Phenylketonuria in a microbial world: Gut-microbiome-brain interactions shaping behavior in PKU

Phenylketonuria (PKU) is a metabolic disorder in which a deficiency in the conversion of phenylalanine leads to severe intellectual disability. Early and continuous treatment with a protein-restricted diet has been very successful, although several behavioral deficits still remain. In this thesis, we examined two elements that might be associated with this suboptimal outcome; the microbiome and sleep. The microbiota as a community will adapt to the elevated phenylalanine concentrations and/or the current dietary treatment. This can lead to changes in metabolites of the microbiome that can communicate with the brain via the “gut-microbiome-brain” (GMB) axis. We showed that the microbiome of the PKU mouse has indeed adapted to the PKU context, in which both diversity and composition are altered, depending on the severity of protein restriction. A pilot for follow-up research showed that both repeated oral gavage and cohousing were sufficient to transplant the microbiome into another mouse. The effects of sleep loss in PKU could directly underlie the suboptimal outcome. Our results confirmed increased fragmentation and diurnality in untreated PKU mice, although this did not seem related to the increased microglia activation in the hippocampus. Moreover, PKU mice showed disruptions in circadian stability and rhythmicity, which suggests a weakened circadian “time-keeping” system that might be a causal factor of sleep disturbances found at a behavioral level. Finally, a study in European PKU patients confirmed an increased prevalence of sleep disorders and other disturbances in men. The findings in this thesis demonstrate that PKU challenges the microbial community and the circadian system. These insights could provide opportunities for new treatment strategies, focusing on all facets of the disorder.