Metabolomics Analysis of Phenylketonuria and Wild Type Mice Fed Casein, Amino Acid and Glycomacropeptide Diets

Abstract

Background Phenylketonuria (PKU) is caused by mutations in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) or glycomacropeptide (GMP) formula to prevent cognitive impairment. Objective: To determine how metabolism differs in PKU & wild type (WT) mice fed diets differing in protein source. Methods: PKU (Pahenu2) and WT female mice were fed isoenergetic high-phe casein, low-phe AA or low-phe GMP diets between 3 to 23 weeks of age. Global metabolic profiles were determined in liver using the Metabolon platform. ANOVA contrasts identified 548 known metabolites that differed between the 6 treatment groups (n=8). Two-way ANOVA identified biochemicals exhibiting significant interaction and main effects for genotype & dietary protein. Results: The PKU mice displayed elevated levels of phe & catabolites formed in the phe-transamination pathway. The extent of these phe-related alterations was greatest in the mice fed the high-phe casein diet, and diminished to a similar extent in the PKU mice fed the low-phe AA or GMP diets. Regardless of diet, the PKU mice displayed altered levels of metabolites of microbial origin compared to WT mice. The casein-fed PKU mice displayed lower levels of glycolytic intermediates compared to casein-fed WT mice. In both WT and PKU mice, the GMP diet induced elevated levels of threonine and isoleucine metabolites. Conclusions These data demonstrate unique effects of the PKU genotype & dietary protein on metabolism and illustrate the utility of global metabolomics in studying complex metabolic diseases.