Microbial diversity on DSS induced colitis mouse model.
Disruption of gut microbiota and circadian rhythms contributes to the development of inflammatory bowel disease. Here, we show that extracellular vesicles derived from Limosilactobacillus fermentum SLAM216 alleviate DSS-induced colitis in mice through coordinated control of intestinal inflammation, barrier integrity, microbiota composition, metabolite profiles, and circadian gene expression. Oral administration of LF216EV reduced body weight loss, disease activity index scores, and colon shortening, while restoring epithelial structure and decreasing pro-inflammatory cytokines and increasing tight junction-related genes. LF216EV modulated the gut microbiota by suppressing harmful taxa and promoting beneficial taxa, including Akkermansia and Bacteroides. At the same time, LF216EV regulated metabolite profiles linked to the tricarboxylic acid cycle and amino acid metabolism, suggesting recovery of energy and nutrient balance. Importantly, DSS-induced disruption of the circadian gene Bmal1 was normalized by LF216EV in both mouse colon tissue and HT-29 intestinal epithelial cells, restoring rhythmicity, period length, and amplitude. Together, these findings indicate that LF216EV coordinates a microbiome-metabolite-circadian axis to restore intestinal homeostasis, highlighting its potential as a postbiotic therapy for inflammatory bowel disease.