Voluntary wheel running exercise attenuates VPA-induced ASD-like behaviors in male rats: implication of the vagal pathway of the gut-brain axis.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with elusive pathogenesis and lack of targeted therapies. While exercise can ameliorate ASD-like behaviors, its underlying mechanisms remain unclear. Recent studies have identified dysbiosis of gut microbiota and altered levels of short-chain fatty acids (SCFAs), as critical contributors to ASD-associated behavioral abnormalities. This study investigated the potential role of the gut-brain axis, specifically the vagal pathway, in mediating the therapeutic effects of voluntary wheel running exercise in a valproic acid (VPA)-induced ASD-like rat models. We demonstrated that six weeks of voluntary wheel running exercise attenuated ASD-like behavioral deficits. Exercise restructured gut microbial communities and elevated SCFA levels, notably butyrate, in feces and plasma. Concurrently, exercise normalized imbalances of neuroactive substances in the hippocampus and prefrontal cortex and suppressed neuroinflammation, evidenced by reduced microglial/astrocytic reactivity and a shift in microglial polarization toward an anti-inflammatory phenotype. Critically, subdiaphragmatic vagotomy attenuated these exercise-induced improvements, including the restoration of neuroactive substance homeostasis, resolution of neuroinflammation, and the amelioration of behavioral deficits. Our findings suggest that intact vagal signaling plays a critical role in coordinating gut-derived microbial and metabolic signals with central neuroadaptations to mediate the benefits of voluntary exercise on ASD-like behaviors.