Abstracts

Rationale:
Nearly a third of children with epilepsy are refractory to pharmacotherapy. The ketogenic diet (KD) is a highly effective alternative therapy, reducing seizure frequency by 50% in more than half of treated children3. Growing interest in the diet has generated a variety of hypotheses to explain the anticonvulsant effects of the KD, however the exact mechanisms remain poorly understood. The KD is associated with significant adverse effects, and is difficult to maintain. Therefore, biomarkers of KD response are needed to pursue novel therapeutic strategies. Recent animal studies have implicated the gut microbiota (GM) as a possible mediator of the anticonvulsant effects of the KD. In mouse models of epilepsy, the anti-seizure effects of the KD are abolished in mice reared in a germ-free environment or those given antibiotics. Replacing the intestinal flora with KD-type species restores the seizure protective effects. Importantly, enriching for these species in mice fed a conventional diet also provides anti-seizure effects suggesting a potential therapeutic target. To date, four studies have been published on the effects of the KD on human GM with inconsistent results. At baseline, the GM of children with RE is less diverse and dysbiotic relative to healthy controls. During KD, diversity of the GM decreases further. Of note, these studies were conducted in Asia and Europe. Given the marked variability of the GM across populations, it is important to investigate whether similar shifts in the GM occur after the KD in North American children. Prebiotics, defined as a ‘substrate that is selectively utilized by host microorganisms conferring a health benefit, are an attractive tool for altering the GM. The prebiotic effects of inulin-type fructans (ITF) are well documented in human trials. We aim to elucidate whether ITF prebiotics can prevent the undesired changes in the GM associated with the KD, and be used to manipulate the GM of children with refractory epilepsy to outcompete epileptogenic taxa thereby reducing seizures.
Method:
The current study is divided into two arms (see Figure). Children with refractory epilepsy, aged 2-18, will enter arm (A) if they are candidates for KD initiation. Otherwise they will enter arm (B). An additional cohort of healthy controls will be recruited for comparison. Primary endpoints include between- and within-patient variability in GM composition and metabolomics profile before and after starting on inulin. Secondary outcomes include seizure frequency, tolerability and feasibility of inulin supplementation in this unique population.
Results:
We are actively recruiting patients to the study. No preliminary results are available.
Conclusion:
The current study will be the first in North America to investigate the composition of the GM in children being treated with the KD, and lay down the foundation for novel microbiome-informed treatments for treatment resistant epilepsy.
Funding:
:Weston Family Microbiome Initiative