Untargeted metabolomics reveals hepatic metabolic disorder in the BTBR mouse model of autism and the significant role of liver in autism

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder, and the etiology is unknown. Metabolic dysfunction is present in patients with ASD. In the current study, untargeted metabolomics was employed to screen the differential metabolites in the liver of BTBR mouse model of autism, and MetaboAnalyst 4.0 was used for metabolic pathway analysis. Mice were killed, and liver samples were collected for untargeted metabolomics analysis and examination of histopathology. Finally, 12 differential metabolites were identified. The intensities of phenylethylamine, 4‐Guanidinobutanoic acid, leukotrieneD4, and SM(d18:1/24:1(15Z)) were significantly upregulated ( p < .01), and the intensities of estradiol, CMP‐N‐glycoloylneuraminate, retinoyl β‐glucuronide,4‐phosphopantothenoylcysteine, aldophosphamide, taurochenodesoxycholic acid, taurocholic acid, and dephospho‐CoA were significantly downregulated ( p < .01) in the BTBR group compared with C57 control group, indicating that differences between BTBR and C57 groups were observed in metabolic patterns. Disturbed pathways of the BTBR mice involved lipid metabolism, retinol metabolism, and amino acid and energy metabolism, revealing that bile acid‐mediated activation of LXRα might contribute to metabolic dysfunction of lipid and leukotriene D4 produced by the activation of 5‐LOX led to hepatic inflammation. Pathological changes in the liver tissue, such as hepatocyte vacuolization, and small amounts of inflammatory and cell necrosis, further supported metabolomic results. Moreover, Spearman's rank correlation revealed that there is a strong relationship between metabolites across liver and cortex, suggesting liver may exert action by connecting peripheral and neural systems. These findings were likely to be of pathological importance or a cause/consequence of autism, and may provide insight into key metabolic dysfunction to target potential therapeutic strategies relating to ASD.