Abstract
The dysbiosis of gut microbiota is an important environmental factor that can induce mental disorders, such as depression, through the microbiota–gut–brain axis. However, the underlying pathogenic mechanisms are complex and not completely understood. Here we utilized mass spectrometry to identify the global phosphorylation dynamics in hippocampus tissue in germ-free mice and specific pathogen-free mice (GF vs SPF), fecal microbiota transplantation (FMT) model (“depression microbiota” and the “healthy microbiota” recipient mice). As a result, 327 phosphosites of 237 proteins in GF vs SPF, and 478 phosphosites of 334 proteins in “depression microbiota” vs “healthy microbiota” recipient mice were identified as significant. These phosphorylation dysregulations were consistently associated with glutamatergic neurotransmitter system disturbances. The FMT mice exhibited disturbances in lipid metabolism and amino acid metabolism in both the periphery and brain through integrating phosphoproteomic and metabolomic analysis. Moreover, CAMKII-CREB signaling pathway, in response to these disturbances, was the primary common perturbed cellular process. In addition, we demonstrated that the spliceosome, never directly implicated in mental disorders previously, was a substantially neuronal function disrupted by gut microbiota dysbiosis, and the NCBP1 phosphorylation was identified as a novel pathogenic target. These results present a new perspective to study the pathologic mechanisms of gut microbiota dysbiosis related depression and highlight potential gut-mediated therapies for depression.
Highlights
As the link to the second brain, the gut microbiota has an important role in regulating various pathophysiological functions in mammals
We demonstrated that the GF and fecal microbiota transplantation (FMT) models exhibited global dysregulation in protein phosphorylation
These phosphorylation dysregulations were consistently associated with glutamatergic neurotransmitter system disturbances
Summary
As the link to the second brain, the gut microbiota has an important role in regulating various pathophysiological functions in mammals. Increasing preclinical evidence indicates that the bidirectional signaling between the gut microbiome and the central nervous system, the microbiota–gut–brain axis, exerts a profound influence on brain development, function, and behavior. Wang et al Translational Psychiatry (2020)10:346 depression-like behaviors, along with changes in hypothalamic–pituitary–adrenal (HPA) axis[10,11], compared with specific pathogen-free (SPF) mice. The colonization of GF mice with “depression microbiota” extracted from fecal samples of MDD patients resulted in increased anxiety- and depression-like behaviors as compared with mice colonized with “healthy microbiota” from healthy controls[6,12]. Through fecal microbiota transplantation (FMT), gut microbiome remodeling mice can be used as an animal model to explore the pathogenic mechanisms of disorders, such as depression[13,14]
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