Análise multi-ômica da microbiota intestinal de ratos com epilepsia do lobo temporal induzida por lítio-pilocarpina

Abstract

The human gastrointestinal tract (TGI) is colonized by trillions of microorganisms that communicate with the central nervous system through bidirectional transmission of signals via the microbiota-intestine-brain axis. The products secreted by the gut microbiota stimulate the central nervous system, and thus its dysregulation, and may be associated with different neurological diseases, including epilepsy. Thus, the present study aimed to evaluate changes in the composition of the gut microbiota and its metabolome in rats submitted to temporal lobe epilepsy, from a multi-omic approach. For this, 6 male Wistar rats were subjected to lithium-pilocarpine-induced Status Epilepticus (SE) and monitored for 60 days. Each animal had fecal material collected before the induction of SE (pre-ELT group) and after the emergence of spontaneous seizures (post-ELT group). Naïve rats (n = 6) were used as controls for the same collection points (Naïve t1 and Naïve t2). Sequencing of the 16S rRNA gene coupled with bioinformatics analysis revealed a taxonomic and compositional change, in epileptic rats. In the post-ELT group, species richness (Chao1 index) was significantly lower, and beta diversity analysis revealed separate clusters from pre-ELT. Taxonomic abundance analysis revealed a significant increase in the phylum Desulfobacterota and a decrease in Patescibacteria. At the genus level, DESEq2 and LEfSe analysis resulted in 18 genera significantly enriched between the post-ELT and pre-ELT clusters. Nuclear magnetic resonance analysis identified 9 classes of metabolites in the pre- and post_ELT groups. Of the 9 classes identified, 6 were positively related to the epileptic state: acetic acid, propionic acid, glutamic acid, butyric acid, alanine, and glycine. microbiota-metabolome correlation analysis showed that the differentially abundant genera in post-ELT rats are associated with altered metabolites, especially the proinflammatory Desulfovibrio and Marvybiatria, which were enriched in epileptic animals and positively correlated with excitatory neurotransmitters. Therefore, our data support that bacterial dysbiosis associated with epilepsy contributes to a seizure state by increasing chronic inflammation, excitatory-inhibitory imbalance, and/or a metabolic disturbance.