Feeding HC diets has been found to induce metabolic dysregulation in the colon. However, the mechanisms by which changes in colonic flora and metabolites damage the colonic epithelium are poorly studied. Therefore, the present experiment used a multi-omics technique to investigate the mechanism of colonic injury induced by high-concentrate diets in lambs. Twelve male Dumont lambs were randomly split into two groups: a low-concentrate diet (LC = concentrate/forage = 30:70) group and a high-concentrate diet (HC = concentrate/forage = 70:30) group. The results showed that the HC group presented significantly increased lipopolysaccharide (LPS) concentrations in the colonic epithelium and significantly decreased serum total cholesterol (TC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels (