Abstract

Porcine epidemic diarrhea virus (PEDV) causes severe intestinal injury and economic losses in the pig industry. Arginine (Arg) promotes barrier repair and immune regulation, but its effects on PEDV-induced damage are unclear. This study aimed to investigate whether Arg could alleviate intestinal injury in PEDV-infected piglets. Thirty-two 7-day-old piglets were randomly divided into four groups: Control, Arg, PEDV, and PEDV+Arg. Piglets in the Arg and PEDV+Arg groups were orally administered 400 mg/kg BW Arg from Day 5 to Day 11. On Day 11, PEDV-infected piglets were orally challenged with the virus at a dosage of 1 × 10 5.5 TCID₅₀ per individual. On Day 14, tissue samples were collected after slaughter. PEDV infection markedly reduced villus height (VH) in the duodenum, jejunum, and ileum, increased crypt depth (CD), decreased plasma D-xylose concentration, and elevated diamine oxidase (DAO) activity, whereas Arg supplementation restored VH, decreased CD in the duodenum and jejunum, increased D-xylose, and reduced DAO activity. Arg also enhanced villin, occludin, and claudin-1 expression, indicating improved barrier integrity. Interestingly, Arg could promote PEDV replication in the small intestine. However, Arg reduced IL-1β , REG3G , and iNOS expression, while upregulating antiviral genes IFITM3 , MX1 , and DHX58 in the jejunum. Transcriptomic and proteomic analyses indicated that Arg administration may enhance interferon signaling cascades through the RIG-I-like receptor signaling pathway. In conclusion, our results show that Arg exhibits multifaceted effects upon PEDV infection. Although it increases PEDV replication, Arg could enhance intestinal barrier function, attenuate intestinal inflammatory responses, and alleviate PEDV-induced intestinal injury in piglets. Graphical Arg supplementation in PEDV-infected piglets alleviates villus atrophy and barrier disruption, improves D-xylose absorption, reduces DAO activity, and down-modulates IL-1β , REG3G , and iN