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Although targeted microbial therapies are an emerging intervention strategy for inflammatory bowel disease (IBD), the mechanisms by which specific probiotics, such as Lactobacillus fermentum 016 (LF), alleviate UC remain unclear. The current study evaluated the effects of LF supplementation on gut health in a basal model using C57BL\/6 mice. Subsequently, the preventive effects and mechanisms of LF supplementation on DSS-induced UC were systematically investigated. According to our findings, LF supplementation revealed immunoregulatory capabilities with significantly altered gut the composition of microbiota and metabolic activities, particularly enhancing tryptophan metabolism. In the UC model, LF supplementation effectively mitigated weight loss, increased the disease activity index (DAI), and alleviated diarrhea, rectal bleeding, and colon shortening. Moreover, it reduced colonic pathological damage and histological injury scores. LF intervention improved antioxidant markers and intestinal mucosal barrier function with the activation of the Nrf2\u2013Keap1 signaling pathway and regulation of systemic inflammatory markers, i.e., IL-1\u03b2, IL-6, TNF-\u03b1, IFN-\u03b3, IL-4, and IL-10. Importantly, LF supplementation reversed metabolic disturbances by significantly increasing the abundance of beneficial genera (e.g., g_Dubosiella, g_Faecalibaculum, g_Odoribacter, g_Candidatus_saccharimonas, g_Roseburia, and g_Eubacterium_xylanophilum_group) and elevating tryptophan metabolites (e.g., melatonin, kynurenic acid, 3-indoleacetic acid, 5-methoxytryptophan, and 5-hydroxyindoleacetic acid). In conclusion, Lactobacillus fermentum 016 exhibits potential for regulating gut microbiota homeostasis, enhancing tryptophan metabolism, and alleviating UC, providing critical insights for developing probiotic-based precision therapeutic strategies for IBD.<\/jats:p>","DOI":"10.3390\/nu17030452","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T09:42:23Z","timestamp":1737970943000},"page":"452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Lactobacillus fermentum 016 Alleviates Mice Colitis by Modulating Oxidative Stress, Gut Microbiota, and Microbial Metabolism"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4132-0946","authenticated-orcid":false,"given":"Huachun","family":"Pan","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Yang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Agriculture Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9512-5230","authenticated-orcid":false,"given":"Md. 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