Diosmetin Alleviates Cerebral Ischemia/Reperfusion Injury by Modulating Tryptophan Metabolism through the Microbiota-Gut-Brain Axis

Cerebral ischemia-reperfusion (I/R) injury involves brain tissue damage caused by a temporary interruption of blood flow followed by reperfusion, leading to inflammation, oxidative stress, and neuronal death. Diosmetin, a flavonoid with known anti-inflammatory and antioxidant properties, has been shown to mitigate I/R injury, but its impact on systemic inflammation is not fully understood. In this study, we investigated its protective effects on I/R injury and the mechanisms mediated through the microbiota-gut-brain axis. Using MCAO-induced rats and OGD/R-induced PC12 cells, we employed multiomics sequencing and molecular biology techniques. The results showed that the IL-6/pJAK1/pSTAT3 signaling pathway was the key mechanism influenced by tryptophan metabolites. Diosmetin alleviated intestinal and systemic inflammation by modulating tryptophan metabolism and gut microbiota dysbiosis. Microbiota transplantation from diosmetin-treated rats produced similar protective effects. In conclusion, diosmetin mitigated I/R injury by influencing tryptophan metabolism through the microbiota-gut-brain axis, offering potential therapeutic strategies for I/R injury.