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Neutrophils, as key effectors of the innate immune system, contribute to IBD through multiple mechanisms, including the release of reactive oxygen species (ROS), pro-inflammatory cytokines, and neutrophil extracellular traps (NETs). NETs are web-like structures composed of DNA, histones, and associated proteins including proteolytic enzymes and antimicrobial peptides. NET formation is increased in IBD and has a context-dependent role; under controlled conditions, NETs support antimicrobial defense and tissue repair, whereas excessive or dysregulated NETosis contributes to epithelial injury, barrier disruption, microbial imbalance, and thrombotic risk. This review examines the roles of neutrophils and NETs in IBD. We summarize recent single-cell and spatial-omics studies that reveal extensive neutrophil heterogeneity in the inflamed gut. We then address the dual role of neutrophils in promoting tissue damage\u2014through cytokine release, immune cell recruitment, ROS production, and NET formation\u2014and in supporting microbial clearance and mucosal healing. We also analyze the molecular mechanisms regulating NETosis, as well as the pathways involved in NET degradation and clearance. Focus is given to the ways in which NETs disrupt the epithelial barrier, remodel the extracellular matrix, contribute to thrombosis, and influence the gut microbiota. Finally, we discuss emerging therapeutic strategies aimed at restoring NET homeostasis\u2014such as PAD4 inhibitors, NADPH oxidase and ROS pathway modulators, and DNase I\u2014while emphasizing the need to preserve antimicrobial host defenses. Understanding neutrophil heterogeneity and NET-related functions may facilitate the development of new therapies and biomarkers for IBD, requiring improved detection tools and integrated multi-omics and clinical data.<\/jats:p>","DOI":"10.3390\/ijms26157098","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:52:47Z","timestamp":1753271567000},"page":"7098","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Neutrophils and NETs in Pathophysiology and Treatment of Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7358-3265","authenticated-orcid":false,"given":"Marina","family":"Ortega-Zapero","sequence":"first","affiliation":[{"name":"LamImSys Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"},{"name":"Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6665-7732","authenticated-orcid":false,"given":"Raquel","family":"Gomez-Bris","sequence":"additional","affiliation":[{"name":"LamImSys Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"},{"name":"Department of Physiology, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid (UAM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Pascual-Laguna","sequence":"additional","affiliation":[{"name":"Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9189-4737","authenticated-orcid":false,"given":"Angela","family":"Saez","sequence":"additional","affiliation":[{"name":"LamImSys Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"},{"name":"Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarc\u00f3n, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1177-869X","authenticated-orcid":false,"given":"Jose M.","family":"Gonzalez-Granado","sequence":"additional","affiliation":[{"name":"LamImSys Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain"},{"name":"Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1001\/jama.2023.15389","article-title":"Ulcerative Colitis in Adults: A Review","volume":"330","author":"Gros","year":"2023","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41572-020-0156-2","article-title":"Crohn\u2019s disease","volume":"6","author":"Roda","year":"2020","journal-title":"Nat. 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