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This study investigated the protective effects of low-molecular-weight fractions (&lt;3 kDa) of the probiotic Limosilactobacillus fermentum CECT5716 (LMW-LF) in a murine model of experimental colitis. Methods: Male C57BL\/6J mice were orally administered LMW-LF for 10 days prior to colitis induction with 3% dextran sodium sulfate (DSS) for 5 days. Colonic damage was assessed via the Disease Activity Index (DAI), histology, and immunofluorescence (Ocln and Ki67). Immune cell populations were analyzed by flow cytometry, while mucosal gene expression and gut microbiota composition were evaluated using RT-qPCR and 16S rRNA sequencing, respectively. Results: LMW-LF administration significantly attenuated clinical symptoms and macroscopic colonic damage. Treatment restored epithelial barrier integrity by upregulating tight junction proteins (Tjp1) and mucin genes (Muc1-3) while normalizing DSS-induced epithelial hyperproliferation. Immunologically, LMW-LF reduced pro-inflammatory monocyte infiltration; downregulated Il6, Tnfa, and Ifng; and promoted an immunoregulatory phenotype by enhancing Ampk expression and partially restoring regulatory T cell (Treg) populations. Furthermore, LMW-LF reshaped the gut microbiota by increasing alpha diversity and promoting the enrichment of beneficial taxa, specifically Akkermansia muciniphila, which correlated with improved mucus layer preservation. Conclusions: LMW-LF is an active fraction acting across the host\u2013microbiota axis. By integrating epithelial protection, immunomodulation, and microbial reshaping, it represents a promising dietary strategy for the management of Inflammatory Bowel Diseases.<\/jats:p>","DOI":"10.3390\/nu18121890","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"1890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bioactive Low-Molecular-Weight Fraction from Limosilactobacillus fermentum CECT5716 Attenuates Intestinal Inflammation and Dysbiosis in DSS-Treated Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9301-632X","authenticated-orcid":false,"given":"Luckman","family":"Gbati","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"},{"name":"Microbiology and Food Quality Control Laboratory (LAMICODA), Higher School of Biological and Food Techniques (ESTBA), University of Lom\u00e9, Lom\u00e9 01 BP 1515, Togo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jes\u00fas","family":"Rodr\u00edguez-Sojo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1554-9226","authenticated-orcid":false,"given":"Jose Alberto","family":"Molina-Tijeras","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"},{"name":"Department of Health, Medicine and Life Sciences, Faculty of Science, Technology and Medicine, University of Luxembourg, 4367 Esch-sur-Alzette, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0925-9441","authenticated-orcid":false,"given":"Jorge","family":"Garc\u00eda-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"},{"name":"Servicio de Microbiolog\u00eda, Hospital Universitario San Cecilio, 18007 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"L\u00f3pez-Esc\u00e1nez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9780-0180","authenticated-orcid":false,"given":"Teresa","family":"Vezza","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"},{"name":"Servicio de Digestivo, Hospital Universitario Virgen de las Nieves, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4323-650X","authenticated-orcid":false,"given":"Antonio Jes\u00fas","family":"Ruiz-Malagon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djeri","family":"Boura\u00efma","sequence":"additional","affiliation":[{"name":"Microbiology and Food Quality Control Laboratory (LAMICODA), Higher School of Biological and Food Techniques (ESTBA), University of Lom\u00e9, Lom\u00e9 01 BP 1515, Togo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-781X","authenticated-orcid":false,"given":"Federico","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"},{"name":"Servicio de Microbiolog\u00eda, Hospital Universitario San Cecilio, 18007 Granada, Spain"},{"name":"CIBER-Enfermedades Infecciosas (CIBER-Infecc), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6876-3782","authenticated-orcid":false,"given":"Julio","family":"G\u00e1lvez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain"},{"name":"CIBER-Enfermedades Hep\u00e1ticas y Digestivas (CIBER-EHD), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-0628","authenticated-orcid":false,"given":"Alba","family":"Rodr\u00edguez-Nogales","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), 18012 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