Chronic acetyl-L-carnitine treatment alleviates behavioral deficits and neuroinflammation through enhancing microbiota derived-SCFA in valproate model of autism

Autism spectrum disorder is characterized by a variety of cellular and molecular abnormalities which leads to autism-associated behaviors. Besides behavioral defects, these individuals also suffer from various associated disorders such as gastrointestinal deficit, altered gut microbiota composition and their metabolite. This study examined the effect of ALC on microbiota SCFA production and its effects on brain inflammation in VPA autism model. After prenatal exposure to valproate (600 mg/kg, i.p.) on embryonic day 12.5, followed by ALC treatment (100 mg/kg during postnatal days 23-51, p.o.), ASD-like behaviors, SCFAs amount in feces, intestine integrity (Occludin and ZO-1 tight junction proteins), systemic and brain inflammation (TNF-alpha and IL-1 beta) were assessed. Then, Golgi-Cox staining and Western blot for Iba1 protein were utilized to identify the changes in microglia profile in cerebral cortex. In the VPA model, we found that induction of autism was associated with demoted levels of SCFAs in feces and disintegration of intestine tissue which led to elevated level of TNF-alpha in the plasma. Further, we characterized an increased number of microglia in our histology evaluation and Iba1 protein in cerebral cortex. We also observed elevated level of TNF-alpha and IL-1 beta in the cerebral cortex of VPA rat. All these abnormalities were significantly alleviated by ALC treatment. Overall, our findings suggest that alleviation of behavioral abnormalities by ALC therapy in the VPA model of autism is associated with an improvement in the gut microbiota SCFAs, intestinal barrier and recovery of microglia and inflammation in the brain.

Automated summary

Autism spectrum disorder is characterized by various cellular and molecular abnormalities that lead to autism-associated behaviors. In addition to behavioral defects, individuals with autism also experience gastrointestinal deficits, alterations in gut microbiota composition, and their metabolites. This study investigated the effects of ALC (acetyl-L-carnitine) on microbiota short-chain fatty acid (SCFA) production and its impact on brain inflammation in a valproate-induced autism model. The results showed that ALC treatment improved ASD-like behaviors, increased SCFA levels, restored intestinal integrity, reduced systemic and brain inflammation, and normalized microglia profile in the cerebral cortex. Overall, these findings suggest that ALC therapy can alleviate behavioral abnormalities in autism by improving gut microbiota SCFAs, intestinal barrier function, and reducing inflammation in the brain.