Dataset Information

Metabolomics analysis reveals perturbations of cerebrocortical metabolic pathways in the Pah^enu2 mouse model of phenylketonuria.

ABSTRACT:

Aims

Phenylketonuria (PKU), which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, is one of the most common inherited diseases of amino acid metabolism. Phenylketonuria is characterized by an abnormal accumulation of phenylalanine and its metabolites in body fluids and brain tissues, subsequently leading to severe brain dysfunction. Various pathophysiological and molecular mechanisms underlying brain dysfunction in PKU have been described. However, the metabolic changes and their impacts on the function of cerebral cortices of patients with PKU remain largely unknown.

Methods

We measured the levels of small molecule metabolites in the cerebrocortical tissues of PKU mice and wild-type control mice using liquid chromatography-mass spectrometry (LC-MS)-based metabolome analysis. Differential metabolites were further subjected to metabolic pathway and enrichment analysis.

Results

Metabolome analysis revealed 35 compounds among 143 detected metabolites were significantly changed in PKU mice as compared to those in their wild-type littermates. Metabolic pathway and enrichment analysis of these differential metabolites showed that multiple metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis; valine, leucine, and isoleucine biosynthesis; alanine, aspartate, and glutamate metabolism; purine metabolism; arginine and proline metabolism and methionine metabolism, were impacted in the cerebral cortices of PKU mice.

Conclusions

The data revealed that multiple metabolic pathways in cerebral cortices of PKU mice were disturbed, suggesting that the disturbances of the metabolic pathways might contribute to neurological or neurodevelopmental dysfunction in PKU, which could thus provide new insights into brain pathogenic mechanisms in PKU as well as mechanistic insights for better understanding the complexity of the metabolic mechanisms of the brain dysfunction in PKU.

SUBMITTER: Lu LH

PROVIDER: S-EPMC7080435 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Metabolomics analysis reveals perturbations of cerebrocortical metabolic pathways in the Pah<sup>enu2</sup> mouse model of phenylketonuria.

Lu Li-Hua LH Xia Zheng-Xiang ZX Guo Jia-Lin JL Xiao Ling-Ling LL Zhang Yong-Jun YJ

CNS neuroscience & therapeutics 20190831 4

<h4>Aims</h4>Phenylketonuria (PKU), which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, is one of the most common inherited diseases of amino acid metabolism. Phenylketonuria is characterized by an abnormal accumulation of phenylalanine and its metabolites in body fluids and brain tissues, subsequently leading to severe brain dysfunction. Various pathophysiological and molecular mechanisms underlying brain dysfunction in PKU have been described. However, the metabolic chang ...[more]

PMID: 31471952

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Project description:Phenylketonuria (PKU) is a metabolic disorder caused by a hepatic enzyme deficiency causing high blood and brain levels of the amino acid Phenylalanine (Phe), leading to severe cognitive and psychological deficits that can be prevented, but not completely, by dietary treatment. The behavioral outcome of PKU could be affected by the gut-microbiome-brain axis, as diet is one of the major drivers of the gut microbiome composition. Gut-microbiome alterations have been reported in treated patients with PKU, although the question remains whether this is due to PKU, the dietary treatment, or their interaction. We, therefore, examined the effects of dietary Phe restriction on gut-microbiome composition and relationships with behavioral outcome in mice. Male and female BTBR Pahenu2 mice received either a control diet (normal protein, "high" Phe), liberalized Phe-restricted (33% natural protein restriction), or severe Phe-restricted (75% natural protein restriction) diet with protein substitutes for 10 weeks (n = 14 per group). Their behavioral performance was examined in an open field test, novel and spatial object location tests, and a balance beam. Fecal samples were collected and sequenced for the bacterial 16S ribosomal RNA (rRNA) region. Results indicated that PKU on a high Phe diet reduced Shannon diversity significantly and altered the microbiome composition compared with wild-type animals. Phe-restriction prevented this loss in Shannon diversity but changed community composition even more than the high-Phe diet, depending on the severity of the restriction. Moreover, on a taxonomic level, we observed the highest number of differentially abundant genera in animals that received 75% Phe-restriction. Based on correlation analyses with differentially abundant taxa, the families Entereococacceae, Erysipelotrichaceae, Porphyromonadaceae, and the genus Alloprevotella showed interesting relationships with either plasma Phe levels and/or object memory. According to our results, these bacterial taxa could be good candidates to start examining the microbial metabolic potential and probiotic properties in the context of PKU. We conclude that PKU leads to an altered gut microbiome composition in mice, which is least severe on a liberalized Phe-restricted diet. This may suggest that the current Phe-restricted diet for PKU patients could be optimized by taking dietary effects on the microbiome into account.

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