Glycomacropeptide impacts the behavioral phenotype of PKU mice, the gut microbiome, obesity, and bone health

Glycomacropeptide (GMP) or caseinomacropeptide is a bioactive 64-amino acid glycophosphopeptide derived from the kappa-casein molecule that is associated with fat metabolism, gastrointestinal (GI) physiology, and metabolic disease due to its unique amino acid composition and structure. We hypothesized that GMP as a dietary treatment will improve the behavioral phenotype of PKU mice, modulate the gut microbiota by functioning as a prebiotic, and improve bone health while concurrently altering body composition. We tested this hypothesis in three separate animal studies: the first examined neurotransmitter concentrations and behavior in wild type (WT) and PKU mice, the second explored compositional changes of cecal and fecal gut microbiota populations in WT and PKU mice, and the third investigated relationships between body composition and bone health in female C57Bl/6 mice.;PKU mice fed a high-phe casein diet displayed a behavioral phenotype characterized by reduced catecholamine and serotonin concentrations, hyperactivity, and reduced digging behavior. The low-phe amino acid (AA) and GMP diets improved these behavioral impairments suggesting that the low-phe diets should be maintained for life. GMP further improved the behavioral phenotype by increasing vertical exploration in PKU mice.;GMP is a putative prebiotic based on its high degree of glycosylation by mucin-like oligosaccharide chains. In both WT and PKU mice, dietary GMP modulated cecal and fecal microbiota, by reducing Desulfovibro, and increased short-chain fatty acids when compared to the casein and AA diets. The changes in the GI microbiota are beneficial, suggesting that GMP is a prebiotic, as it was associated with anti-inflammatory effects such as a reduction in inflammatory plasma cytokines.;Female mice, with high-fat diet induced obesity, increase fatty acid oxidation capacity in muscle tissue and do not develop glucose metabolism impairment or inflammation suggesting they adapt to long-term high-fat feeding. Female mice fed the high-fat diets develop a bone phenotype of increased strength and increased brittleness. The GMP diet reduces brittleness of the bone and increases mineralization and femur length.;In support of our hypothesis, these data demonstrate that dietary GMP positively impacts behavior of PKU mice and gut microbiota composition. Moreover, our data support that GMP improves bone health and impacts body composition by increasing fat-free mass in female mice.