Abstract
Background and Aims: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of sudden unexpected death in epilepsy (SUDEP). The DBA/1 mouse is an animal model of SUDEP since the mouse exhibits audiogenic seizure-induced respiratory arrest (S-IRA). The synthesis of central 5-HT is closely related to the gut microbiota. Moreover, emerging studies suggest a possible role for the microbiota in mitigating seizure likelihood. Based on this, we aimed to explore the effect of a high-tryptophan diet (HTD) on SUDEP as well as the synthesis and metabolism of central 5-HT. Furthermore, we investigated the involvement of the gut microbiota in this process.Methods: All DBA/1 mice were subjected to acoustic stimulation to induce seizures. Only those mice that exhibited S-IRA were randomly assigned to the normal diet (ND) group (n = 39) or HTD group (n = 53). After 1 month of dietary intervention, (1) S-IRA rates were evaluated, (2) the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the plasma and brain were determined by ultra-high-pressure liquid chromatography, and (3) the fecal flora biodiversity and species composition were analyzed by 16S rDNA microbiota profiling.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in the control group. HTD increased the levels of 5-HT and 5-HIAA in both the telencephalon and midbrain. HTD significantly elevated the species richness and diversity of the gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the two groups, and the intestinal flora was dominated by Proteobacteria and Actinobacteria after HTD.Conclusions: HTD is efficient in lowering S-IRA rates and elevating the central 5-HT level in DBA/1 mice. The gut microbiota was altered after HTD intervention. The significant increase in Proteobacteria and Actinobacteria may be related to the SUDEP-protective effect of HTD. Our findings shed light on a candidate choice of dietary prevention for SUDEP.
Highlights
Sudden unexpected death in epilepsy (SUDEP) is one of the main causes of death in patients with epilepsy [1,2,3]
The incidence of seizureinduced respiratory arrest (S-IRA) was significantly lower in the high-tryptophan diet (HTD) group than in the normal diet (ND) group (50.94% vs. 71.79%, p < 0.05) (Figure 1)
Alpha Diversity The alpha diversity analysis showed significantly higher Chao (479.29 ± 18.02 vs. 341.95 ± 110.18, p < 0.001) (Figure 3A), Sobs (412.00 ± 17.39 vs. 300.20 ± 99.27, p < 0.001) (Figure 3B), and Shannon (4.36 ± 0.21 vs. 3.91 ± 0.56, p < 0.05) indexes (Figure 3C) in the HTD group than in the ND group. This suggests that HTD treatment significantly increased the number of observed Operational taxonomic units (OTUs) sequence tags and the observed richness and species diversity
Summary
Sudden unexpected death in epilepsy (SUDEP) is one of the main causes of death in patients with epilepsy [1,2,3]. The mouse can present generalized audiogenic seizures (AGSz), followed by seizureinduced respiratory arrest (S-IRA) and sudden death induced by acoustic stimulation. This is consistent with the respiratory dysfunction most often witnessed in patients with SUDEP [6, 7]. Evidence has shown that cardiac dysfunction in DBA/1 mice lagged behind S-IRA, and dying animals could be resuscitated by assisted ventilation [7]. This suggests that S-IRA may be the main cause of death in this SUDEP model. We investigated the involvement of the gut microbiota in this process
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