{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:30:52Z","timestamp":1786336252922,"version":"build-2736575974"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Severe combat trauma is associated with long-lasting systemic changes, yet standard anatomical injury scales may not adequately capture biological differences in patient recovery. To explore this variability, we analyzed the systemic molecular profiles of 53 combat trauma survivors during the rehabilitation phase and compared them to those of 46 uninjured active-duty military controls. Using a multidimensional biomarker panel (IL-33, ST2, TGF-\u03b21, CTGF, galectin-3, heparan sulfate, NT-proBNP, and annexin A5) alongside routine clinical parameters, we applied unsupervised clustering and Random Forest machine learning to identify distinct patient endotypes. Our results showed that patients grouped into distinct molecular phenotypes, independent of their initial structural injury patterns. While localized structural injuries and associated infections (e.g., limb amputations) significantly influenced pro-fibrotic and pro-coagulant pathways, the overarching systemic features defining the machine-learning endotypes closely linked to an immuno-metabolic axis. This axis is characterized by elevated IL-33, endothelial glycocalyx shedding, and markers of metabolic, hepatic, and hematological strain (hemoglobin, white blood cells, AST, ALT, and total protein) rather than classical fibrotic markers. Notably, while circulating IL-33 levels varied significantly among patients, its soluble receptor, ST2, remained stable. These findings suggest that high-risk trauma patients may experience ongoing, ligand-driven systemic exhaustion. Integrating molecular endotyping into military medicine could improve clinical monitoring and guide targeted rehabilitation strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1906285","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:21:35Z","timestamp":1786335695000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Machine learning reveals an interleukin-33-associated immuno-metabolic axis defining recovery endotypes in severe combat trauma"],"prefix":"10.3389","volume":"17","author":[{"given":"Vladyslav","family":"Bardash","sequence":"first","affiliation":[{"name":"Center for Nephrology and Dialysis, St. Panteleimon Hospital, First Lviv Medical Union","place":["Lviv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleh","family":"Samchuk","sequence":"additional","affiliation":[{"name":"General Directorate, First Territorial Medical Union of Lviv","place":["Lviv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Skrypnyk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine No. 1, Poltava State Medical University","place":["Poltava, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Sklyarov","sequence":"additional","affiliation":[{"name":"Department of Therapy No. 1, Medical Diagnostics, Hematology, and Transfusiology, Faculty of Postgraduate Education, Danylo Halytsky Lviv National Medical University","place":["Lviv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60687-5","article-title":"The systemic immune response to trauma: an overview of pathophysiology and treatment","volume":"384","author":"Lord","year":"2014","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0064-8","article-title":"Innate immune responses to trauma","volume":"19","author":"Huber-Lang","year":"2018","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13054-017-1605-5","article-title":"Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism","volume":"21","author":"Johansson","year":"2017","journal-title":"Crit Care"},{"key":"B4","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s12967-015-0481-5","article-title":"Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients","volume":"13","author":"Rahbar","year":"2015","journal-title":"J Transl Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00068-019-01235-w","article-title":"Damage-associated molecular patterns in trauma","volume":"46","author":"Relja","year":"2020","journal-title":"Eur J Trauma Emerg Surg"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.95","article-title":"Interleukin-33 in health and disease","volume":"16","author":"Liew","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1146\/annurev-pathmechdis-012419-032847","article-title":"DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation","volume":"15","author":"Zindel","year":"2020","journal-title":"Annu Rev Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-\u03b2: the master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2938-9","article-title":"Fibrosis: from mechanisms to medicines","volume":"587","author":"Henderson","year":"2020","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.injury.2015.07.003","article-title":"Defining major trauma using the 2008 Abbreviated Injury Scale","volume":"47","author":"Palmer","year":"2016","journal-title":"Injury"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2025.1638451","article-title":"Advancing the allostatic load model in military training research: from theory to application","volume":"16","author":"Feigel","year":"2025","journal-title":"Front Physiol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-019-0202-0","article-title":"Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies","volume":"6","author":"Thompson","year":"2019","journal-title":"Mil Med Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s13054-022-04103-z","article-title":"Development of clinical phenotypes and biological profiles via proteomic analysis of trauma patients","volume":"26","author":"Tachino","year":"2022","journal-title":"Crit Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0000000000004805","article-title":"Augmenting decision making in acute care surgery: a systematic review of machine learning\u2013driven risk prediction models","volume":"100","author":"Lee","year":"2026","journal-title":"J Trauma Acute Care Surg"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbs034","article-title":"Data mining in the life sciences with Random Forest: a walk in the park or lost in the jungle","volume":"14","author":"Touw","year":"2013","journal-title":"Brief Bioinform"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccc.2016.08.006","article-title":"Postinjury inflammation and organ dysfunction","volume":"33","author":"Sauaia","year":"2017","journal-title":"Crit Care Clin"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000981","article-title":"Evidence for persistent immune suppression in patients who develop chronic critical illness after sepsis","volume":"49","author":"Stortz","year":"2018","journal-title":"Shock"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002352","article-title":"Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: a prospective cohort study","volume":"14","author":"Cabrera","year":"2017","journal-title":"PloS Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12619","article-title":"Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family","volume":"281","author":"Cayrol","year":"2018","journal-title":"Immunol Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2012.575","article-title":"Role of elevated liver transaminase levels in the diagnosis of liver injury after blunt abdominal trauma","volume":"4","author":"Tian","year":"2012","journal-title":"Exp Ther Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000513","article-title":"The glycocalyx and trauma: a review","volume":"45","author":"Chignalia","year":"2016","journal-title":"Shock"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/s12950-022-00303-0","article-title":"Key early proinflammatory signaling molecules encapsulated within circulating exosomes following traumatic injury","volume":"19","author":"Walsh","year":"2022","journal-title":"J Inflammation"},{"key":"B23","doi-asserted-by":"publisher","first-page":"265sr6","DOI":"10.1126\/scitranslmed.3009337","article-title":"Wound repair and regeneration: mechanisms, signaling, and translation","volume":"6","author":"Eming","year":"2014","journal-title":"Sci Transl Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14450","article-title":"Trauma-induced coagulopathy: the past, present, and future","volume":"17","author":"Kornblith","year":"2019","journal-title":"J Thromb Haemost"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000002577","article-title":"Phenotyping the immune response to trauma: a multiparametric systems immunology approach","volume":"45","author":"Seshadri","year":"2017","journal-title":"Crit Care Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000002074","article-title":"Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome","volume":"45","author":"Mira","year":"2017","journal-title":"Crit Care Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2019.4917","article-title":"Artificial intelligence and surgical decision-making","volume":"155","author":"Loftus","year":"2020","journal-title":"JAMA Surg"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2660","article-title":"The IL-33\/ST2 pathway: therapeutic target and novel biomarker","volume":"7","author":"Kakkar","year":"2008","journal-title":"Nat Rev Drug Discov"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00475","article-title":"The ST2\/IL-33 axis in immune cells during inflammatory diseases","volume":"8","author":"Griesenauer","year":"2017","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/MCC.0b013e32835ec9e6","article-title":"Hypoxic liver injury and cholestasis in critically ill patients","volume":"19","author":"Horvatits","year":"2013","journal-title":"Curr Opin Crit Care"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature21363","article-title":"Inflammation, metaflammation and immunometabolic disorders","volume":"542","author":"Hotamisligil","year":"2017","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1519\/JSC.0b013e31825d8263","article-title":"Strength training for the warfighter","volume":"26","author":"Kraemer","year":"2012","journal-title":"J Strength Cond Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0000000000001596","article-title":"Towards precision medicine: accurate predictive modeling of infectious complications in combat casualties","volume":"83","author":"Dente","year":"2017","journal-title":"J Trauma Acute Care Surg"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000395","article-title":"Impact of injury severity on dynamic inflammation networks following blunt trauma","volume":"44","author":"Almahmoud","year":"2015","journal-title":"Shock"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.92280","article-title":"Artificial intelligence in trauma and orthopaedic surgery: a comprehensive review from diagnosis to rehabilitation","volume":"17","author":"Mohamed","year":"2025","journal-title":"Cureus"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0224365","article-title":"Machine learning algorithm validation with a limited sample size","volume":"14","author":"Vabalas","year":"2019","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1097\/TA.0b013e3182ab1ab5","article-title":"Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma","volume":"76","author":"Vanzant","year":"2014","journal-title":"J Trauma Acute Care Surg"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0000000000004087","article-title":"The persistent inflammation, immunosuppression, and catabolism syndrome 10 years later","volume":"95","author":"Efron","year":"2023","journal-title":"J Trauma Acute Care Surg"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1906285\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:21:35Z","timestamp":1786335695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1906285\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2026.1906285"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1906285","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"article-number":"1906285"}}