Gut microbiota regulates autism-like behavior by mediating vitamin B6 metabolism in EphB6-deficient mice

Background Autism spectrum disorder (ASD) is a developmental disorder with limited effective pharmacological treatments for the core autistic symptoms so far. Increasing evidences, especially the clinical studies in ASD patients, suggest a functional link between gut microbiota and development of ASD. However, the mechanisms linking gut microbiota and brain dysfunctions (gut-brain axis) in ASD are still not well-established. With genetic mutations and down-regulated expression in patients with ASD, EPHB6 , which is also important in homeostasis of gut, has been generally considered to be a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 involved in regulating gut microbiota and development of ASD have been unclear. Results Here, we found deletion of EphB6 induced autism-like behavior and disturbed gut microbiota in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated autism-like behavior in EphB6-deficient mice. At the metabolic levels, disturbed gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Conclusions Our study uncovers a key role for gut microbiota in regulation of autism-like social behavior by mediating vitamin B6 metabolism, dopamine synthesis and E/I balance in EphB6-deficient mice, suggesting new strategies for understanding and treatment of ASD.