Seizure modulation by the gut microbiota and tryptophan-kynurenine metabolism in an animal model of infantile spasms

Background The infantile spasms syndrome is an early-onset epileptic encephalopathy presenting in the first 2 years of life, often with severe developmental consequences. The role of the gut microbiota and metabolism in infantile spasms remains unexplored. Methods Employing a brain injury neonatal rat model of infantile spasms intractable to anticonvulsant medication treatments, we determined how the ketogenic diet and antibiotics affected specific microbial communities and the resultant circulating factors that confer spasms protection in the infantile spasms model. To confirm a role of kynurenine metabolism pathway in spasms protection, indoleamine 2,3-dioxygenase I was pharmacologically inhibited and comprehensive metabolomics was applied. Findings We show that antibiotics reduced spasms and improved the effectiveness of the ketogenic diet when given in combination. Examination of the gut microbiota and metabolomics showed the downregulation of indoleamine 2,3-dioxygenase I and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. To further test the involvement of indoleamine 2,3-dioxygenase I, a specific antagonist I-methyltryptophan and minocycline, an antibiotic and inhibitor of kynurenine formation from tryptophan, were administered, respectively. Both treatments were effective in reducing spasms and elevating hippocampal kynurenic acid. A fecal microbiota transplant experiment was then performed to examine the contribution of the gut microbiota on spasm mitigation. Transplant of feces of ketogenic diet animals into normal diet animals was effective in reducing spasms. Interpretation These results highlight the importance of tryptophan-kynurenine metabolism in infantile spasms and provide evidence for new-targeted therapies such as indoleamine 2,3-dioxygenase I inhibition or microbiota manipulation to promote kynurenic acid production as a strategy to reduce spasms in infantile spasms. Copyright (C) 2022 The Authors. Published by Elsevier B.V.

Automated summary

The study found that the combination of antibiotics and a ketogenic diet can reduce the occurrence of infantile spasms and improve the efficacy of the ketogenic diet. Examination of the gut microbiota and metabolomics showed downregulation of indoleamine 2,3-dioxygenase I and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. Inhibitors of indoleamine 2,3-dioxygenase I and antibiotics that inhibit kynurenine formation were effective in reducing spasms and elevating hippocampal kynurenic acid. Additionally, a fecal microbiota transplant experiment demonstrated the important role of the gut microbiota in improving spasms.