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

Abstract

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 1 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 1 and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. To further test the involvement of indoleamine 2,3-dioxygenase 1, a specific antagonist 1-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 1 inhibition or microbiota manipulation to promote kynurenic acid production as a strategy to reduce spasms in infantile spasms.

Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome

“…At present, the mechanisms underlying the beneficial impacts of the diet are unclear. However, recent work implicates the gut microbiota, the trillions of microorganisms that inhabit our intestines as playing a fundamental role [ 3 , 4 ].…”

“…Employing antibiotics and fecal microbiota transfer into germ-free mice, Olson and colleagues [ 7 ] demonstrated that the seizure-reducing effects of the diet are dependent on the gut microbiota in two rodent models of epilepsy. Likewise, gut-microbiome-based manipulations, including the KD, antibiotics, and probiotics, have been shown to suppress seizures (spasms) in a neonatal brain injury rat model of infantile spasms [ 3 , 8 , 9 ]. Similar to the abovementioned study, the protective impacts of the diet could also be transferred to another animal by fecal transplant alone, showing the gut-based dependency of the treatment [ 3 ].…”

“…Likewise, gut-microbiome-based manipulations, including the KD, antibiotics, and probiotics, have been shown to suppress seizures (spasms) in a neonatal brain injury rat model of infantile spasms [ 3 , 8 , 9 ]. Similar to the abovementioned study, the protective impacts of the diet could also be transferred to another animal by fecal transplant alone, showing the gut-based dependency of the treatment [ 3 ].…”

The gut microbiome and the ketogenic diet: A pathway towards treatment optimization in infantile spasms

“… 1 Recently, tantalising discoveries have suggested that such modifications could target the gut microbiome, an apparent key player in the causal chain leading from the ketogenic diet to anti-seizure changes in the brain. 2 Two research papers by Mu and colleagues published recently in eBioMedicine 3 , 4 make valuable progress in the direction of ketogenic diet optimization, in the specific case of infantile spasms syndrome. Their findings are particularly noteworthy for their direct clinical implications, but also advance our understanding of particular mechanisms of the ketogenic diet in infantile spasms.…”

“…The first of these publications 4 reveals that a variety of mechanistically-overlapping gut microbiome-based manipulations are capable of suppressing infantile spasms in the brain injury neonatal rat model. These manipulations included the ketogenic diet itself (observed here and elsewhere to significantly adjust the microbiome), a 3-day broad spectrum oral antibiotic regime (both together with and independently of the ketogenic diet), and fecal microbial transplants from ketogenic diet-fed rats.…”