Lactiplantibacillus plantarum AS21 Reduces Colitis in Mice by Modulating Inflammation, Gut Barrier Function, and Microbiota in an Intervention Dose and Time-dependent Manner.

Ulcerative colitis is a chronic inflammatory disease with rising global incidence and limited treatment options. Despite growing interest in probiotic-based therapies, the dose- and time-specific efficacy of antioxidant strains remains poorly defined. Here, we investigated the therapeutic effects of intervention doses (Low, Medium, High) and pre-treatment times (7, 14, 21 days) of Lactiplantibacillus plantarum AS21 on DSS-induced colitis in mice. L. plantarum AS21 significantly reduced disease activity index and histological scores, enhancing IL-10 expression while suppressing IL-1β, IL-6, TNF-α, and IFN-γ (p < 0.05). Colon length shortening was attenuated, and spleen weight was reduced in the treated groups. Oxidative stress markers MDA and MPO decreased, whereas SOD, CAT, and GSH increased in a dose- and time-dependent manner (p < 0.05). Mucosal barrier integrity was restored through claudin-1 and occludin upregulation and increased goblet cell counts (p < 0.05). Alpha diversity showed no significant differences, but beta diversity revealed significant separation across groups (p < 0.05). Beneficial taxa (Firmicutes, Ileibacterium, Allobaculum) were enriched, while pathogenic taxa (Akkermansia, Proteobacteria) were reduced in treated groups (p < 0.05). Anti-inflammatory metabolites (7-dehydrocholesterol, riboflavin, citric acid, lipid derivatives) and short-chain fatty acids were significantly upregulated (p < 0.05). Medium and high doses, together with 14- and 21-day pre-treatment, conferred significantly greater protective effects than 7-day pre-treatment or low-dose groups (p < 0.05). These findings establish precise dose- and time-dependent parameters for maximizing L. plantarum AS21 anti-colitic efficacy, positioning it as a promising candidate for microbiota- and metabolism-targeted UC therapy.