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Intestinal mucositis is a common side effect of anticancer regimens that exerts a negative impact on chemotherapy.Superoxide dismutase (SOD) is a potential therapy for mucositis but efficient product is not available because the enzyme is degraded following oral administration or induces an immune reaction after intravascular infusion.Multi-modified Stable Anti-Oxidant Enzymes· (MS-AOE·) is a new recombinant SOD with better resistance to pepsin and trypsin.We referred it as MS-SOD to distinguish from other SODs.In this study we investigated its potential to alleviate S-FU-induced intestinal injury and the mechanisms.An intestinal mucositis model was established in C57/BL6 mice by 5-day administration of 5-FU (50 mg/kg every day,ip).MS-SOD (800 IU/10 g,ig) was given once daily for g days.5-FU caused severe mucositis with intestinal morphological damage,bodyweight loss and diarrhea;MS-SOD significantly decreased the severity.S-FU markedly increased reactive oxygen species (ROS) and inflammatory cytokines in the intestine which were ameliorated by MS-SOD.Furthermore,MS-SOD modified intestinal microbes,particularly reduced Verrucomicrobia,compared with the 5-FU group.In Caco2 cells,MS-SOD (250-1000 U/mL) dosedependently decreased tBHP-induced ROS generation.In RAW264.7 cells,MS-SOD (500 U/mL) had no effect on LPS-induced inflammatory cytokines,but inhibited iNOS expression.These results demonstrate that MS-SOD can scavenge ROS at the initial stage of injury,thus play an indirect role in anti-inflammatory and barrier protein protection.In conclusion,MS-SOD attenuates 5-FU-induced intestinal mucositis by suppressing oxidative stress and inflammation,and influencing microbes.MS-SOD may exert beneficial effect in prevention of intestinal mucositis during chemotherapy in clinic.