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Exclusive enteral nutrition (EEN) is a first-line therapy for inducing remission in pCD, yet its precise mechanisms remain poorly understood. This review summarizes the complex interplay of EEN-induced protective changes in the gut microbiota, epithelial barrier function and mucosal immune responses. EEN reshapes the gut microbiome by excluding potential pathobionts from the gut mucus layer and increasing protective bacterial and dietary metabolites. Emerging evidence highlights the role of EEN in modulating mitochondrial function, tryptophan metabolism and other metabolites in the intestinal epithelium and immune cells, which may contribute to its therapeutic efficacy. However, high variability in microbiome responses across clinical cohorts and discrepancies between clinical trials and animal models warrant further research to identify functional consequences and therapeutic mechanisms of EEN.<\/jats:p>","DOI":"10.1007\/s00281-025-01053-w","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T11:54:41Z","timestamp":1751457281000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Therapeutic mechanisms of exclusive enteral nutrition in Crohn\u2019s disease"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7587-3250","authenticated-orcid":false,"given":"Tina","family":"Krammel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3192-0095","authenticated-orcid":false,"given":"Jiatong","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-9470","authenticated-orcid":false,"given":"Deborah","family":"H\u00e4cker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2281-4852","authenticated-orcid":false,"given":"Tobias","family":"Schwerd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4154-3592","authenticated-orcid":false,"given":"Doriane","family":"Aguanno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6977-4085","authenticated-orcid":false,"given":"Dirk","family":"Haller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"issue":"1","key":"1053_CR1","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41572-020-0156-2","volume":"6","author":"G Roda","year":"2020","unstructured":"Roda G et al (2020) Crohn\u2019s disease. 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