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Porcine epidemic diarrhea virus (PEDV) has reemerged throughout the world in the past ten years and caused huge economic losses to the swine industry. No drugs are available to prevent or treat PEDV infection in piglets. Zinc oxide (ZnO) has been shown to reduce diarrhea. However, little is known about its role in PEDV infection. In this study, twenty-four 7-day-old piglets were randomly divided into three treatment groups: control, PEDV, and ZnO+PEDV. Piglets in the ZnO+PEDV group were orally administered with 100 mg/kg·BW ZnO and then inoculated PEDV at a dose of 10 4.5  TCID 50  (50% tissue culture infectious dose) per pig. Growth performance, histologic lesions, viral load, indicators of intestinal damage, inflammation, and oxidative stress were recorded or detected to determine the effect of ZnO on PEDV infection. And the underlying mechanisms were revealed by microarray and proteomic analyses. Results showed that ZnO administration mitigated diarrhea and the reduction of average daily weight gain induced by PEDV infection. ZnO could inhibit PEDV replication in the small intestine and colon. Both villus height and crypt depth were affected by PEDV infection in the duodenum and jejunum, which could be rescued by ZnO administration. Moreover, the activity of catalase was decreased both in plasma and intestine after PEDV infection, while increased in the intestine by ZnO administration. PEDV infection also significantly increased the concentration of H 2 O 2  in jejunal and ileum and decreased the activity of total superoxide dismutase and glutathione peroxidase in plasma, whereas ZnO administration obviously increased the activity of total superoxide dismutase and decreased the concentration of H 2 O 2  in the ileum. The concentrations of IL-1 β , IL-6, and IL-8 in the plasma were all decreased upon ZnO administration. A large number of differentially expressed genes and proteins were identified in the ileum among the three groups by microarray and proteomic analyses. Gene Ontology and Reactome pathway analyses indicated that neutrophil degranulation and nutrient metabolism were the main biological process and pathways in both PEDV infection and ZnO administration. Overall, ZnO administration could improve growth performance, intestinal redox status, morphology, and function and reduce diarrhea in PEDV-infected piglets; ZnO could exert antiviral and anti-inflammatory effects on PEDV-infected piglets probably through regulating neutrophil degranulation. Our findings have important implications in piglet and infant nutrition.

Protective Effect of Zinc Oxide and Its Association with Neutrophil Degranulation in Piglets Infected with Porcine Epidemic Diarrhea Virus