Abstract: Objective: To explore the mitigation effects of fermented wax gourd microorganisms and mouse intestinal flora on Staphylococcus aureus. Methods: The ICR mice were randomly divided into the control group (CT), smelly wax gourd group (SW), Staphylococcus aureus group (SA) and Staphylococcus aureus + smelly wax gourd group (SA+SW) according to gender. 16S rDNA high-throughput sequencing was used to analyze the dominant flora of the mouse intestines, the differences in flora, the changes of probiotics in the mouse intestines, and the correlation between the intestinal flora and short-chain fatty acids. Results: Whether male or female mice, fermented wax gourd could change the structure of the intestinal flora of mice infected with Staphylococcus aureus to make it closer to the CT group. Compared with the CT group, the relative abundance of Lactobacillus sp. in the SW group of male and female mice decreased from 32.51% and 44.34% to 7.56% and 6.86%, respectively. The Lactobacillus sp. in the SA group also decreased to 15.68% and 11.02%.The relative abundance of Lactobacillus sp. in SA+SW group rose to 25.30% and 39.16%. The change trend of Bacteroides sp. and Lactobacillus sp. was the same. Clostridium sp. and Muribaculum sp. of male and female mice. The relative abundance increased in the SW group, while the relative abundance decreased in the SA+SW group; compared with the control group, males infected with Staphylococcus aureus. The abundance of probiotics producing bacteria in the mouse intestine decreased from 51.37% to 13.56%, and the SA+SW group recovered to 43.61%. Fermented wax gourd acts on mice infected with Staphylococcus aureus to increase the synthesis of SCFAs and reduce the body's inflammatory response. Conclusion: Fermented wax gourd could improve the intestinal flora, thereby effectively alleviating the effect of Staphylococcus aureus on the intestines of mice.