Gut microbiota-related glutathione metabolism is key mechanism for sulforaphane ameliorating ulcerative colitis.

Gut barrier dysfunction is associated with dysbiosis of the gut microbiota and its metabolites, which is closely linked to the pathogenesis of ulcerative colitis (UC). Recent studies have demonstrated that Sulforaphane (SFN) exerts beneficial effects on UC. However, the role of the gut microbiota and microbial metabolism in the anti-UC mechanisms of SFN remains inadequately understood. In this study, we observed that SFN administration significantly improved the pathological phenotype, restored gut barrier integrity, and reduced colon inflammation in dextran sulfate sodium (DSS)-induced colitis mice. Gut microbiota analysis illustrated that SFN administration rebalances the alterations in gut microbiota composition, including genera such as Turicibacter, Lactobacillus and Bacteroides, in DSS-induced mice. Furthermore, untargeted metabolomics analysis indicated that the levels of microbial arachidonic acid metabolism, as well as the metabolism of alanine, aspartate, and glutamate, and glutathione metabolism in the gastrointestinal tract, were significantly altered in DSS-induced mice. Interestingly, SFN treatment significantly restore the alterations in glutathione metabolism and the levels of associated metabolites. Additionally, we observed that the MAPK/NF-κB signaling pathway, regulated by glutathione metabolism, was inhibited in the colon of DSS-induced mice following SFN treatment. Collectively, these results suggest that SFN can alleviate DSS-induced colitis in mice by restoring dysregulated gut microbiota and glutathione metabolism, thereby modulating the MAPK/NF-κB signaling pathway, enhancing intestinal barrier function and reducing colonic inflammation. Importantly, our findings elucidate a novel mechanism by which SFN improves gut barrier function, highlighting its potential to advance the development of SFN-derived therapeutics for the clinical management of colitis.