Abstract
BackgroundAutism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear.ResultsHere, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice.ConclusionsOur study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD.2_9YiW_C1D8LkcjpnFnSoXVideo abstract.
Highlights
Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited
To address these unanswered questions, we established EphB6-knockout (KO) mice and found that EphB6 was deleted in different tissues, including the colon, brain, lung, and spleen, in these mice compared with EphB6+/+ mice (Additional file 1: Figure S1c-d)
In the olfactory habituation/dishabituation test, repeated presentation of cotton swabs saturated with the same odor resulted in increasingly decreased lengths of time spent sniffing at cotton swabs, and the presentation of cotton swabs saturated with a new odor increased the time spent sniffing; these findings were obtained with both the WT and KO mice
Summary
Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. A clinical study showed that microbiota transfer therapy can improve gastrointestinal problems and autistic symptoms in ASD patients aged 7 to 16 years, and this benefit can last for 2 years [11, 12]. These studies suggest that the gut-brain-microbiota axis might have a significant impact on the development of ASD. The contribution of the gut microbiota to the dysregulation of brain function has not been fully elucidated
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