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Characterization of the gut microbiome in patients with different forms of epilepsy and autoimmune encephalitis using a metagenomic analysis

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Diana Marcela Mejía Granados
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Íscia Teresinha Lopes Cendes; Mario José Abdalla Saad; Andre Schwambach Vieira; Wilson Araújo da Silva Junior; José Eduardo Peixoto Santos
Advisor: Íscia Teresinha Lopes Cendes

Introduction: Epilepsies are heterogeneous and disabling diseases characterized by a persistent predisposition to generate epileptic seizures. Despite the availability of many antiseizure medications (ASM), about one-third of patients will be refractory to clinical treatment. Studies in animal models have demonstrated that the intestinal microbiota plays a regulatory role in the central nervous system through neuroimmune, metabolic, and neuroendocrine pathways. However, studies evaluating these interactions in individuals with epilepsy remain scarce. Therefore, the main objective of this work was to characterize the composition of the intestinal microbiome in individuals with different forms of epilepsy and autoimmune encephalitis using a metagenomic analysis. Methods: A total of 96 users of the Hospital das Clínicas at the University of Campinas (HC-UNICAMP) were enrolled in this study. Participants were divided into four groups: mesial temporal lobe epilepsy (MTLE), genetic generalized epilepsy (GGE), autoimmune encephalitis (AE), and control group (CG). Microbial DNA was extracted from frozen stool samples using the QIAamp POWERFECAL PRO DNA KIT (Qiagen®). Genomic libraries were constructed from the V3 and V4 hypervariable regions of the 16S rRNA gene marker. Sequencing reads were analyzed using Galaxy Australia (version 21.01) and the QIIME software. Results: The Chao1 statistic showed lower species richness in the control group ([KW] p-value: 0.013982). Beta diversity profiling measured by the Bray-Curtis index at genus and species levels revealed different microbiome compositions in patients compared to controls (PERMANOVA: p-value: 0.05; p-value: 0.033). At the genus level, the Linear Discriminant Analysis (LDA) demonstrated that important genera such as Oxalobacteraceae_unclassified ([KW], p: 0.000174), Catenibacterium (p: 0.029512), Lactobacillus (p: 0.029561), Butyricimonas (p: 0.041936), Victivallis (p: 0.018568), Akkermansia (p: 0.024671) Clostridium_IV (p: 0.031173), Methanobrevibacter (p: 0.046593) and Subdoligranulum (p: 0.050545) were associated with drug-resistant and MTLE groups. Also, some organisms belonging to the Proteobacteria phylum such as Pasteurellaceae_unclassified and Desulfovibrio were enriched in patients with AE (KW, p-value: 0.022761; p-value: 0.036555) compared with the CG. Discussion: The overgrowth of the genus Akkermansia could promote excessive mucin degradation leading to an increase in epithelial permeability that, in turn, could affect the gut brain-axis signaling pathways. Also, several metabolites or components of the cell wall of bacteria from the Proteobacteria phylum can trigger neuroinflammatory processes, a cardinal sign in AE. In addition, we found that Oxalobacteraceae organisms were more abundant in patients with MTLE, the type of epilepsy characterized by a high proportion of patients with drug-resistant phenotypes. Finally, we observed a predominance of the Faecalibacterium genus among individuals from the CG. This butyrate-producing bacteria has been associated with a widespread benefit for host health involving energy metabolism, histone deacetylases inhibition, and anti-inflammatory cytokines upregulation. Therefore, an increment in this genus in the CG may indicate a microbial signature of healthy individuals. Conclusion: This study reveals that patients with epilepsy exhibit alterations in fecal microbiota composition, and specific microbial markers might mediate seizure occurrence (AU)

FAPESP's process: 18/00142-3 - Characterization of the intestinal microbiome in patients with different forms of epilepsy and autoimmune encephalitis by metagenomic analysis
Grantee:Diana Marcela Mejia Granados
Support Opportunities: Scholarships in Brazil - Doctorate