Oral lichen planus (OLP) is a chronic inflammatory oral disease associated with immune dysregulation and malignant transformation risk. Vitamin D and probiotics may modu-late immune and microbial pathways involved in OLP. In this study, we evaluated their effects on clinical outcomes and multi-omics profiles in 25 adult OLP patients. Vitamin D-deficient patients received 2,000 IU/day vitamin D3, and all participants received a probiotic blend (Limosilactobacillus reuteri LRE11, Lactica-seibacillus rhamnosus LR04, and Lacticaseibacillus casei LC04) for 16 weeks. Clinical assess-ments and analyses of saliva, serum, oral swabs, and stool samples were performed be-fore and after treatment. Following the intervention, 76% of participants achieved clinical remission. Significant metabolomic changes were observed mainly in saliva and feces. Serum cytokines, me-tabolites, and lipoproteins showed no significant differences. Microbiome profiling demonstrated treatment-related compositional shifts in oral and fecal samples, including increased Lacticaseibacillus abundance. Multi-omics integration identified coordinated in-teractions among microbial, metabolic, immune, and lipid pathways, highlighting inter-connected gut-oral biological responses. Combined vitamin D and probiotic supplementation was associated with clinical im-provement and coordinated oral-intestinal multi-omics changes, supporting a sys-tems-level understanding of OLP remission. These findings suggest that modulating the microbiota-metabolism-immunity axis could represent a promising therapeutic strategy for achieving sustained disease control and clinical remission.

Oral lichen planus (OLP) is a chronic inflammatory oral disease associated with immune dysregulation and malignant transformation risk. Vitamin D and probiotics may modulate immune and microbial pathways involved in OLP. In this study, we evaluated their effects on clinical outcomes and multi-omics profiles in 25 adult OLP patients (median age: 68 years). Vitamin D-deficient patients received 2000 IU/day vitamin D3, and all participants received a probiotic blend (Limosilactobacillus reuteri LRE11, Lacticaseibacillus rhamnosus LR04, and Lacticaseibacillus casei LC04) for 16 weeks. Clinical assessments and analyses of saliva, serum, oral swabs, and stool samples were performed before and after treatment. Clinical outcomes improved significantly, with reductions in lesion number (p < 0.001), lesion size (p = 0.004), and bleeding lesions (p = 0.014); 76% of patients were classified as in remission. Vitamin D levels increased significantly among deficient patients receiving correction (p < 0.01). Salivary and fecal metabolomics showed significant remodeling of amino acid and carbohydrate pathways, including decreases in branched-chain amino acids in saliva and modulation of nicotinamide- and amino acid-related metabolites in feces. Microbiome α-diversity remained stable, whereas β-diversity shifted significantly across oral and fecal sites, with enrichment of Lacticaseibacillus and other context-dependent commensals. Multi-omics integration identified three latent factors linking salivary cytokines, microbial taxa, metabolites, and systemic lipid profiles, suggesting coordinated mucosal–metabolic–immune remodeling across the oral–gut axis.