms27198838","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:31:31Z","timestamp":1791203491000},"page":"8838","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biopsy-Based Molecular Signatures Predicting Therapeutic Response in Ulcerative Colitis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7940-4977","authenticated-orcid":false,"given":"Ilaria","family":"Grassi","sequence":"first","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8766-1869","authenticated-orcid":false,"given":"Marina","family":"Liso","sequence":"additional","affiliation":[{"name":"IBD Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Mauro","family":"Mastronardi","sequence":"additional","affiliation":[{"name":"IBD Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6798-808X","authenticated-orcid":false,"given":"Anna Maria","family":"Valentini","sequence":"additional","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Margherita","family":"Curlo","sequence":"additional","affiliation":[{"name":"IBD Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1661-5504","authenticated-orcid":false,"given":"Raffaele","family":"Armentano","sequence":"additional","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2952-0053","authenticated-orcid":false,"given":"Elisabetta","family":"Cavalcanti","sequence":"additional","affiliation":[{"name":"IBD Unit, National Institute of Gastroenterology\u2014IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/S0140-6736(16)32126-2","article-title":"Ulcerative Colitis","volume":"389","author":"Ungaro","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrgastro.2015.186","article-title":"Immunopathogenesis of IBD: Current State of the Art","volume":"13","author":"Fiocchi","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1053\/j.gastro.2020.12.031","article-title":"STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target Strategies in IBD","volume":"160","author":"Turner","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1056\/NEJMoa050516","article-title":"Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis","volume":"353","author":"Rutgeerts","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Marsal, J., Barreiro-de Acosta, M., Blumenstein, I., Cappello, M., Bazin, T., and Sebastian, S. (2022). Management of Non-Response and Loss of Response to Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front. Med., 9.","DOI":"10.3389\/fmed.2022.897936"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gibble, T.H., Naegeli, A.N., Grabner, M., Isenberg, K., Shan, M., Teng, C.-C., and Curtis, J.R. (2023). Identification of Inadequate Responders to Advanced Therapy among Commercially Insured Adult Patients with Crohn\u2019s Disease and Ulcerative Colitis in the United States. BMC Gastroenterol., 23.","DOI":"10.1186\/s12876-023-02675-w"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S2468-1253(19)30012-3","article-title":"Predictors of Anti-TNF Treatment Failure in Anti-TNF-Naive Patients with Active Luminal Crohn\u2019s Disease: A Prospective, Multicentre, Cohort Study","volume":"4","author":"Kennedy","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Khoury, T., and Ilan, Y. (2019). Introducing Patterns of Variability for Overcoming Compensatory Adaptation of the Immune System to Immunomodulatory Agents: A Novel Method for Improving Clinical Response to Anti-TNF Therapies. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02726"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1002\/med.21893","article-title":"Inflammatory Bowel Disease Biomarkers","volume":"42","author":"Liu","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104442","DOI":"10.1016\/j.phrs.2019.104442","article-title":"Can Molecular Stratification Improve the Treatment of Inflammatory Bowel Disease?","volume":"148","author":"Wang","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12967-024-05058-1","article-title":"Predictive Biomarkers for Anti-TNF Alpha Therapy in IBD Patients","volume":"22","author":"Kumar","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"jjae197","DOI":"10.1093\/ecco-jcc\/jjae197","article-title":"Multi-Omics Data Integration Identifies Novel Biomarkers and Patient Subgroups in Inflammatory Bowel Disease","volume":"19","author":"Preto","year":"2025","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.tips.2024.08.003","article-title":"Ulcerative Colitis: Clinical Biomarkers, Therapeutic Targets, and Emerging Treatments","volume":"45","author":"Wangchuk","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00011-026-02195-9","article-title":"Inflammatory Bowel Disease and Extracellular Matrix: When Victim Becomes Double Agent","volume":"75","author":"Sferra","year":"2026","journal-title":"Inflamm. Res."},{"key":"ref_15","first-page":"97179","article-title":"Perspectives on the Extracellular Matrix in Inflammatory Bowel Disease and Bowel Decellularization Protocols","volume":"14","author":"Miglino","year":"2024","journal-title":"World J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41420-024-02015-1","article-title":"Current Understanding of the Interplay between Extracellular Matrix Remodelling and Gut Permeability in Health and Disease","volume":"10","author":"Vilardi","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/intimm\/dxaf015","article-title":"Roles of Fibroblasts in the Pathogenesis of Inflammatory Bowel Diseases and IBD-Associated Fibrosis","volume":"37","author":"Ito","year":"2025","journal-title":"Int. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00082","DOI":"10.14309\/ctg.0000000000000082","article-title":"Fibrosis Mediators in the Colonic Mucosa of Acute and Healed Ulcerative Colitis","volume":"10","author":"Gundersen","year":"2019","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1093\/ecco-jcc\/jjaa009","article-title":"Stromal Cells in the Pathogenesis of Inflammatory Bowel Disease","volume":"14","author":"Barnhoorn","year":"2020","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Park, S.-K., Lee, G.-Y., Kim, S., Lee, C.-W., Choi, C.-H., Kang, S.-B., Kim, T.-O., Chun, J., Cha, J.-M., and Im, J.-P. (2023). Enrichment of Activated Fibroblasts as a Potential Biomarker for a Non-Durable Response to Anti-Tumor Necrosis Factor Therapy in Patients with Crohn\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914799"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, H., Zhang, Y., Du, S., Shen, J., Liu, X., and Jing, J. (2025). \u201cRemodeling the Intestinal Immune Microenvironment\u201d: Immune Regulation and Tissue Regeneration by Mesenchymal Stem\/Stromal Cells in the Repair Microenvironment of Inflammatory Bowel Disease. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1543702"},{"key":"ref_22","unstructured":"O\u2019Sullivan, S., Gilmer, J.F., and Medina, C. (2025). Matrix Metalloproteinases in Inflammatory Bowel Disease: An Update. Mediat. Inflamm., 964131."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1097\/MIB.0000000000000080","article-title":"Fibrosis in Ulcerative Colitis: Mechanisms, Features, and Consequences of a Neglected Problem","volume":"20","author":"Gordon","year":"2014","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Garlatti, V., Lovisa, S., Danese, S., and Vetrano, S. (2021). The Multiple Faces of Integrin-ECM Interactions in Inflammatory Bowel Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910439"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41392-025-02345-1","article-title":"Ulcerative Colitis: Signaling Pathways, Therapeutic Targets and Interventional Strategies","volume":"11","author":"Jia","year":"2026","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e35020","DOI":"10.1097\/MD.0000000000035020","article-title":"Pathological Mechanism and Targeted Drugs of Ulcerative Colitis: A Review","volume":"102","author":"Guo","year":"2023","journal-title":"Medicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s40259-021-00496-5","article-title":"Targeting Leukocyte Trafficking in Inflammatory Bowel Disease","volume":"35","author":"Wyatt","year":"2021","journal-title":"BioDrugs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.medj.2022.05.002","article-title":"Cross-Tissue, Single-Cell Stromal Atlas Identifies Shared Pathological Fibroblast Phenotypes in Four Chronic Inflammatory Diseases","volume":"3","author":"Korsunsky","year":"2022","journal-title":"Med"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2409419","DOI":"10.1002\/advs.202409419","article-title":"Elevated SPARC Disrupts the Intestinal Barrier Integrity in Crohn\u2019s Disease by Interacting with OTUD4 and Activating the MYD88\/NF-\u03baB Pathway","volume":"12","author":"Wang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Karasalih, B., Duman, H., Bechelany, M., and Karav, S. (2025). Osteopontin: Its Properties, Recent Studies, and Potential Applications. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202505.0170.v1"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lang, F., Li, Y., Yao, R., and Jiang, M. (2025). Osteopontin in Chronic Inflammatory Diseases: Mechnisms, Biomarker Potential, and Therapeutic Strategies. Biology, 14.","DOI":"10.3390\/biology14040428"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1093\/ecco-jcc\/jjy113","article-title":"ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications","volume":"13","author":"Maaser","year":"2019","journal-title":"J. Crohns Colitis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"jjaf106","DOI":"10.1093\/ecco-jcc\/jjaf106","article-title":"ECCO-ESGAR-ESP-IBUS Guideline on Diagnostics and Monitoring of Patients with Inflammatory Bowel Disease: Part 1: Initial diagnosis, monitoring of known inflammatory bowel disease, detection of complications","volume":"19","author":"Kucharzik","year":"2025","journal-title":"J. Crohns Colitis"},{"key":"ref_34","unstructured":"Stenson, W.F. (1995). Inflammatory Bowel Diseases. Textbook of Gastroenterology, Lippincott Wiliams and Wilkins. [2nd ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1186\/s40001-024-01932-2","article-title":"Inflammation Accelerating Intestinal Fibrosis: From Mechanism to Clinic","volume":"29","author":"Xin","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1136\/gut.2005.082909","article-title":"The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications","volume":"55","author":"Satsangi","year":"2006","journal-title":"Gut"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.crohns.2012.09.003","article-title":"Second European Evidence-Based Consensus on the Diagnosis and Management of Ulcerative Colitis Part 1: Definitions and Diagnosis","volume":"6","author":"Dignass","year":"2012","journal-title":"J. Crohn\u2019s Colitis"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8838\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T08:16:59Z","timestamp":1791879419000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8838"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,3]]},"references-count":37,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198838"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198838","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,3]]}}}