The role of the microbiome in disease–associated mental and behavioral problems: The case of phenylketonuria (PKU)

The microbiota has been implicated in the evolution of social behavior and developmental programming of the brain, affecting social and cognitive behaviors. It has been demonstrated that strain-specific behavioral profiles could be transplanted by interchanging microbiota between strains. This is interesting as recent PKU research in our facility has demonstrated that identical mutations in the liver enzyme phenylalaninehydroxylase – leading to highly elevated Phenylalanine-levels in blood and brain that correlate with the severity of behavioral deficits in PKU patients – generate strain-specific behavioral consequences. Surprisingly, one strain (C57Bl/6) does not show the expected PKU-specific behavioral deficits whereas the other strain (BTBR) does. Considering the similarities between behaviors, neurotrophins and synaptic proteins affected by altered microbiota and PKU, we hypothesize that the microbiome could be a determining factor for the different consequences of PKU found between these strains.

In this project we will address the following research questions: 1) How does the PKU environment influence the gut microbiota in PKU mice of both strains? 2) To what degree does the gut microbiota influence behavior in the PKU mice of both strains? and 3) Can manipulation of the gut microbiota (e.g. by diet or transplantations) normalize the PKU-specific behavioral deficits? In collaboration with the UMCG we will also analyse the microbiota of PKU patients, to further substantiate the potential decisive role of microbiota in PKU. This research could provide 1) new insights in the link between the composition of the microbiota and behavior in general and more specifically in the PKU mice and 2) new therapeutic approaches to prevent cognitive and emotional malfunctioning of PKU patients. Within GELIFES, this proposal is anticipated to be a starting point of a long-term research topic on the microbiome, the gut-brain axis determining behavior, and its relevance to health and disease.