Dr. Shelly Buffington, Assistant Professor of Department of Neuroscience, Cell Biology, & Anatomy, and Member of Microbiome Research has a paper published in Cell (Cell 2021 184:1740-1756.e16. doi: 10.1016/j.cell.2021.02.009), demonstrating that microbiome and host genes interdependently regulate behaviors in neurodevelopmental disorders. Congrats Dr. Buffington!

Traditionally, neurodevelopmental disorders and the underlying pathology were exclusively attributed to variation in the human genome; however, it is becoming increasingly evident that the microbiome can likewise contribute to host brain and behavioral dysfunction. Microbiome-directed therapies are, accordingly, emerging as a new and exciting avenue for ameliorating maladaptive behaviors associated with neurodevelopmental disorders. In previous work, we found that treatment with the commensal bacteria Limosilactobacillus (L.) reuteri rescued social dysfunction and underlying synaptic plasticity deficits within the mesocorticolimbic dopaminergic reward circuit of maternal high-fat diet offspring, an environmental model for autism spectrum disorder, in an oxytocin receptor-dependent fashion (Buffington et al., Cell 2016; Sgritta et al., Neuron 2019). Here, we sought to determine whether L. reuteri could likewise rescue social impairments in a classic genetic model for ASD, the Cntnap2^–/– mice, with established deficits in the oxytocinergic system (Peñagarikano et al., Cell 2011; Peñagarikano et al., Sci Trans Med 2015). We found that L. reuteri selectively rescued the social phenotype in Cntnap2^–/– mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Moreover, we discovered that whereas the hyperactivity phenotype in Cntnap2^–/– mice was determined by host genetics, the social behavior phenotype was mediated by the gut microbiome (for an informative perspective on host-microbiome interactions regulating host phenotype, check out Stappenbeck & Virgin, Nature 2016). Together, our results reveal the importance of studying mammalian brain function and behavior (and related disorders) in the context of the holobiont, accounting for the contributions of both host and microbial genes and their interactions. Finally, they highlight the potential of therapeutic targeting of the microbiome to treat neurological disorders.

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