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Impact of faecal microbiota transplantation of children with Refractory Epilepsy under ketogenic diet treatment in animal model of Temporal Lobe Epilepsy

Grant number: 19/24609-0
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2020
Effective date (End): April 30, 2023
Field of knowledge:Health Sciences - Nutrition - Nutrition Biochemistry
Principal Investigator:Carla Taddei de Castro Neves
Grantee:Mariana Baldini Prudencio
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Epilepsy is a neurological disease characterized by a lasting predisposition to generate epileptic seizures. The prevalence of is estimated to be 0,5 to 1% in the world population, of which 20 to 40% are refractory to drug treatment. Ketogenic Diet (KD) is an adjuvant treatment capable of generating ketone bodies, the main substance involved in seizure control, with consequent activation of anti-inflammatory and antioxidant pathways. With the advancement of studies on microbiota, it is plausible that KD can modulate the intestinal microbiome and through direct and indirect pathways it exerts a function on Epilepsy. Despite this possibility, there are still modest studies aimed at proving this hypothesis. Objective: to evaluate the impact of KD on the diversity of intestinal microbiota and its relationship with lipid, inflammatory and oxidative stress markers at the brain and intestinal level. Methodology: This study will be a translational study with a preclinical phase and a clinical trial phase. In both stages there will be longitudinal and prospective follow-up, being in the preclinical phase the follow-up for 3 months and the clinical phase for 6 months. In the preclinical phase, Wistar rats will be used, whose epileptic status will be induced by the pilocarpine model published by Cavalheiro (1995). The animals will be randomized into 4 groups: Group 1: Classic KD (CKD) treatment; Group 2: treatment with Modified KD (MKD); Group 3: treatment with Normal Diet (ND); and Group 4: Negative control for the disease and treatment with Normal Diet (NND). The rats will be fed ad libitum with DC for the treatment groups or with standard diet AIN93 for the control groups. In the clinical phase, patients with refractory Epilepsy, aged from 1 to 10 years old, with indication for treatment with CD whose preclinical pattern has been more effective will be selected. In the preclinical phase will be evaluated: seizure frequency by video monitoring; diet adherence by urinary and plasma beta-hydroxybutyrate evaluation; lipid and apolipoprotein profile at plasma level; plasma inflammatory profile; plasma lipopolysaccharide (LPS) concentration; integrity of intestinal mucosa by plasma markers; intestinal microbiota diversity; lipidomic composition of feces and brain; morphometric parameters of the intestine and brain; synthesis and expression of inflammatory markers in the intestine and brain. In the clinical phase will be evaluated: frequency of seizures; diet adherence through plasma and urine measurement of beta-hydroxybuitrate; nutritional status; plasma lipid and inflammatory profile; lipopolysaccharide concentration (LPS); integrity of intestinal mucosa by plasma markers; intestinal microbiota diversity and fecal lipid composition. The study will be conducted after approval by the ethics committees in research with humans and animals, following the ethical principles. Statistical tests will be performed based on the Statistical Package for Social Sciences® (SPSS) version 20.0. (AU)

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