Background: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of audiogenic seizure-induced respiratory arrest (S-IRA) in DBA/1 mice, an animal model of sudden unexpected death in epilepsy (SUDEP). We aimed to explore the effect of a high tryptophan diet (HTD) on SUDEP and its possible mechanism involving 5-HT metabolism via gut microbiota.Methods: Primed animals were randomly assigned to the normal diet (ND) group or HTD group. Before and after diet interventions,

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... S-IRA rates were evaluated, 2) the concentrations of upstream-to-downstream 5-HT metabolites in the plasma and brain were detected by ultra-high-pressure liquid chromatography, and 3) the fecal flora biodiversity and species composition were analysed by 16S rDNA microbiota profiling. Second, antibiotics or probiotics combined with the HTD and S-IRA rates were reassessed.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in control. The HTD obviously increased the levels of tryptophan in the telencephalon and 5-HT and 5-hydroxyindoleacetic acid levels in both the telencephalon and midbrain. The HTD significantly increased the species richness and diversity of gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the HTD and ND groups. However, antibiotics or probiotics had no synergistic or antagonistic effects on S-IRA reduction mediated by the HTD.Conclusions: An HTD is efficient in lowering S-IRA rates in DBA/1 mice, possibly via modulation of 5-HT metabolism and gut microbiota. Our findings shed light on dietary prevention of SUDEP.