Neuropeptide Y causes sex dependent changes in microbiota-intestinal-brain communication in a mouse model of autism spectrum disorder

The microbiome-gut-brain axis plays a role in anxiety and social development and is of growing interest in neuropsychiatic conditions, including autism spectrum disorder (ASD). The present study investigated the behavioral phenotype and the molecular profile of neuropeptide Y (NPY), an anxiolytic peptide, in microbiome-gut-brain communication of Nf1 ^+/− mice, a well-established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Our data revealed that females Nf1 ^+/− exhibited more prominent anxious-like behavior. In addition, molecular analyses indicated sex-related differences in expression of NPY and NPY receptors’ transcripts in transgenic animals, with a more prominent effect in females. In addition, the analysis of microbiota revealed sex-specific changes in the Lactobacillus content which correlated with NPY and Y2 receptor changes in transgenic females. Remarkably, the Y2 receptor exhibited sex-dependent expression in both gut and brain of Nf1 ^+/− mice, suggesting its potential as a molecular biomarker for ASD symptoms, namely social anxiety and gastrointestinal issues. For the first time, our findings suggest NPY-mediated regulation of gut-brain communication to be altered in autism and hold potential for the development of new interventions addressing sex-specific aspects of ASD.