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Background: Colonic and serum inosine are significantly reduced in patients with inflammatory bowel disease (IBD). Methods: This study aimed to explore whether microbiome-derived inosine alleviates colitis and its underlying mechanisms. Results: An inosine intervention effectively improved the clinical signs in colitis mice, suppressed inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β) by regulating the nuclear factor-kappa B (NF-κB) pathway, and elevated the activities of anti-oxidative enzymes (including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)) by regulating the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway. Additionally, the inosine intervention significantly elevated the expression of tight junction proteins (ZO-1, occudin, and claudin-1) in mice with colitis. High-throughput sequencing revealed that the inosine intervention also prevented gut microbiota disorder by increasing the abundance of beneficial bacteria (<i>Lachnospiraceae NK4A136 group</i>, <i>Romboutsia</i>, <i>Marvinbryantia</i>, <i>Clostridium sensu stricto</i> 1, and <i>Bifidobacterium</i>) and reducing the abundance of harmful bacteria (<i>Pseudomonas</i>, <i>Acinetobacter</i>, and <i>Tyzzerella</i>) in mice with colitis. Conclusions: Inosine played a significant role in mitigating colitis-related intestinal barrier injury and could potentially be used for therapy in clinical practice.