Metabolomics is a powerful technology for assessing the global changes of small molecule metabolites in a biological system,discovering novel biomarkers and better understanding of the pathogenesis of a disease.Classical swine fever (CSF) is a highly contagious swine infectious disease and causes significant economic losses for the pig industry worldwide.However,it remains unclear if small molecule metabolites contribute to progression of the disease.In present study,serum metabolomics of CSFV Shimen strain-infected pigs was performed by using ultraperformance liquid chromatography/electrospray ionization time-of-flight mass spectrometry (UPLC/ESI-Q-TOF/MS) in combination with multivariate statistical analysis.Compared with healthy control animals,differential metabolites were identified in CSFV-infected pigs at days 3 and 7 post challenge.These changed metabolites are associated with several key metabolic pathways,including tryptophan catabolism and kynurenine pathway,phenylanaline metabolism,fatty acid and lipid metabolism,tricarboxylic acid cycle,urea cycle,branched-chain amino acid metabolism,and nucleotide metabolism.Unexpectedly,several pathways involved in energy metabolism were significantly inhibited in CSFV-infected pigs.In addition,we also observed the changes of several metabolites that are exclusively associated with gut microbiota.The metabolomics profiling suggest that CSFV-Host-Gut microbiome interactions likely play a role in the development of CSF.This study presents the first serum metabolomics profiles of CSF and provides a new perspective for understanding the pathophysiological progression during CSFV infection.