Abstracts

Rationale: Infantile spasms (IS) is an age-dependent epileptic encephalopathy characterized by epileptic spasms, hypsarrhythmia and cognitive arrest or regression. Emerging clinical and preclinical data from animal models suggest a role for central nervous system inflammatory pathways in the pathogenesis and treatment of IS. The ketogenic diet (KD) has been shown to be an effective treatment for some patients with intractable IS and is known to have anti-inflammatory effects. The KD has also been shown to alter the gut microbiota in a mouse model of autism spectrum disorder. In the present study, we examined the effects of the KD on the overall expression of gut bacteria and in particular, pro-inflammatory gut microbiota in the triple-hit (symptomatic) model of intractable IS. Methods: Neonatal rats were intracerebrally injected with doxorubicin and lipopolysaccharide at postnatal day (P)4, and subcutaneously injected with chlorophenylalanine at P5 to induce spasms. Rats with spasms were fed the normal diet (ND; n=10) or KD (n=9) from P4 to P12. Feces were collected at P12 for bacterial genomic DNA extraction and 16S pyrosequencing. Results: The KD significantly increased bacterial diversity as reflected by the higher numbers of operational taxonomic units, Chao1, ACE, and Jackknife indices (P < 0.05) than the ND group. There was a strong trend indicating that overall bacteria structure was different between KD and ND groups (analysis of molecular variance algorithm P=0.079). At the taxonomy level, Firmicutes and Proteobacteria were the dominant bacteria in the feces of P12 rats, accounting for approximately 58%-59% and 40-41% of total bacteria, respectively. The KD increased the relative abundance of Streptococcaceae and Micrococcaceae (P<0.05), especially that of Streptococcus, Lactococcus, Rothia (P<0.05). Among the species affected, the KD increased the relative abundance of Streptococcus lactarius-related bacteria but decreased the pro-inflammatory Escherichia coli-related bacteria (P<0.05). Conclusions: The KD produced alterations in the gut microbial composition in rats with spasms as compared to those fed the normal diet. Some of the changes may be associated with anti-inflammatory effects. Further studies are required to determine if these changes alter brain excitability, and specifically whether these contribute to spasms control in the triple-hit model of IS. Funding: Supported by CIHR and Alberta Children's Hospital Research Institute.