{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:57:16Z","timestamp":1785430636676,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016317","name":"Chenzhou National Sustainable Development Agenda Innovation Demonstration Zone","doi-asserted-by":"publisher","award":["2025sfq04"],"award-info":[{"award-number":["2025sfq04"]}],"id":[{"id":"10.13039\/501100016317","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Hospital Administration","award":["2023YFC3605005"],"award-info":[{"award-number":["2023YFC3605005"]}]},{"award":["2023YFC3605005"],"award-info":[{"award-number":["2023YFC3605005"]}],"id":[{"id":"https:\/\/ror.org\/00xdrzy17","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2023JJ30801"],"award-info":[{"award-number":["2023JJ30801"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002822","name":"Central South University","doi-asserted-by":"crossref","award":["2026ZZTS0517"],"award-info":[{"award-number":["2026ZZTS0517"]}],"id":[{"id":"10.13039\/501100002822","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2026ZZTS0517"],"award-info":[{"award-number":["2026ZZTS0517"]}],"id":[{"id":"https:\/\/ror.org\/00f1zfq44","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Crohn\u2019s disease (CD) is characterized by transmural inflammation and intestinal fibrosis, in which metabolic reprogramming may contribute to fibrotic remodeling through lactate-associated epigenetic and transcriptional regulation, but key cellular states and candidate biomarkers remain unclear. Therefore, we integrated single-cell RNA sequencing (scRNA-seq) with a lactylation-associated transcriptional score to estimate lactate\/lactylation-related transcriptional activity in CD intestinal tissues. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and an integrated machine learning framework identified core lactylation-associated biomarkers, which were validated in clinical tissue and a TNBS-induced mouse model. Additionally, we evaluated the ability of these core genes to predict anti-TNF-\u03b1 treatment response in an independent clinical cohort, and analyzed cellular communication and trajectories, using CellChat, Monocle 2, and spatial transcriptomics. In this study, an enterocyte state with high lactylation-associated transcriptional scores was identified. CALD1 and CALM1 were identified as core transcriptional biomarkers associated with this high-lactylation-score epithelial state. A diagnostic nomogram exhibited robust predictive performance (AUC &gt; 0.75, p &lt; 0.05). Notably, increased CALM1 expression was associated with favorable anti-TNF-\u03b1 response (AUC &gt; 0.70, p &lt; 0.05). Mechanistically, CALD1\/CALM1 dysregulation was associated with enhanced GDF15- and MIF-related signaling, potentially contributing to endothelial and macrophage-associated microenvironmental remodeling. Together, CALD1 and CALM1 represent lactylation-score-associated transcriptional biomarkers that may link metabolic reprogramming, epithelial dysfunction, and fibrotic remodeling in CD, serving as candidate diagnostic and treatment-response-associated biomarkers.<\/jats:p>","DOI":"10.3390\/ijms27146343","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"6343","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Omics and Machine Learning-Based Characterization of the Lactylation Microenvironment and Biomarker Identification in Crohn\u2019s Disease Intestinal Fibrosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6984-5958","authenticated-orcid":false,"given":"Qi","family":"Sun","sequence":"first","affiliation":[{"name":"Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, China"},{"name":"Institute of Aging and Age-Related Disease Research, Central South University, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Yu","family":"Cui","sequence":"additional","affiliation":[{"name":"Institute of Aging and Age-Related Disease Research, Central South University, Changsha 410011, China"},{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Kun","family":"Zhan","sequence":"additional","affiliation":[{"name":"Institute of Aging and Age-Related Disease Research, Central South University, Changsha 410011, China"},{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha 410011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/S0140-6736(23)02586-2","article-title":"Crohn\u2019s Disease","volume":"403","author":"Dolinger","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1016\/S0140-6736(12)60026-9","article-title":"Crohn\u2019s Disease","volume":"380","author":"Baumgart","year":"2012","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1097\/MIB.0000000000000043","article-title":"The Mechanisms That Mediate the Development of Fibrosis in Patients with Crohn\u2019s Disease","volume":"20","author":"Li","year":"2014","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Adegbola, S.O., Sahnan, K., Warusavitarne, J., Hart, A., and Tozer, P. (2018). Anti-TNF Therapy in Crohn\u2019s Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082244"},{"key":"ref_5","first-page":"902","article-title":"Surgical Strategies for Intestinal Crohn\u2019s Disease","volume":"47","author":"Dan","year":"2022","journal-title":"J. Cent. South Univ. (Med. Sci.)"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hayashi, Y., and Nakase, H. (2022). The Molecular Mechanisms of Intestinal Inflammation and Fibrosis in Crohn\u2019s Disease. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.845078"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"360","DOI":"10.5009\/gnl220045","article-title":"Cellular and Molecular Mechanisms of Intestinal Fibrosis","volume":"17","author":"Wu","year":"2023","journal-title":"Gut Liver"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhou, Z., Plug, L.G., Patente, T.A., de Jonge-Muller, E.S.M., Elmagd, A.A., van der Meulen-de Jong, A.E., Everts, B., Barnhoorn, M.C., and Hawinkels, L.J.A.C. (2022). Increased Stromal PFKFB3-Mediated Glycolysis in Inflammatory Bowel Disease Contributes to Intestinal Inflammation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.966067"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Che, X., Zhang, Y., Chen, X., Xie, G., Li, J., Xu, C., Zhang, C., Zhu, Y., and Yang, X. (2025). The Lactylation-Macrophage Interplay: Implications for Gastrointestinal Disease Therapeutics. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1608115"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1186\/s12967-025-06748-0","article-title":"Lactate and Lactylation: Novel Perspectives on Fibrosis Pathogenesis and Therapeutic Directions","volume":"23","author":"Liang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/s42255-020-0243-4","article-title":"Lactate: The Ugly Duckling of Energy Metabolism","volume":"2","author":"Rabinowitz","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1164\/rccm.201201-0084OC","article-title":"Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-\u03b2","volume":"186","author":"Kottmann","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.7150\/ijbs.91492","article-title":"Histone Lactylation: From Tumor Lactate Metabolism to Epigenetic Regulation","volume":"20","author":"Yu","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic Regulation of Gene Expression by Histone Lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1093\/ibd\/izz188","article-title":"Systematic Review and Meta-Analysis: Short-Chain Fatty Acid Characterization in Patients with Inflammatory Bowel Disease","volume":"25","author":"Zhuang","year":"2019","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.cmet.2019.10.004","article-title":"Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring","volume":"30","author":"Pucino","year":"2019","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1042\/CS20242737","article-title":"Insight into the Roles of Lactylation in Macrophages: Functions and Clinical Implications","volume":"139","author":"Shu","year":"2025","journal-title":"Clin. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the Full Spectrum of Macrophage Activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"(2014). Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines. Immunity, 41, 14\u201320.","DOI":"10.1016\/j.immuni.2014.06.008"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature13490","article-title":"Functional Polarization of Tumour-Associated Macrophages by Tumour-Derived Lactic Acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Xie, Y., Hu, H., Liu, M., Zhou, T., Cheng, X., Huang, W., and Cao, L. (2022). The Role and Mechanism of Histone Lactylation in Health and Diseases. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.949252"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1186\/s12967-024-05092-z","article-title":"Immunological Profile of Lactylation-Related Genes in Crohn\u2019s Disease: A Comprehensive Analysis Based on Bulk and Single-Cell RNA Sequencing Data","volume":"22","author":"Wu","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3810\/pgm.2014.07.2779","article-title":"Gut Microbiota and Inflammatory Bowel Disease: The Role of Antibiotics in Disease Management","volume":"126","author":"Kerman","year":"2014","journal-title":"Postgrad. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103293","DOI":"10.1016\/j.ebiom.2021.103293","article-title":"Short Chain Fatty Acids and Its Producing Organisms: An Overlooked Therapy for IBD?","volume":"66","author":"Deleu","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.chom.2022.02.004","article-title":"Gut Microbiota-Derived Bile Acids in Intestinal Immunity, Inflammation, and Tumorigenesis","volume":"30","author":"Cai","year":"2022","journal-title":"Cell Host Microbe"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1056\/NEJMra2002697","article-title":"Pathophysiology of Inflammatory Bowel Diseases","volume":"383","author":"Chang","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1038\/s41467-026-69127-3","article-title":"SOD1 Lactylation Impair Its Enzymatic Activity by Conformational Change to Aggravate Intervertebral Disc Degeneration","volume":"17","author":"Zhang","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17943","DOI":"10.1038\/s41598-026-45451-y","article-title":"An Integrated Analysis of Lactylation Signature Reveals PRDX1 as a Therapeutic Target of Keloid Pathogenesis","volume":"16","author":"He","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14891","DOI":"10.2147\/JIR.S539938","article-title":"Lactylation-Related Gene CALM1 Promotes Aortic Dissection via Immune Microenvironment Remodeling: Insights from Bioinformatics and Clinical Evidence","volume":"18","author":"Yu","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.4251\/wjgo.v16.i3.1029","article-title":"CALD1 Facilitates Epithelial-Mesenchymal Transition Progression in Gastric Cancer Cells by Modulating the PI3K-Akt Pathway","volume":"16","author":"Ma","year":"2024","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1096\/fj.201800535R","article-title":"Calcium\/Calmodulin\u2013Dependent Protein Kinase IV (CaMKIV) Activation Contributes to the Pathogenesis of Experimental Colitis via Inhibition of Intestinal Epithelial Cell Proliferation","volume":"33","author":"Cunningham","year":"2019","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.31083\/j.rcm2403081","article-title":"Role of the Stress- and Inflammation-Induced Cytokine GDF-15 in Cardiovascular Diseases: From Basic Research to Clinical Relevance","volume":"24","author":"Schwarz","year":"2023","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s12959-023-00547-7","article-title":"GDF15 Affects Venous Thrombosis by Promoting EndMT through Smad2\/p-Smad2 Pathway","volume":"21","author":"Li","year":"2023","journal-title":"Thromb. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.exphem.2022.08.005","article-title":"CXCR4 and CD74 Together Enhance Cell Survival in Response to Macrophage Migration-Inhibitory Factor in Chronic Lymphocytic Leukemia","volume":"115","author":"Thavayogarajah","year":"2022","journal-title":"Exp. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Youness, R.A., Elemam, N.M., Abdelhamid, A.M., Mohamed, A.H., Elsherbiny, L.M., Ramzy, A., and Assal, R.A. (2025). Macrophage Migration Inhibitory Factor (MIF) and the Tumor Ecosystem: A Tale of Inflammation, Immune Escape, and Tumor Growth. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1636839"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"102004","DOI":"10.1016\/j.redox.2021.102004","article-title":"The Histone Methyltransferase SETD2 Modulates Oxidative Stress to Attenuate Experimental Colitis","volume":"43","author":"Liu","year":"2021","journal-title":"Redox Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1038\/s41467-019-09982-5","article-title":"CUT&tag for Efficient Epigenomic Profiling of Small Samples and Single Cells","volume":"10","author":"Wu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2307216","DOI":"10.1002\/advs.202307216","article-title":"Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis-Associated Acute Kidney Injury","volume":"11","author":"Qiao","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"295","DOI":"10.5217\/ir.2023.00029","article-title":"Animal Models of Inflammatory Bowel Disease: Novel Experiments for Revealing Pathogenesis of Colitis, Fibrosis, and Colitis-Associated Colon Cancer","volume":"21","author":"Lee","year":"2023","journal-title":"Intest. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21475","DOI":"10.1038\/s41598-020-78359-2","article-title":"Development of a Human Primary Gut-on-a-Chip to Model Inflammatory Processes","volume":"10","author":"Beaurivage","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6591","DOI":"10.1038\/s41598-022-10587-0","article-title":"High Serum Concentrations of Growth Differentiation Factor-15 and Their Association with Crohn\u2019s Disease and a Low Skeletal Muscle Index","volume":"12","author":"Yamamoto","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S2468-1253(24)00044-X","article-title":"Mechanisms and Management of Loss of Response to Anti-TNF Therapy for Patients with Crohn\u2019s Disease: 3-Year Data from the Prospective, Multicentre PANTS Cohort Study","volume":"9","author":"Chanchlani","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/j.cgh.2024.01.026","article-title":"Biomarkers for Personalizing IBD Therapy: The Quest Continues","volume":"22","author":"Atreya","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Silva, I., Solas, J., Pinto, R., Mateus, V., Silva, I., Solas, J., Pinto, R., and Mateus, V. (2022). Chronic Experimental Model of TNBS-Induced Colitis to Study Inflammatory Bowel Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094739"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1093\/ecco-jcc\/jjac084","article-title":"CD147 Targeting by AC-73 Induces Autophagy and Reduces Intestinal Fibrosis Associated with TNBS Chronic Colitis","volume":"16","author":"Butera","year":"2022","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"106426","DOI":"10.1016\/j.intimp.2020.106426","article-title":"Andrographolide Sulfonate Ameliorates Chronic Colitis Induced by TNBS in Mice via Decreasing Inflammation and Fibrosis","volume":"83","author":"Gao","year":"2020","journal-title":"Int. Immunopharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6343\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T04:12:54Z","timestamp":1784434374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":47,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146343"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146343","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}