Comprehensive analysis of the lysine acetylome and succinylome in the hippocampus of gut microbiota-dysbiosis mice

INTRODUCTION: Major depressive disorder is caused by gene–environment interactions, and the host microbiome has been recognized as an important environmental factor. However, the underlying mechanisms of the host–microbiota interactions that lead to depression are complex and remain poorly understood. OBJECTIVES: The present study aimed to explore the possible mechanisms underlying gut microbiota dysbiosis-induced depressive-like behaviors. METHODS: We used high-performance liquid chromatography-tandem mass spectrometry to analyze alterations in the hippocampal lysine acetylome and succinylome in male mice that had received gut microbiota from fecal samples of either patients with major depressive disorder or healthy controls. This was followed by bioinformatic analyses. RESULTS: A total of 315 acetylation sites on 223 proteins and 624 succinylation sites on 494 proteins were differentially expressed in the gut microbiota-dysbiosis mice. The significantly acetylated proteins were primarily associated with carbon metabolism disruption and gene transcription suppression, while the synaptic vesicle cycle and protein translation were the most significantly altered functions for succinylated proteins. Additionally, our findings suggest that gut microbiota dysbiosis disturbs mitochondria-mediated biological processes and the MAPK signaling pathway through crosstalk between acetylation and succinylation on relevant proteins. CONCLUSIONS: This is the first study to demonstrate modifications in acetylation and succinylation in gut microbiota-dysbiosis mice. Our findings provide new avenues for exploring the pathogenesis of gut microbiota dysbiosis-related depression, and highlight potential targets for depression treatment.