Intestinal metabolomic profiling provides insights into the molecular mechanisms for hyperuricemia-induced intestinal barrier dysfunctions in a hyperuricemia mouse model.

Abstract

Cadmium exposure could damage the liver, which is suggested to be associated with the hyperuricemia (HUA)-induced intestinal barrier injury. To reveal the mechanism for HUA-induced intestinal barrier injury, the HUA mice constructed by knockout (Ko) of the urate oxidase (Uox) gene and their corresponding controls were used for the metabolomics analysis. Clinical biochemistry from the plasma was assessed, and the histopathological changes of the intestines were evaluated. Metabolomics was performed to explore the intestinal metabolomic profiles from the Uox-Ko mice, and the potential metabolic biomarkers were identified. Compared with controls, Uox-Ko mice showed dramatically increased uric acid, creatinine, and urea nitrogen levels, along with sparse intestinal villi, mucosal and submucosal edema. Metabolomics found the five metabolites were significantly dysregulated in intestines from the Uox-Ko mice, which includes N-acetylornithine, palmitoleic acid, 4-pyridoxic acid, phenylacetylglycine and 3-indoxyl sulphate. These altered pathways were involved fatty acid biosynthesis, biosynthesis of amino acids, arginine biosynthesis, vitamin B6 metabolism and 2-oxocarboxylic acid metabolism. 4-pyridoxic acid was identified as the most promising metabolic biomarker for predicting HUA-induced intestinal barrier damage. Our findings suggest the metabolic disturbances may contribute to the development of HUA-induced intestinal barrier injury, which may shed light on the mechanisms of cadmium-induced liver damage.