Proteomic Profiling of Lysine Acetylation Indicates Mitochondrial Dysfunction in the Hippocampus of Gut Microbiota-Absent Mice

Major depressive disorder (MDD) is a leading cause of disability around the world and contributes greatly to the global burden of disease. Mounting evidence suggests that gut microbiota dysbiosis may be involved in the pathophysiology of MDD through the microbiota–gut–brain axis. Recent research suggests that epigenetic modifications might relate to depression. However, our knowledge of the role of epigenetics in host–microbe interactions remains limited. In the present study, we used a combination of affinity enrichment and high-resolution liquid chromatography tandem mass spectrometry analysis to identify hippocampal acetylated proteins in germ-free and specific pathogen-free mice. In total, 986 lysine acetylation sites in 543 proteins were identified, of which 747 sites in 427 proteins were quantified. Motif analysis identified several conserved sequences surrounding the acetylation sites, including D*Kac, DKac, KacY, KacD, and D**Kac. Gene ontology annotations revealed that these differentially expressed acetylated proteins were involved in multiple biological functions and mainly located in mitochondria. In addition, pathway enrichment analysis showed that oxidative phosphorylation and the tricarboxylic acid (TCA) cycle II (eukaryotic), both of which are exclusively localized to the mitochondria, were the primarily disturbed functions. Taken together, this study indicates that lysine acetylation changes may play a pivotal role in the mitochondrial dysfunction by which gut microbiota regulate brain function and behavioral phenotypes.